In April 2024 Gritstone bio announced “positive” preliminary data from an ongoing Phase II portion of the Phase II/III study to evaluate GRANITE. GRANITE is Gritstone’s personalised neoantigen cancer vaccine and is being evaluated in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC). The study is designed to quantify the clinical benefit of maintenance therapy with GRANITE in combination with immune checkpoint blockade and fluoropyrimidine/bevacizumab compared to fluoropyrimidine/bevacizumab alone.
Gritstone takes on cancer
Gritstone outlines how its founders identified that, in patients with solid tumours who respond to checkpoint inhibitors, new targets called tumour-specific neoantigens are produced. These are unique to the tumour cells and can be “recognised and targeted for destruction by the patient’s own immune system”. Although these neoantigens present a critical target, identifying them is a “key therapeutic challenge”.
“Some tumours have hundreds of mutations, but only a minority result in true tumour-specific neoantigens found on the surface of tumour cells – making them difficult to find and target appropriately.”
New progress
Gritstone “successfully manufactured” GRANITE product candidate for every eligible patient; 104 patients were randomised in the study and 67 patients were included in the treated analysis shared. 36 patients left the study before randomised treatment due to early progressive disease or withdrawal of consent, and 1 patient is yet to begin study treatment start.
Key highlights from the data include:
Progression Free Survival (PFS) – an early trend in PFS benefit was observed for GRANITE recipients.
Biomarker results – Circulating Tumour DNA (ctDNA) – short-term molecular response is “uninformative” but long-term ctDNA responses “align with PFS trends and favour GRANITE”.
Safety and tolerability – GRANITE demonstrated a “favourable” safety and tolerability profile.
Encouraging results
Dr Andrew Allen, Co-founder, President, and CEO of Gritstone bio commented that the preliminary Phase II results are “highly encouraging” and “represent the first randomised trial evidence, albeit early, that a personalised neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumour”.
“The overall trend of PFS improvement in GRANITE recipients is great to see, and the exploratory PFS hazard ratio of 0.52 in the high-risk group, a more mature dataset, is a striking signal.”
Dr Allen reflected that “pioneering new spaces carries inherent risks”, suggesting that regarding defining molecular response, “we simply got it wrong”. As ctDNA levels in both arms “decreased on chemotherapy for longer than we anticipated”, the protocol measure of ctDNA change was “uninformative”.
“Fortunately, long-term analysis demonstrates the expected correlation of ctDNA with clinical benefit and favours GRANITE patients. We believe these preliminary findings put us in a strong position to share mature PFS data in the third quarter and then enter regulatory discussions.”
Dr Allen described the “growing body of evidence” that favours GRANITE as “exciting”, stating that it “suggests GRANITE is working in this notoriously underserved patient population”.
Dr J. Randolph Hecht, Professor of Clinical Medicine and Director of the UCLA GI Oncology Programme, is an investigator in the Phase II/III study.
“Up to 97% of patients with metastatic colorectal cancer, the second most common cause of cancer death, are MSS. Unlike patients with melanoma and lung cancer, they have not benefited from standard immunotherapies such as checkpoint inhibitors.”
Considering the preliminary results, Dr Hecht infers that GRANITE is “inducing a potentially significant immune response in a disease that has been felt to be immunologically cold”. Not only does the PFS difference, in a “poor prognosis group of patients”, indicate the “potential for clinical benefit”, but the team is learning “how to better analyse ctDNA continuously to “study the efficacy of this novel immunotherapy”.
“Expanding the scope of immunotherapy to a broader spectrum of cancer patients is the ‘holy grail’ of oncology, especially for MSS colorectal cancer. While early, these promising results suggest GRANITE has potential to deliver clinically meaningful benefit in MSS-CRC and other cold tumours.”
It was great to hear more from Dr Allen at the Congress in Washington as he joined us to chair and present, and we look forward to further updates from the Gritstone team. For more like this, don’t forget to subscribe here.
In March 2024 Croda and The Access to Advanced Health Institute (AAHI) announced the signing of a partnership agreement on innovation and development of adjuvant formulations. The agreement will allow the organisations to “leverage their combined expertise” to make novel vaccine adjuvant formulations “globally accessible”. This will facilitate the development of “next generation, robust, and durable vaccines”.
AAHI meets Croda
AAHI is described as a “leading nonprofit biotech research institute” that has developed platform technologies to harness the immune system against disease. It “boasts a diverse portfolio of adjuvant formulations”, which are used in “numerous vaccine candidates”.
“With deep adjuvant and vaccine formulation expertise and years of experience developing cost-effective, sustainable products and processes for making them, AAHI stands at the forefront of vaccine innovation.”
Croda was “founded on the principle of using smart science to turn bio-based raw materials into innovative ingredients that help to improve lives”.
“We envision a future where everyone gets the vaccines they need. This reality relies on maintaining vaccines access and continuing to innovate in this realm. The responsibility is on us all to not only select sustainable ingredients, but to secure supply chains and sources that will not deplete in the future.”
The exclusive agreement between the two organisations includes a “collaborative effort in research and development” to “propel rapid development of innovative adjuvants and formulations” and to develop “efficient manufacturing processes to enable production at scale, to meet vaccine industry and global needs”. Croda is to apply its “unparalleled cGMP manufacturing expertise” to scale up manufacturing and support for Phase III clinical trials and commercial use.
The vaccines of tomorrow
President Life Sciences at Croda is Daniele Piergentili, who commented that the partnership represents “another significant milestone” in the team’s “endeavour to offer a comprehensive portfolio of adjuvants for the vaccines of tomorrow”.
“It perfectly aligns with our pharmaceutical strategy to ‘Empower biologics delivery’ and underscores our commitment to making substantial contributions to the successful development and commercialisation of WHO-listed pipeline vaccines.”
Dr Corey Casper, President and Chief Executive Officer of AAHI, identifies “tremendous” opportunities for AAHI and “collaborators and vaccine developers who rely on adjuvant formulations for the deployment of effective health solutions”.
“Croda’s commitment to and passion for developing sustainable adjuvant formulation solutions from bench to clinic to market is in direct alignment with our mission to create worldwide access to vaccines and immunotherapies.”
In March 2024 researchers at Wyss Institute announced the publication of research that indicates the possibility that DNA origami could serve as a platform for “controlling adjuvant spacing and co-delivering antigens in vaccines”. Their platform, DoriVac, enables the “precise spacing and geometrical arrangement of molecules” on nanoparticles to produce “highly effective and personalised immunotherapies”. Developed in collaboration with Dana-Farber Cancer Institute, Harvard Medical School, and Korea Institute of Science and Technology, the platform is intended to overcome several “problems” associated with cancer immunotherapy.
Identifying a need
Wyss Institute comments that “serious diseases” such as cancer and autoimmune conditions demand “multiple drugs”. However, combining drugs is “challenging” for several reasons, including toxicity. This occurs when the side effects of multiple drugs “compound each other” to produce “much greater patient suffering”. Furthermore, drug combinations can lead to “increased costs for patients and insurers”.
The team specifically address the problem in personalised immunotherapy, where both tumour antigens and adjuvants need to be presented to antigen-presenting cells (APCs).
“It is yet unknown how these molecules might interact with each other when co-delivered, or how to optimise the process and the dosages to produce the strongest anti-cancer response.”
Enter DoriVac
DoriVac is a DNA origami platform that has identified “molecular patterns” to produce “superior immune responses while minimising” the drugs required. This reduces costs and off-target side effects.
“DoriVac also has numerous advantages over other nanoparticle platforms, including targeting to specific compartments within cells and co-delivering multiple types of molecules to desired targets at the lowest possible doses.”
The “core component” of DoriVac is a “self-assembling square block-shaped nanostructure”. On one face of the block, defined numbers of adjuvant molecules can be attached in “highly tunable, nanoprecise patterns”, with the opposite face binding tumour antigens.
In study
The study, which is not open access, identified that molecules of the CpG adjuvant spaced exactly 3.5 nanometres apart resulted in the “most beneficial stimulation of APCs” that induced a “highly desirable profile of T cells”. The adjuvant is a synthetic strand of DNA comprising repeated CpG nucleotide motifs that “mimic the genetic material from immune cell-invading bacterial and viral pathogens”. It binds to a “danger receptor” called TLR9, which induces an inflammatory response that “works in concert” with the antigen-induced response.
First author Dr Yang (Claire) Zeng commented that previous work highlighted the importance to TLR9 receptors dimerising and aggregating into multimeric complexes binding to multiple CpG molecules.
“The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesised we could mirror with DNA origami structures presenting precisely spaced CpG molecules.”
Dr Zeng and the team were “excited” to find that the DoriVac vaccine “preferentially induced an immune activation state that supports anti-tumour immunity”, something that “researchers generally want to see in a good vaccine”.
As well as the spacing, the numbers of CpG molecules in DoriVac vaccines made a difference, with 18 providing the “best APC activation”. The key finding is that the observations “translated to in vivo mouse tumour models”. The vaccines, injected under the skin of mice prophylactically, accumulated in the closest lymph nodes to stimulate DCs. A vaccine loaded with a melanoma antigen prevented the growth of aggressive melanoma cells upon challenge.
Although the control animals “succumbed” to the cancer by day 42 of the experiment, DoriVac-protected animals were alive, and displayed inhibited tumour growth in mice that already had formed melanoma tumours. The team also investigated if DoriVac vaccines could boost immune responses produced by neoantigens in melanoma tumours. A DoriVac vaccine with four neoantigens enabled them to “significantly suppress growth of the tumour in mice that produced the neoantigens”.
The last test was if DoriVac could “synergise with immune checkpoint therapy”. The combination resulted in the “total regression” of melanoma tumours, and prevented recurrence when the animals were exposed to the same tumour cells four months later. Dr Zeng believes that “DoriVac’s value for determining a sweet spot in adjuvant delivery” and “enhancing the delivery and effects of coupled antigens” could “pave the way to more effective clinical cancer vaccines”.
Technology for the future
Dr William Shih, who led the team at the Wyss Institute with Dr Zeng, suggests that the DNA origami technology “merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes”.
“We envision that in the future, antigens identified in patients with different types of tumours could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalised cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies.”
Dr Donald Ingber, Founding Director of the Wyss Institute, states that the platform is “our first example of how our pursuit of what we call Molecular Robotics – synthetic bioinspired molecules that have programmable shape and function – can lead to entirely new and powerful therapeutics”.
“This technology opens an entirely new path for the development of designed vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic.”
In March 2024 Vaxxinity announced “positive clinical data” from the UB-312 programme in Parkinson’s disease, presented by Dr Jean-Cosme Dodart, SVP of Research, at a conference. Vaxxinity identifies UB-312 as the “first active immunotherapy candidate” to show “reduction of pathological alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) of Parkinson’s Disease (PD) patients. UB-312 targets aggregated forms of aSyn, the toxic species that “underlies” PD and other synucleinopathies. It is being assessed in a randomised, double-blind, placebo-controlled Phase I clinical trial.
Preferential binding to aSyn
Vaxxinity reports that UB-312-induced antibodies showed “preferential binding” to aggregated aSyn and “almost no binding” to normal monomeric aSyn, measured by dot blot. Participants treated with UB-312 in a single priming regimen in the 300/100/100µg dosing group showed a 20% decrease from baseline in aggregated aSyn in the CSF, compared to a 3% increase in the placebo group. Additionally, a post hoc analysis showed that patients with detectable UB-312-induced antibodies in the CSF exhibited “improvement in activities of daily living” as measured by the MDS-UPDRS II clinical scale.
Changing the conversation
Co-Founder and Executive Chair of Vaxxinity, Lou Reese, identifies a “potential to change the whole conversation around Parkinson’s treatment and prevention” in the UB-312 programme.
“Our findings suggest UB-312 could transform Parkinson’s care, offering hope for improved outcomes with a disease-modifying treatment. The future isn’t decades away: today’s Parkinson’s patients may have hope for the near, not distant future.”
Dr Dodart is also “very excited” about the target engagement data, particularly as there are “no treatments that address the underlying conditions of Parkinson’s”.
“This provides us confidence that we are going after the right target and in a way that is statistically and clinically relevant to patients. There is new hope on the horizon.”
Parkinson’s is the “fastest growing neurodegenerative disease in the world”, but the team is “committed to developing safe, convenient, and effective disease-modifying active immunotherapies for all.”
In March 2024 Ultimovacs announced topline results from the Phase II clinical trial INITIUM, which evaluates the therapeutic cancer vaccine candidate UV1 as a first-line treatment in unresectable or metastatic malignant melanoma. While primary and secondary endpoints were not met, Ultimovacs seems resolved to continue investigating UV1.
Falling short
The primary endpoint of the study was to investigate progression-free survival (PFS) in the experimental arm compared to the control arm. The experimental arm comprised UV1 in combination with checkpoint inhibitors ipilimumab and nivolumab. Secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR) and safety. The combination treatment approach showed “similar clinical benefits”, which means that “the primary and secondary endpoints of the study were not met”.
The median PFS was not achieved in either of the arms, and the Hazard Ratio (HR) between the arms for PFS was 0.95. While UV1 “maintained a positive safety and tolerability profile”, the evaluation of secondary endpoints did not reveal a difference in OS or ORR.
A high bar
Dr Jens Bjørheim, Chief Medical Officer, commented that the team had “set a very high bar” for the vaccine candidate by comparing it to the ipilimumab and nivolumab combination, which is “currently considered the most effective treatment for this patient population”.
“Nevertheless, we are disappointed that UV1 did not add further clinical benefit for these late-stage melanoma patients in the INITIUM trial. Looking forward, our first objective is complete the analysis of the full data set in depth to gain further insights on UV1’s effects.”
Dr Bjørheim thanked the patients for “their trust” and the investigators for “their collaboration”.
Looking for the best path forward
Dr Carlos de Sousa, CEO, emphasised that the team will “remain committed to UV1”.
“Our objective is to define the best path forward for our development strategy for UV1.”
Dr de Sousa reportedly told investors that “this was a failed study, not a failed UV1”.
“I think it is important to reinforce that notion. UV1 has shown benefits, and we hope that it will continue to show these benefits.”
Another of our Congress Conversations from our European event in October last year was with start-up Deepflare, represented by Piotr Grzegorczyk and Grzegorz Preibisch. We were glad to welcome them back to the start-up zone, which hosts organisations who are challenging the vaccine status quo with innovation and enthusiasm! If you are interested in joining us as a start-up at a future event, please get in touch with Isabella Aung (isabella.aung@terrapinn.com) for more information. We hope you enjoy the interview!
Introducing Deepflare
We start with Piotr, CEO and co-founder, who brings a theoretical mathematics and strategic consulting background to the team. He explains that Deepflare develops models and partners with biotech with a clear goal:
“To help to build better vaccines, faster.”
They focus on viral vaccines and cancer immunotherapies, trying to increase efficacy and “bring them to market faster”. Grzegorz brings a combination of theoretical mathematics and medicine to the team, and the pair met at the mathematics faculty! He is Head of R&D, focusing on knowledge transfer and identifying problems to tackle with AI.
A team on a mission
We asked for a bit more insight into the team’s mission; what are they hoping to achieve in the vaccine space? Grzegorz answers that the key aim is “to make vaccines which weren’t possible in the past”. This previous impossibility could be due to many challenges, but Deepflare focuses on variable pathogens or cancers, seeking a “robust” T cell response. Piotr hopes that “in the future, we won’t be scared of viruses or cancer anymore”, instead fighting both “very easily” with prophylactic or therapeutic vaccines.
Technology that works
With technology evolving rapidly, what sets Deepflare apart from the field? Piotr believes that bringing the “technological angle” is a distinction. Furthermore, every partnership brings learning opportunities.
“With every collaboration we get more and more data; we are able to much better augment our systems, so we see much better results with each one.”
Grzegorz adds his view as well!
“Short answer is: it works!”
However, the long answer is that data are “important” and the team has “curated” data that are “way better” than publicly available alternatives. Additionally, they go “beyond” the data. Grzegorz makes an interesting comparison to ChatGPT, with which some of our community may be familiar. He suggests that “for ages” the data used by ChatGPT have been available.
“What has changed was the use of it.”
For Deepflare, the task is to “integrate the biological knowledge” and “deep understanding of the process inside” to ensure that the algorithms “understand” the data.
Deepflare for the future
After exploring the technology that Deepflare deploys we asked what the future holds. Piotr explains that the team is currently “focused on two different paths”: viral vaccines and cancer. He reflects that at the start of their journey, they interviewed over 100 representatives from the community, discovering that, where tools are being used, they are very outdated!
“It can be improved so vastly.”
Piotr considers the “AI hype”, suggesting that the “real change” that it will bring about will be in the healthcare space. Both Piotr and Grzegorz look forward to myriad vaccine possibilities!
Why WVC?
Finally, as always, we asked about Deepflare’s reasons for joining us at the event. Grzegorz states that “really meaningful connections” are key, particularly for partnerships.
“Building partnerships is how we can build innovation.”
Furthermore, there are opportunities to learn from “a lot of really, really interesting, smart experts”, with discussions that are “extremely insightful and inspiring”. Piotr agrees that they are looking for partnerships and to participate in the discussions that are taking place. We hope the event was fruitful!
We are so grateful to Piotr and Grzegorz for their time for this interview, which we hope you enjoyed! For more interviews in this series don’t forget to subscribe to our weekly newsletter here!
In February 2024 UC Davis Health announced the results of a study, published in Advanced Science, which show that a single dose of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG) reduced liver tumour burden and extended the survival of mice with liver cancer. BCG is known for “immune-boosting properties”, but this trial found that it could be a “promising treatment option” for hepatocellular carcinoma (HCC), which is often “associated with unfavourable treatment outcomes”.
HCC: significant challenges
The study describes hepatocellular carcinoma (HCC) as a “common” liver cancer that causes “numerous deaths” globally. Although conventional systemic cytotoxic chemotherapeutic agents, protein kinase inhibitors, and immunotherapy options exist, HCC “continues to pose significant challenges in terms of treatment”. Therefore, the authors identify a “pressing need” for alternative therapeutic approaches.
Distinguished Professor Yu-Jui Yvonne Wan, vice chair for research in the Department of Pathology and Laboratory Medicine at UC Davis, commented that “HCC is very difficult to treat”. It is “considered a cold tumour, which does not respond well to immunotherapy”. However, Professor Wan’s team had “a good reason to believe that the BCG vaccine could stimulate an immune response”.
BCG
BCG, derived from live attenuate Mycobacterium bovis, has been used as the primary tuberculosis vaccine since the 1920s. Although it has specific effects against tuberculosis, it has “non-specific effects”. These could be attributed to trained immunity.
BCG was approved by the FDA for the treatment of non-muscle invasive bladder cancer, which involves the administration of BCG directly into the bladder. However, there is “limited information available regarding the potential therapeutic effect of BCG” in the treatment of other solid tumours. Therefore, authors conducted a study to investigate the anti-HCC effects of BCG in orthotopic HCC mouse models.
A positive response
The researchers found that BCG reduced inflammation and encouraged the deployment of T cells, specifically allowing the infiltration of CD4+ and CD8+ T cells and M1 macrophages into the tumour. BCG also induced IFN- γ signalling, which resulted in cancer cell death. Furthermore, Professor Wan states that “while previous studies have shown sex differences in BCG effects on immunity”, the data indicate that “both male and female HCC mice responded to the BCG treatment”.
“Our study showed that BCG immunotherapy for HCC is different from and superior to other immunotherapies. It requires only a single injection. In animal models, BCG generated better anti-liver cancer treatment outcomes than other standard immunotherapies, such as anti-PD-1.”
The authors conclude that the study offers “compelling evidence” in support of BCG treatment for HCC. Additionally, because it is “widely used with a known safety profile”, BCG bacterial immunotherapy “should be considered for HCC as well as other solid cancers”.
In January 2024 Vaxxinity announced that it is collaborating with the University of Florida’s (UF) Centre for Translational Research in Neurodegenerative Disease (CTRND) to support efforts on the development of vaccines for neurodegenerative diseases. With a grant from the state of Florida to fund their work, the teams hope to further the development of Vaxxinity’s active immunotherapies to “prevent and mitigate” neurodegenerative diseases. This project has the potential to offer an “affordable and accessible” therapeutic option.
The researchers at UF will conduct preclinical studies to investigate the effects of Vaxxinity’s candidates for neurodegenerative disease on “relevant biological targets” like beta-amyloid, tau, and alpha-synuclein. These will be carried out through various in vitro and in vivo studies, including models of disease and antibody-target binding assays. The project is to complement Vaxxinity’s preclinical work, which has demonstrated immunogenicity, target engagement, and efficacy in animal models of several neurodegenerative diseases including Alzheimer’s and Parkinson’s.
Vaxxinity has developed a platform that is designed to “harness and selectively activate the immune system by overcoming immune tolerance, stimulating the production of antibodies against endogenous targets”. Vaxxinity is to provide materials to support the research, including candidates derived from its platform and antibodies generated by active immunotherapy treatment.
Tackling big challenges
Mei Mei Hu, CEO of Vaxxinity, commented that the collaboration “will support the continued development of vaccines for neurodegenerative diseases affecting millions of people worldwide”.
“Our work with UF will drive a deeper understanding of how to neutralise toxic proteins in the brain implicated in diseases such as Alzheimer’s and Parkinson’s. This work builds upon years of research on our synthetic peptide technology platform to target endogenous proteins and can help us to develop better candidates for neurodegenerative diseases in the future.”
Hu is “not afraid to tackle the biggest challenges in science” and believes that the collaboration is an “important way” of “advancing our vision to provide cheaper, safer, more convenient, and effective medicines for chronic disease to all”.
Dr Matthew J. LaVoie is director of UF’s CTRND, which is “committed to advancing biomedical research that can make a significant impact on human health”.
“Our focus on neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease is expanding to include vaccine candidates, and we believe this partnership will drive scientific progress and create exciting and impactful new opportunities for our faculty and students.”
Dr LaVoie is “grateful” for the state of Florida’s “commitment to advancing medical science for our ageing population”.
In February 2024 Imperial College London announced the beginning of a Phase I/II trial in patients at Imperial College Healthcare NHS Trust to evaluate the safety and potential of an experimental mRNA therapy: mRNA-4359. The vaccine targets melanoma, lung cancer, and other ‘solid tumour’ cancers.
The Mobilize trial is a partnership between Imperial College London and Imperial College Healthcare NHS Trust; the first UK patients are being dosed at the National Institute for Health and Care Research (NIHR) Imperial Clinical Research Facility at Hammersmith Hospital. It is sponsored by Moderna and aims to recruit a global cohort of patients over the coming years.
Early stages
Although the primary aim is to assess the safety and tolerability of the vaccine, either alone or in combination with pembrolizumab, the researchers are also exploring the possibility that the combination can “actively shrink” tumours. Dr David Pinato, Clinician Scientist at Imperial College London’s Department of Surgery & Cancer and Consultant Medical Oncologist at Imperial College Healthcare NHS Trust is investigator of the UK arm of the trial. He commented that “despite huge advances in screening, detection, and care” an estimated “half of us will experience cancer in our lifetime”.
“New mRNA-based cancer immunotherapies, such as mRNA-4359, offer a new avenue for recruiting the patient’s own immune system to fight their cancer.”
Dr Pinato emphasised that the “research is still in the early stages” and could be “a number of years from being available to patients”. However, the trial “is laying crucial groundwork that is moving us closer to new therapies that are potentially less toxic and more precise”.
“We desperately need these to turn the tide against cancer.”
Reflecting that “we’re only able to do this kind of research thanks to our patient volunteers”, Dr Pinato thanked every patient who is taking part. This gratitude was echoed by a member of the clinical research delivery team at Hammersmith Hospital, Dr Nichola Awosika.
“It has been a great experience to contribute to the development of innovative new treatments like this and it all depends on the willingness of patients taking part, so we are grateful for their participation.”
Getting involved in research
Imperial quoted an 81-year-old patient with treatment-resistant malignant melanoma, the first person in the UK to receive the vaccine last year. The man, who remains anonymous, is “pleased to be offered a chance to take part in a new trial”.
“The options were either do nothing and wait or get involved and do something.”
The patient stated that “taking part in a trial gives you a sense that you’re contributing to something which can help a lot of other people”. While he recognised that there are also “personal reasons”, it’s a “mixture of those two”.
“I’m extremely grateful to the hospitals and the individuals that are running these trials. You know, somehow, we have to change the fact that one in every two people gets cancer at some point and we have to make the odds better.”
A brilliant example
Professor Peter Johnson, NHS national clinical director for cancer, described the NHS as “at the vanguard of trials of cancer vaccines”.
“This trial at Imperial is a brilliant example of the pioneering work happening at hospitals up and down the country, with teams of experts looking into ways of harnessing the body’s own immune system to treat a range of cancers.”
Professor Johnson knows how “worrying” a cancer diagnosis can be but considers “access to these groundbreaking trials” and “other innovations” a source of hope. Secretary of State for Health and Social Care Victoria Atkins agreed that a cancer diagnosis can be “devastating”.
“This vaccine has the potential to save even more lives while revolutionising the way in which we treat this terrible disease with therapies that are more effective and less toxic on the system. It underlines our position as a life sciences superpower and our commitment to research and development.”
As her comments coincided with World Cancer Day, Atkins offered her “deepest gratitude” to the teams behind this “groundbreaking development” and the patients who were contributing to a trial that “could make such a difference to countless lives”.
With our Congress in Barcelona mere days away we are glad to share another of our exclusive speaker interviews, this time with Dr Ruben Rizzi. Dr Rizzi will join us for two panels next week, so if you are going to be at the event do make sure you are attending his sessions. We are grateful for Dr Rizzi’s participation in this interview, which was conducted over email, and to his team for facilitating the conversation.
Introducing Dr Rizzi
Dr Rizzi joined BioNTech at the end of 2019 to start work on “investigational candidates in immuno-oncology and infectious diseases”.
“Then the pandemic hit and for more than two years I have been fully involved as global regulatory lead for our COVID-19 vaccine jointly developed with Pfizer.”
During this time, the regulatory team has grown, and “amazing colleagues” have taken over the “day-to-day lifecycle activities for the COVID-19 vaccine”.
“Currently, as Vice President of Global Regulatory Affairs, I work with the regulatory teams supporting our pipeline projects and, with regards to our COVID-19 vaccine, post-approval activities and labelling.”
“Our entire pipeline has grown and matured especially with regards to product candidates in oncology, and we are continuing to develop our organisation and our processes to ensure state-of-the-art regulatory support to our ambitious projects, to translate science into survival by developing novel immunotherapies.”
The “future of vaccinology”
Dr Rizzi’s first panel explores the “future of vaccinology” so we asked about the changes we can expect to see in the future, and how significant COVID-19 vaccines have been in driving them.
“The COVID-19 vaccines have certainly been a turning point in different ways.”
For example, Dr Rizzi highlights the “crucial experience for pandemic preparedness”, in a field where “hands-on experience is scarce and therefore valuable”.
“Pandemic preparedness frameworks were already in place before the COVID-19 pandemic and were used to address the urgent need for medicinal products, tests, and interventions to curb the pandemic.”
In the regulatory space, Dr Rizzi identifies “a number of tools” that were employed to “expedite the processes to develop products” without “cutting corners”.
“The combination of these tools with newly available techniques, as well as the commitment from all stakeholders involved, have created the conditions for the unprecedented rapid development of COVID-19 vaccines.”
For the future, Dr Rizzi suggests that “there is a lot we can learn from this experience” to “improve our pandemic preparedness frameworks”. COVID-19 vaccines “represented a turning point” in the “dawn of an innovative technology in the world of infectious disease vaccines”: mRNA. This has “proven to be well suited” because it “allows for the quick design of vaccine candidates” and “subsequent adaption” of such vaccines to emerging variants.
“We will continue to further explore the potential of mRNA for other infectious disease indications, and beyond, for example in immuno-oncology where BioNTech initiated the first clinical trial ten years ago.”
Regulatory expectations
Dr Rizzi already touched on the regulatory scene during COVID-19, so we asked what expectations we might see as we move forward with other vaccines. He indicates that “we will observe the development of a more concise pandemic preparedness guidance” based on “lessons learned” during the pandemic. We will also see “new regulatory definitions”, such as around the “concept of platform technologies” to help make developments “more rapid and efficient” by “leveraging existing knowledge and avoiding repetition and redundancies”.
WHO has already issued some “regulatory considerations” specific to the development of mRNA-based vaccines for infectious disease indications. Dr Rizzi believes that “in the coming months”, major regulators “might also issue specific guidance” to “harmonise requirements and address inconsistencies”. Finally, Dr Rizzi reflects that “we are closely monitoring the evolution of the regulatory landscape” for “in-vitro diagnostics and use of artificial intelligence and machine learning”.
“These are areas of very active regulatory innovation with the potential to shape the future landscape for individualised therapies.”
A post-pandemic path for mRNA
Dr Rizzi’s second panel considers the “post-pandemic path” of mRNA vaccines, so we asked about how pandemic experience will inform non-pandemic practice, and what this “path” might look like. He states that “we will continue to advance our multiple mRNA developments in immuno-oncology and infectious diseases”.
“Messenger RNA is a very flexible platform that can be used to express a number of antigens, and this gives it a unique potential to be used in multiple areas.”
For Dr Rizzi, an “obvious next step” is the application of mRNA to prevent other infectious disease, especially those with “high unmet medical needs” where “preventative vaccines may not be broadly available”.
“While all these developments are based on similar or identical platforms, they obviously represent different challenges, and I think in the next few years it will be exciting to see where mRNA will show the most encouraging results. There is real potential to revolutionise multiple therapeutic areas – it’s a privilege being part of this journey.”
Why WVC?
Our final question, as always, invites speakers to share their hopes for, and highlights of, the Congress. Dr Rizzi says “one thing I love” is the “opportunity to share our experience with others”.
“In our day-to-day work we tend to focus on our specific roles within our organisations. The Congress serves as a reminder that we don’t do our work behind closed doors only but are also part of a vast community all working in the same field and sharing common goals; exchanging our results and ideas is what helps us grow and answer new questions.”
Finally, as “relevant restrictions” wind down for many, Dr Rizzi looks forward to the “pleasure” of meeting with colleagues and friends in person!
Thank you to Dr Rizzi and his team for working with us to bring you this content, which we hope you enjoyed. Don’t forget that it’s not too late to get your tickets for next week, but if you can’t join us do subscribe for more interviews with our experts.
As we gear up for October’s World Vaccine Congress in Europe, we are delighted to see our start-up zone growing with new and familiar names. Read on to hear about some of the companies joining us, and to learn about the opportunities you could secure by adding your name to the list.
Why be a start-up at the World Vaccine Congress?
Start-ups whose applications are successful are entitled to several unique benefits, including exhibition wall space, 2 complimentary passes, and marketing materials. For the first time at this event, there is the opportunity to participate in a 5-minute pitch during lunch breaks, an exciting way of introducing yourselves to colleagues and potential partners.
Our wonderful start-up manager, Isabella Aung, will receive your application and guide you through the process. She is looking forward to hearing more from interested companies, so do get in touch with her here via email (isabella.aung@terrapinn.com) or head straight to the application page here.
“I am super excited to connect with and welcome even more start-ups to our start-up zone at our Congress this October! It’s going to be our biggest and most exciting start-up zone yet!”
Introducing…
This week we are pleased to introduce a further four start-ups who have already secured their spot in the start-up zone. To see the full list and find out more click here.
Deepflare
A biotech AI company helping pharmaceutical companies design vaccines and immunotherapies.
Modelling MHC binding to peptides and using generative AI to generate candidates of the antigens.
The team’s previous project was recognised by the Polish Health Ministry and deployed in a programme where the software processed over 50% of Polish PCR test results.
Over the past 18 months the team has been refining its technology and assembling a group of 12 scientists, AI engineers, and PhDs.
Global Malaria Vaccines GmbH (GMV)
A Berlin-based biotechnology company focused on malaria control and ultimate eradication through vaccination.
The company is solving the challenges of large-scale and low-cost industrialisation of new malaria vaccines and targeting both major species.
With a particular focus on vaccines that will aid elimination and eradication campaigns, GMV seeks to accelerate the development of new vaccines.
Staff have experience in the management and conduct of vaccine development projects and undertake horizon scanning for early awareness and potential access to new technologies, help partners with commercialisation opportunities, and help develop business cases for new investment.
The team’s strengths lie in technology transfer and vaccine development. GMV supports vaccine candidates through preclinical, CMC, clinical, and regulatory challenges. It also provides freedom-to-operate analyses and surveillance of the IP landscape surrounding key technologies.
Immunize.io
An established not-for-profit organisation that is dedicated to improving global vaccination rates with a mission statement of “taking our best shot at immunising the world”.
Works globally to raise awareness of vaccine-preventable diseases and support the implementation of vaccination programmes.
The organisation has strong relationships within Canada and has delivered educational programmes, with a strong track record of digital content creation and delivery.
Ideally situated to address healthcare provider learning needs, with a team of healthcare professionals and dedicated technology experts who continue to reinvent educational programme delivery methods in line with learners’ evolving needs.
With practical experiences from immunisation providers and the power of technology, the organisation strives to improve vaccine accessibility and confidence across the world.
The team believes that the benefit of vaccinations is realised once they are administered to at-risk populations, so the focus is on the delivery of vaccinations and innovative implementation strategies to support community vaccination uptake.
Pegasus Biotech Inc.
A Contract Research Organisation focused on biopharmaceuticals and DNA vaccines for human and animal health markets.
The mission is to work with clients to bring cutting-edge innovation to the global human and animal health markets.
The team’s area of expertise is ensuring that CMC development activities for client projects (process and analytical development), in the proof-of-concept stage or moving into production, result in commercially viable products that are compliant with global regulations.
If you would like to join your colleagues in this exciting and continuously growing start-up zone, fill out an application here or contact Isabella here: isabella.aung@terrapinn.com
Stay tuned for more start-up news, and make sure you subscribe to our weekly newsletters!
Following the signing of a memorandum of understanding between the UK government and BioNTech in January 2023, an agreement has been established to provide cancer patients with “improved access” to cancer trials. The partnership will ensure that more patients are able to explore personalised cancer treatments. Trials have already begun in the UK, but most patients are expected to enrol from 2026 onwards. The goal is to provide personalised treatments to around 10,000 patients by 2030.
Leading the field
BioNTech intends to establish new laboratories in Cambridge with over 70 “highly skilled” scientists, and a regional hub for the UK. Prime Minister Rishi Sunak commented that the “landmark new agreement” brings the country “one step closer” to life-saving treatments for thousands of patients.
“The UK is a global leader in life sciences – helping to create thousands of highly skilled jobs and pioneering research – and it is a testament to this success that BioNTech have chosen to make this significant investment here today.”
Mr Sunak believes that a personalised vaccine approach to cancer has potential to “completely revolutionise the way we treat this cruel disease”. Secretary of State for Health and Social Care, Steve Barclay, agrees that the partnership is a “huge step forward in the fight against cancer”.
“This further demonstrates that the UK is an attractive location for innovative companies to invest and pioneer cutting edge treatments for our patients and underlines this government’s commitment to research and development.”
Working with the NHS
The Cancer Vaccine Launch Pad (CVLP) will be led by NHS England and Genomics England. This will encourage quick identification of eligible cancer patients to join trials. It does this through a database of suitable NHS patients. The NHS CEO Amanda Pritchard emphasised that the NHS “will not stop” efforts to “pioneer new treatments”. The CVLP, she said, will give patients the “earliest possible access to cutting-edge technology”.
“Thanks to advances in treatment and care alongside NHS awareness campaigns, cancer survival is at an all-time high, but the potential to stop cancer from returning is truly remarkable.”
Chris Wigley is Genomics England’s CEO and describes the CVLP as a “rocket” being launched.
“Since the times of Darwin, Franklin, and Sanger, the UK has been a true world leader in genomic science and healthcare.”
He is “thrilled” that the partnership takes genomics “beyond diagnosis” towards “a future of personalised cancer treatment”.
Personalised mRNA
The trials are centred around the revolutionary mRNA platform, with immunotherapies to target shared mutations or individual tumours. CEO and co-founder of BioNTech, Professor Uğur Şahin, is “truly honoured” to be an “integral part of this landmark partnership”.
“The United Kingdom’s expertise in genomic analyses in cancer patients is a critical component of our shared endeavour to make mRNA-based and precision cancer immunotherapies widely accessible through clinical trials.”
Professor Şahin hopes this partnership will facilitate better outcomes for patients “worldwide”.
In June 2023 Vaxxinity announced positive results from Part B of the Phase I clinical trial of UB-312, an investigational vaccine for Parkinson’s disease. The results show that the vaccine was well tolerated and induced anti-alpha-synuclein (aSyn) antibody responses in participants with early Parkinson’s disease. The primary endpoints of the trial were met and support the advancement of UB-312 to Phase II trials.
Parkinson’s disease and aSyn
Parkinson’s disease (PD) affects over 10 million people across the globe. It is a “chronic and progressive neurodegenerative disorder”, affecting predominately dopamine-producing (dopaminergic) neurons in the substantia nigra part of the brain. There are no approved disease- modifying therapeutics and current treatments aim to provide symptomatic relief whilst causing “significant side effects”.
Alpha-synuclein (aSyn) is a protein that is highly expressed in neurons, mostly at presynaptic terminals. Mutations in the gene encoding aSyn are “known to cause or increase the risk of developing PD” and have been shown to alter the secondary structure of aSyn. This produces misfolded and aggregated forms of the protein. Immunotherapies that target aSyn have demonstrated an ability to “ameliorate aSyn pathology” and functional deficits in mouse models of PD.
UB-312 in trial
The investigational vaccine is a synthetic peptide vaccine targeting toxic forms of aggregated aSyn to address PD and other synucleinopathies. The Phase I trial was placebo controlled and double blind, comprising two parts. Part A tested escalating doses of UB-312 against placebo in 50 health volunteers between the ages of 40 and 85. Part B tested two doses of UB-312 versus placebo in 20 age-matched subjects with early PD. These were conducte at the Centre for Human Drug Research (CHDR) in the Netherlands.
Previous results from 2022 have suggested that the vaccine is highly immunogenic. All individuals in the target dose group showed detectable anti-aSyn antibodies in serum and cerebrospinal fluid (CSF).
A closer look at Part B
Part B comprised a 20-week treatment period before 24 weeks of observation. The study evaluated the safety, tolerability, and immunogenicity of the vaccine in patients with PD, and primary endpoints were met. 92% of patients who completed the dosing developed anti-aSyn antibodies. The vaccine was “generally safe and well-tolerated” and all serious adverse events (SAEs) were resolved.
A promising candidate
Vaxxinity’s CEO Mei Mei Hu, whom we interviewed at the Congress in Washington this year, commented that the results demonstrate “several important features necessary for an immunotherapy”.
“UB-312 was observed to safely break immune tolerance, inducing antibodies against toxic aggregated forms of alpha-synuclein. Importantly, these antibodies crossed the blood brain barrier, and the data also suggest potential target engagement in the periphery, where pathological alpha-synuclein is known to be concentrated.”
She considers the candidate “promising” and looks forward to further development. Dr Geert Jan Groeneveld is the CMO/CSO of CHDR and principal investigator of the Phase I trial. He commented that this is a “revolutionary concept” that could have “immense impact” in the treatment of diseases like Parkinson’s.
To learn more about Vaxxinity’s work make sure you check out our exclusive interview with Mei Mei here. Subscribe to our newsletter for regular updates on vaccine development.
A study in Human Vaccines and Immunotherapies in June 2023 found that confidence in vaccines declined across much of sub-Saharan Africa during the pandemic. The authors conducted a study across data from 16 national surveys including more than 17,000 people in 8 countries. The researchers acknowledge that “globally, few countries have managed to avoid losses in uptake rates of routine childhood immunisation”. This has been emphasised in the recent UNICEF ‘State of the World’s Children’ report. However, this trend has “particularly affected” low- and middle-income countries. Identifying a gap in the global understanding of vaccine confidence in sub-Saharan Africa, the authors aim to examine attitudes to routine immunisation during the COVID-19 pandemic.
Waning confidence and COVID-19’s consequences
As we know from the UNICEF report, the world is currently “not meeting” the goal of vaccinating every child. The study recognises that lowered rates of routine immunisation during the pandemic have been caused by a range of contributory factors, such as supply chain disruptions, reallocation of limited resources, and travel restrictions.
Another key element in uptake of vaccinations is the attitude of decision makers towards vaccines and the systems and people behind their delivery. Although the study focuses specifically on perceptions towards vaccines, the authors acknowledge that the role played by confidence in systems and people is also significant. In this study, the idea of vaccine confidence relates to three elements of vaccines: their importance, their safety, and their effectiveness.
The study
The study spans 8 countries in Africa: Democratic Republic of the Congo (DRC), Ivory Coast, Kenya, Nigeria, Senegal, South Africa, and Uganda. The surveys were conducted between October and December 2020 and again between January and March 2022. To read the specific methods used by the researchers, click here to access the study.
To identify shifts in the public perception of vaccines respondents were asked to engage with several general statements such as “vaccines are important for children” or “vaccines are safe”. Although many people expressed positive views of COVID-19 vaccines and other vaccines, the findings reveal “perceptions toward the importance of vaccines for children falling across all eight countries studied”. Notable falls in confidence were observed in DRC and Nigeria, with specific regard to vaccine safety and effectiveness.
The study in context
Consistent with the existing literature, the study identifies the largest falls in vaccine confidence in South Africa within “predominantly rural providences”. By contrast, the “reverse seems to be true in Senegal”, where the results indicate that “vaccine refusal is higher in large cities”. However, only two sub-national regions were considered, which means a better-informed conclusion cannot be drawn.
A review in Science reflects that the reason for varying trends across the countries studied is “not clear”. However, Dr Alex de Figueirido of the London School of Hygiene and Tropical Medicine suggests that the overall trends fit other survey patterns. Furthermore, the research “allows identification of specific regions that may be facing confidence concerns”.
A worrying decline
The authors state that their results paint a “worrying picture of declining vaccine confidence trends across many sub-national regions in sub-Saharan Africa”. Although there are national estimates and models of local vaccination rates across Africa, there is “limited evidence of routinely collected vaccine confidence data”.
“As there is precedent for vaccine confidence losses in one vaccine to trigger confidence losses in others, the losses in confidence in COVID-19 vaccines found in this study may be a cause for concern with respect to childhood immunisations.”
Do you think this is a useful contribution to the landscape of understanding vaccine attitudes? Was your country involved in the survey? How do you respond to these results?
In January 2023 BioNTech announced that it had signed a Memorandum of Understanding (MoU) with the UK government to “benefit patients”. The goal will be to accelerate clinical trials for personalised mRNA therapeutics with a target of providing personalised cancer therapies for “up to 10,000 patients by the end of 2030”.
A statement from BioNTech describes the objective as a component of a “multi-year collaboration focused on three strategic pillars: cancer immunotherapies based on mRNA or other drug classes, infectious disease vaccines, and investments into expanding BioNTech’s footprint in the UK”.
MoU
Under the MoU trial site development and patient recruitment for clinical candidates will accelerate. Using the UK’s clinical trial network, genomics, and health data assets, they hope to move faster along BioNTech’s pipeline. Following this acceleration, the collaboration will select candidates, trial sites, and set up a development plan. The aim is to be “ready to enrol the first cancer patient in the second half of 2023”.
The plans involve BioNTech’s investment in an R&D “hub” in Cambridge, with an “expected capacity of more than 70 highly skilled scientists”. It will also establish a regional headquarters in London. Furthermore, the company will “remain the local sponsor of current and upcoming new clinical trials of its programmes in the UK and will design the clinical trial protocols”.
What does this mean for patients?
The government statement suggests that cancer patients will get “early access” to trials for personalised therapies such as cancer vaccines. Access will be through the Cancer Vaccine Launch Pad, which is being developed by NHS England and Genomics England. The launch pad is intended to “rapidly identify large numbers of cancer patients who could be eligible”.
From COVID-19 to cancer
Professor Ugur Sahin is CEO and Co-Founder of BioNTech recognised the collaboration between the UK’s NHS, academia, regulatory bodies, and the private sector during the COVID-19 pandemic as “exemplary”.
“This agreement is a result of the lessons learnt from the COVID-19 pandemic as we all experience that drug development can be accelerated without cutting corners if everyone works seamlessly together towards the same goal. Today’s agreement shows that we are committed to do the same for cancer patients.”
BioNTech has been working on the relevant technologies for “over 20 years”. The collaboration will therefore accelerate better outcomes for patients in the UK and worldwide. Health and Social Care Secretary Steve Barclay emphasised the importance of ensuring the “best possible treatments are available as soon as possible” for cancer.
“BioNTech helped lead the world on a COVID-19 vaccine and they share our commitment to scientific advancement.”
Cancer research under pressure
Although Cancer Research UK “welcomed” the news, the charity stated concern over delays in diagnosis and treatment. Staff are coming under increasing pressure and may struggle to facilitate clinical trials. CRUK spokesperson Dr Iain Foulkes suggested that “mRNA vaccines are one of the most exciting research developments to come out of the pandemic, and there are strong hints that they could become powerful treatment options for cancer”.
“Getting there will require lots more research.”
For more on cancer vaccine development at the World Vaccine Congress in Washington 2023 get your tickets today.
With the World Vaccine and Immunotherapy Congress kicking off in San Diego today we are delighted to share another exclusive interview with the community. We were lucky to hear from Dr Ariel Weinberger, founder and CEO of Autonomous Therapeutics since 2017. Autonomous is a “scientist-led company” working on the development of the “first variant-proof RNA therapeutics”. Looking ahead, the team is hoping to create “effective countermeasures” before the next pandemic.
The consequences of the mRNA revolution for therapeutics
As mRNA entered its heyday during the COVID-19 pandemic, scientists and industry leaders rushed to make the most of the emerging potential. We asked Dr Weinberger about how the storming success of the mRNA vaccines might influence therapeutic interventions, and what challenges might be associated with an mRNA-based future. He began by suggesting that the “comparison to mRNA vaccines highlights a number of the challenges faced by mRNA therapeutics”.
Vaccines vs therapeutics
“If you think about vaccines, a core idea is to harness the body’s adaptive immune system for both signal amplification and memory. So, a relatively small vaccine dose can, in principle, confer immunity for years—although, of course, that hasn’t yet been the outcome for COVID-19 vaccines.”
Dr Weinberger explained that “the barriers for mRNA therapeutics arise, in large part, because they cannot leverage the body’s adaptive immune system for amplification and persistence”.
“As a result, you often need to administer far higher therapeutic doses—a recent review noted that mRNA doses are often 100 to 1000-fold higher for therapeutics than vaccines. And you may need to administer those doses repeatedly, because current RNA technologies can degrade in hours to days. And there’s another barrier: current RNAs, including those delivered in lipid nanoparticles, can lead to substantial immunogenicity. This may provide an adjuvant advantage for vaccines, but it’s unfortunately an additional way to accelerate the loss of therapeutic RNA.”
Despite the challenges, Dr. Weinberger believes that mRNA therapeutics are likely to succeed.
“It’s worth noting that these challenges were previously overcome for siRNA therapeutics. The drug that comes to mind is Alnylam’s Onpattro. So, there’s a clear precedent for believing that we’ll find solutions for mRNA therapeutics, too.”
Mining opportunities
We then asked Dr Weinberger about the opportunities for mRNA therapeutics, and how he understands a next-generation approach will enable us to use them. In his answer he highlighted the importance of “novel technologies” to “tackle the barriers” he explored above. He is particularly excited to encounter some of these next-generation mRNA technologies at the Congress (he gets brownie points for being enthusiastic about other people’s sessions)!
For example, self-amplifying RNAs are being developed to directly amplify RNA in vivo, circular RNAs are being developed to enhance RNA persistence, and novel transcription and purification strategies are being developed to minimise inherent RNA immunogenicity. But I also think that some of the greatest opportunities of mRNA technologies may be paradigmatically different. If you think about it, current mRNA therapies are often focused on producing proteins in vivo. I think a fair question is: “why don’t you just deliver the protein directly’? We may not like asking that question in the mRNA field, but we clearly have to—since some of our competitors are in the protein field.
Asking the right questions
Once this question has been asked, Dr Weinberger has another for his colleagues: “what can we do with mRNA therapeutics that we can’t do with proteins?” He suggests that “if we can answer that question, we have a potential path to developing next-generation drugs that weren’t previously possible”.
“Here are some examples. I think about proteins that are extremely difficult to produce, purify, or effectively deliver—for example, transmembrane proteins. Or therapeutic proteins that you don’t want to express constitutively and systemically, but that are life-saving in certain contexts. Ultimately, I think about how mRNA could be used as a circuit board to precisely control therapeutic protein production both temporally and spatially.
For Dr Weinberger, mRNA “2.0” moves from “plug-and-play production to plug-and-play control”.
“There are a few companies already thinking about this in the cancer context—imagine if we could localise chemotherapies or immunotherapies—and I think there will be more from cancers to autoimmune diseases.”
Autonomous’ pandemic protection against the unknown
We identified on Autonomous’ website the intention to develop countermeasures “before” the next pandemic. So, naturally, we were curious to understand how this works. First and foremost, Dr Weinberger was keen to emphasise that they’re not trying to “predict the future”.
“Before I started Autonomous, I spent years mathematically modelling the evolution and spread of pandemic viruses. And the lesson I kept learning is that you can’t predict a stochastic process with scores of unmeasurable parameters and “heavy” tails to the level of detail that you need to develop an effective precision therapy in advance. And even if we could know the random genotype of a future viral variant, we wouldn’t have a way to map its pandemic potential. Some have proposed using new AI approaches to solve these problems—but the pandemic prediction problem is likely a lot less tractable (and deterministic) than problems in, say, computer vision where AI has changed the world.”
For Dr Weinberger, the solution is “to develop broad-spectrum or variant-proof countermeasures that can control whatever viral variant ultimately emerges—even if the precise genomic confirmation of that variant is frankly unpredictable months to years in advance”.
How can we do this?
“One option is to target the part of the system that doesn’t change from virus to virus: the host. And we’ve seen a ton of recent interest in host-directed therapeutics; I think it’s an extremely promising avenue. The concern has always been that targeting the host means targeting the host, and raises the spectre of toxicity”.
“The other approach is to find the kernels of viral genomes or proteins that don’t change from virus to virus. These conserved viral elements are not likely to be in the Spike or receptor-binding proteins of a virus that vaccines generally target—those proteins are under too much diversifying selection from the immune system. In fact, the conserved regions that we want to target are often the regions that are the least well-suited for vaccine and antibody approaches. But these regions can be targeted using RNA technologies.”
Although there is “too much viral genomic diversity” for us to be able to develop a single virus-targeted drug, Dr Weinberger suggests that we “find elements that are conserved within a viral genus or species”.
“For example, we can find targets that are conserved across all the variants of SARS-CoV-2 or across all influenza variants. And then we have the possibility of developing countermeasures that don’t lose efficacy every 6 months—and that can be effectively administered for lifetimes. More broadly, we have the possibility of pre-developing an armamentarium of pan-variant countermeasures for each major viral family. That’s what Autonomous uses RNA to do.”
Money matters
As terribly vulgar as it is to discuss money, in some situations curiosity just gets the better of us. Particularly in a post-pandemic world, we wondered what the funding landscape looks like for early-stage companies. Dr Weinberger thinks that “substantial funding will remain in the space, at least in the near term”. Although there is “always some reversion”, as the money moves where the “next hottest thing” is, he believes that “financial incentives are hard to ignore for an investor”.
“You’re talking about $75B that’s likely to be grossed for COVID this year alone by just two companies (and we keep hearing that the pandemic is over). At the same time, these numbers were clear before the pandemic. The market sizes for viral pathogens with pandemic potential are (unfortunately) massive. And there were already blockbuster returns for earlier antivirals and vaccines—from HIV and HCV to HPV.”
Taking responsibility
“I think that some of the historical shortfalls for antiviral and vaccine funding have also been on us: the companies. We haven’t always been developing new classes of approaches that offer major benefits over state-of-the-art strategies. How many similar monoclonal antibody or Spike vaccine approaches can we keep funding? More fundamentally, some of the issues have been at the Government and academic level. If we keep funding the same sorts of basic science studies, we’ll get more of the same translational products, and less of the same investment funding.”
“My view is that new classes of drugs and vaccines for major market indications will always have substantial investor interest—and that’ll especially be the case in the ID space after COVID. It’s just that you have established biopharma companies that have already developed and clinically tested existing products. The bar is high: you have to disrupt and supplant these existing approaches to enable the kinds of potential returns that would really excite investors.”
Future threats
Eventually our conversation turned to the future, and what we should be most worried about, or invested in. As Dr Weinberger specialises in viruses, he believes, for “good reason” that these the “critical global health threats”. Previously, he suggested that “we can’t predict the next outcome of a random process”. We don’t know if the next pandemic will be “another flu, COVID, or an entirely different pathogen”.
“I think that we can fairly assume that there are going to be more viral pandemics – we’re still in one. And many of the pandemic strains that emerge will likely be close relatives (i.e. variants) of viruses that have previously infected large numbers of humans. After all, these viruses have already crossed the major evolutionary barrier: transmission across humans. To me, the critical threat is that the next pandemic variant is again untreatable or is resistant to all approved therapeutics and vaccines. In other words, after years of COVID and millions of deaths, we could be back in March 2020 all over again.”
“Sure, new platform technologies (including mRNA) could speed up response times—so maybe we’ll have an authorised vaccine or monoclonal antibody in 6 months. But we know that’s six months too late and that it’s fundamentally impossible to develop, clinically test, and manufacture a new countermeasure faster than a pandemic virus can spread.”
Final thoughts
So, fail to prepare and prepare to fail. Thankfully, Dr Weinberger and his colleagues are working to prepare for future threats. It’s encouraging to hear that some of hard lessons from COVID-19 have been taken on board.
“We were based in New York City in March 2020. Being in that environment is something that you never forget. People felt helpless and knew that there were few medical countermeasures for them or their families if an infection took a turn for the worse. It’s incumbent on us to do everything possible to make sure that doesn’t happen again.”
It was a pleasure to hear from Dr Weinberger, and we are so grateful that he put so much thought into his answers. To participate in his roundtable at the World Vaccine and Immunotherapy Congress this week make sure you sign up in advance – it is surely not to be missed!
A study by researchers led by the University of Houston demonstrates potential to eliminate the high caused by the synthetic opioid fentanyl. The hope that it will block its ability to enter the brain has positive implications for tackling a widespread opioid epidemic. Although Opioid Use Disorder (OUD) is treatable, up to 80% of patients with a dependency on the drug experience a relapse. The publication in Pharmaceutics states that the data support “further clinical development of [the] vaccine to address OUD in humans”.
An opioid epidemic
The authors reflect in their publication that a “significant public health crisis” has been caused by “illicit synthetic opioid use”. Between 2019 and 2020 overdose deaths in the US increased to the “highest ever recorded” at 81,000, and more recent statistics are “even higher”. So, what is driving this?
“Fentanyl (FEN) is a synthetic opioid agonist that is approximately 100 times more potent than morphine.”
It is “decidedly lipophilic” and quickly enters the central nervous system, activating mesocorticolimbic circuitry to produce “highly reinforcing euphoria”. The study reports that in the early 2000s there was a significant rise in overdose deaths. This showed that “FEN and its derivatives adulterated other misused substances that led to increased lethality”. Furthermore, between 2010 and 2016 more than 50% of stimulant-related overdose deaths involved it.
Current treatments are effective based on formulation, compliance, access, and the opioid in question; FEN is a “particular treatment challenge” because of its “pharmacodynamics”. This challenge can be addressed with immunotherapies that prevent FEN from entering the brain, thus “pre-emptively circumventing its reinforcing and overdose effects”.
Vaccine immunotherapy
With “poor medication compliance” OUD has almost 90% relapse rates. The authors believe that vaccine immunotherapy could address this by demanding a less intense administration schedule.
“Vaccine immunotherapy targets small molecule antigens such as opioid compounds consisting of the antigen (hapten) linked to an immunogenic carrier protein that stimulates the immune system to generate antibodies.”
An adjuvant is often added to increase immunogenicity. Then, post-vaccination, when an opioid is consumed, antibodies “prevent it from getting into the brain or affecting other organs”. This vaccine comprises a “FEN-like hapten containing a linker with a carboxyl moiety suitable for carbodiimide coupling chemistry to form amide bonds to lysine residues on the carrier protein CRM197, a genetically deactivated diphtheria toxin contained in several FDA-approved conjugate vaccines”.
The study in rats
The study involved 60 Sprague Dawley rats. 32 were used for the schedule-controlled responding experiments and 28 were used for the physiology experiment. FEN was then obtained, as well as morphine, and both were dissolved in sterile saline and administered subcutaneously.
The vaccine formulation was prepared “immediately before administration”. Animals were injected at 0, 3, and 6 weeks. Blood samples were then collected during weeks 4, 6, 8, and 10 post-initial vaccination.
The conclusion states that the vaccine “produced significant amounts of anti-FEN antibodies” in both sexes. It also reduced FEN entry into the brain. The results “warrant further development as a potential therapeutic for OUD and overdose in humans”, with minimal side effects expected.
Lead author Dr Colin Haile describes this study as having “significant impact”. The vaccine’s ability to prevent FEN from entering the brain will subsequently prevent “euphoric effects” and promote an easier road to “sobriety”. Furthermore, the anti-FEN antibodies “did not cross-react with other opioids”, meaning a vaccinated person would “still be able to be treated for pain relief with other opioids”. For Dr Therese Kosten, this vaccine could be a “game changer”.
For more on adjuvanted opioid vaccines at the World Vaccine Congress in Washington 2023 get your tickets now.
“Pioneering a new era of human health”, scientists at the Human Immune Project are tackling “one of the greatest remaining frontiers”: the human immune system. Formerly known as the Human Vaccines Project, and modelled after the Human Genome Project, they are “unlocking the mechanisms of human immunity”. Their aim is to “transform how we fight our most devastating diseases” and their methods combine systems biology and artificial intelligence. In this piece we take a closer look at who they are and what they do.
The future of immunity
The HIP identifies a major challenge in vaccine research: the “limits of scientific knowledge”. Fighting “insidious and biologically complex diseases” is no mean feat, and examples of HIV, tuberculosis, and various cancers underpin the difficulty we face. Furthermore, as we prepare blindly for the next pandemic, we can only make (reasonably scientific) guesses at what it might bring.
“A new approach is necessary now, one that is rooted in identifying and understanding the common elements of the human immune system that overlap across global populations and that allow us to harness this knowledge and the collective intelligence of scientists”
Recognising this need, the HIP is putting “breakthrough advances in biomedicine merged with AI” into the hands of the “world’s top scientists”. Across a worldwide network, partners are “compiling the biggest dataset of biomedicine at a population scale”. With this, an AI model of the immune system can be created, to accelerate and reduce the cost of vaccine and treatment development.
“Our goal is nothing short of enabling people to live much healthier – and longer – lives.”
A helping hand from AI
Dr Wayne Koff is the President and CEO of the Human Immunome Project. He describes everyone’s immune system as “unique” but asks why vaccines can be 90% effective at protecting against disease.
“Our task is to develop a model or a series of models that will eventually be able to explain this and that will eventually allow us to predict how the immune system will respond to pathogens, vaccines, drugs, and immunotherapies.”
The task will be made possible with the power of AI and deep learning. A platform known as AlphaFold is already solving protein structures in rapid time. Further possibilities include ever improving interpretation of retinal imaging to predict risks of disease. For Dr Koff, this is “extraordinary”.
“All of this is giving us new opportunities.”
Writing for the Human Immunome Project, Kristen Jill Abboud suggests that AI can “accelerate and vastly improve the use of in silico studies to prioritise vaccines or therapies without the need for large clinical trials”. The Project is therefore working to “develop and implement” a plan with partners. The future looks bright for the project but will need careful consideration and collaboration. Part of this will involve a “consensus on how immunome data should be generated, accessed, and managed”. With “social and ethical implications”, the project certainly has its work cut out!
Researchers in Europe published results in Cancer Discovery in November 2022 that indicate promising responses to vaccination with senescent cells. The researchers suggest that these cells “combine several features that render them highly efficient in activating dendritic cells (DCs) and antigen-specific CD8 T cells”. Furthermore, the immune response to this study is “superior to the gold standard of immunogenic cell death”.
Senescence
The Barcelona Institute for Research in Biomedicine (IRB) states that “senescence is a state of latency reached by damaged or aged cells in which they do not reproduce”. They “emit information signals into their environment”, alerting the immune system to their presence, which stimulates an “inflammatory response and tissue regeneration”.
The team used these cells because of these useful characteristics. As they are living, they stimulate the immune system for longer, but as they don’t divide, they can’t “regenerate the tumour”. Ines Marin is a doctoral student and author of the study who believes their findings are “very positive”.
“Our study concludes that the induction of senescence in tumour cells improves the recognition of these cells by the immune system and it also increases the intensity of the response they generate.”
Next level immune responses
Led by Dr Manuel Serrano and Dr Federico Pietrocola the group explored the effectiveness of senescence in immunisation. The IRB describes how this was a two-pronged approach looking at preventing and improving cancer in mice. As a therapeutic option, although limited by the “protective barrier of the tumour”, some “improvements were also observed”. Dr Serrano explained that this could be a positive step in understanding the immune response.
“Our results indicate that senescent cells are a preferred option when it comes to stimulating the immune system against cancer, and they pave the way to considering vaccination with these cells as a possible therapy.”
The study is supported
Using animal models of melanoma and pancreatic cancer, as well as samples from cancer patients, they found that “human cancer cells also have a greater capacity to activate the immune system when they are previously rendered senescent”. The next step is a combined approach of vaccination and immunotherapy.
This study was published in the same journal as another article that IRB describes as “completed in collaboration with IRB Barcelona”. This reaches “complementary conclusions” from a “different approach”. The work reveals that these senescent cells are better able to “receive” signals from their environment, which “amplifies the anti-tumour effects of signals such as interferon, making tumour cells more visible to the immune system”.
These studies present further potential for cancer therapies, which we know to be a huge task for researchers across the globe. To learn more about progress in cancer and immunotherapies at the World Vaccine Congress in Washington next year, get your tickets now.
In Nature in September 2022 an article by Anthony King identified the difficulties associated with creating an immunotherapy for prostate tumours. The 2010 FDA-approved vaccine, sipuleucel-T, “raised hopes for a surge of cancer treatments”, which the article suggests have not been delivered for the prostate.
Sipuleucel-T
The vaccine originally targeted prostate tumours. The process involves extracting antigen-present cells from the patient’s blood and inserting a marker found on prostate tumours, before returning them to the patient. The idea, the article explains, is to direct “other immune cells” to “attack the cancer”.
Dr Lawrence Fong of the University of California is quoted emphasising the “big challenge” of prostate cancer. Although sipuleucel-T “delivered a slight survival benefit”, the American Cancer Society suggests that it “hasn’t been shown to stop prostate cancer from growing”.
Later attempts
Since 2010 there have been several “disappointing” immunotherapy attempts for prostate cancer. There are still gaps in our knowledge, which present a “key obstacle to getting immunotherapy to work”. However, momentum will not be stopped. Researchers are beginning to better understand this cancer, and promising approaches are progressing through trials.
So, what do we know about prostate cancer? Dr Charles Drake of Janssen Pharmaceutical suggests that because prostate cancers mutate less than other cancers, they offer fewer targets: “there’s just not as much fodder for T cells to recognise”. Another issue is that the prostate “has an unusually dialled-down immune environment”.
“Researchers using genetic sequencing to look for immune cells in the prostate will often come away empty-handed.”
The low T cell count means that checkpoint inhibitors encounter problems. When combined with the cancer, which “secretes a chemical messenger that further dampens immunity”, a “tricky environment” is created.
Vaccine candidates
So far, therapeutic candidates have been “a bit of a let-down”. However, some scientists believe that a combination approach could be effective. This would involve a vaccine and a checkpoint inhibitor, working together. This could work based on a study of sipuleucel-T; it revealed that “people who received the treatment contained three times as many activated T cells”.
Trialling this is Dr James Gulley and his group in the US. Using a vaccine called Prostvac (PSA-TRICOM), which “disappointed in a phase III trial”, he hopes to “break the blockade”. Although Prostvac was insufficient alone, Dr Gulley’s group is trialling it alongside a checkpoint inhibitor targeting PD1, which tumours use to dodge detection by the immune system. Early signs a promising; “not a home run, but an interesting early signal”, for Dr Gulley. His “next step”, the article reports, is adding a third element. Interleukin-15 is a cytokine molecule that is involved in immune signalling. Despite positive early responses, this project must “clear tough regulatory hurdles”.
Targeting treatment and looking ahead
In order to achieve the most successful outcome, immunotherapies must be “targeted to the right people”. The article suggests that personalisation is common in other cancers but is “lagging” for prostate cancer. Furthermore, there is a “consensus” that the timing of immunological intervention “could be crucial”. We often see immunotherapy in patients with advanced disease, but the longer the battle with cancer, the “more entrenched it can become”. Considering immunotherapy “immediately after surgery or radiation therapy” is an avenue to explore.
In the face of numerous challenges, there is optimism. Dr Gulley identifies “little signals” that we can achieve “long-term durable responses”. Although “we haven’t quite cracked it” he believes there could be a “path forward”.
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