Interview: Combination therapies for cancer treatment

DNA Vaccine Potential

Recently, Dr Marc Mansour, Chief Operating Officer and Director at Immunovaccine Inc sat down with Vaccine Nation to talk about cancer vaccines and particularly the need for combination therapies:

What’s the need for combination therapies and how much of an improvement can we see compared to individual vaccines?

I think that for a number of reasons there’s growing recognition now in the research community, and in pharma, of the limitations of cancer vaccines as standalone therapies. This is largely due to the manner in which cancer vaccines are designed to work.  In most cases cancer vaccines are working to generate an immune response against a self-antigen, which we know is very difficult to achieve.   Of course, effective adjuvant technologies might help in this area by addressing immunologic tolerance, but it’s still going to be difficult.

There is, however, wide acceptance for the potential powerful impact a cancer vaccine might have when combined with the proper complementary compounds.  For example, there is a potentially important role for a compound that can modulate the immune system so that it becomes more receptive to vaccination and gives the vaccine a boost to generate a stronger immune response.  It makes perfect sense to pursue this avenue of combination therapy if there are compounds available that you could use safely and efficiently with vaccines. This thinking shapes the way we approach development of our vaccines and explains why we refuse to do any trial with cancer vaccines as a monotherapy.  We will always combine our vaccines with a potential synergistic compound.

With that philosophy in mind, the question for us then becomes: what compounds do we have access to and what can we use as part of our ongoing clinical development programs? Initially, we’re focusing on metronomic low dose cyclophosphamide. At this low dose the compound does not act as a chemotherapeutic agent. Instead it is used to modulate the immune system to make it more receptive to vaccination.    We administered low dose cyclophosphamide orally and continuously throughout the vaccination period in our Phase I trial and were able to demonstrate that it added to the immunogenicity of the vaccine. We had a group of patients that received the vaccine alone versus a group of patients that received the vaccine plus cyclophosphamide, and the difference in the T cell responses was dramatic. There were statistically significant differences in the immune response. It was clear-cut, unequivocal: the immune modulation enhanced the immunogenicity of the vaccine.  Low dose cyclophosphamide is very well tolerated. There’s a lot of experience with it in the clinic. And so for us it is a sure immune modulator that we could easily use and have access to for ovarian cancer patients and for other cancers. With this data in hand, it is clear to us that the correct path is to leverage this combination approach.

Another example of the combination approach is the pairing of cancer vaccines with low dose temozolomide in brain cancer.   Temozolomide, which is the standard of care maintenance therapy after surgery and initial chemotherapy in brain cancer, is a chemotherapeutic agent with known immunomodulaory benefits.  Celldex has proven in Phase II trials that the combination of their vaccine with maintenance temozolomide in glioblastoma can dramatically enhance the immunogenicity of the vaccine. So there’s another example of how you could use chemotherapeutic agents to boost an immune response to a cancer vaccine.

Yet another approach is to combine a cancer vaccine with a compound that is able to reset the immune system through lymphodepletion.  As the immune system is regenerating itself following the lymphodepletion, a cancer vaccine can be administered.  This leads to a preferential expansion of immune cells directly targeting the vaccine and a resulting strong immune response to the vaccine.  

As we continue to think creatively about combination approaches, we can imagine even more exciting strategies that involve combining cancer vaccines with some of the hot immunotherapies that are currently getting broad attention, particularly checkpoint inhibitors. The industry is very excited about monotherapies and combination therapies that include anti-PD1 immunotherapy. Bristol-Myers (BMS), Merck, Roche and Astra Zeneca/Medimmune are all driving their checkpoint inhibitor programs, and what these monoclonal antibodies are good at is activating T cells in a broad and general manner. The treatments might activate T cells directly or they might inhibit regulatory T cells to allow T cells to become more activated. This is very exciting.  However, what you ultimately need is a T cell that is not just active but one that recognises a cancer cell and targets it.  As a result, pharmas are now investigating the combination of their checkpoint inhibitors with targeted T cell activation therapies – in other words: vaccines. With vaccines, you are essentially training the immune system to recognise a very specific target, and you’re trying to raise T cell responses to that target.   Accordingly, vaccines and checkpoint inhibitors have the potential to be a great combination. There’s a lot of preclinical data and some clinical data to support that approach.

As compelling as the ability to boost a vaccine is, there is another important reason for using combination immunotherapies in cancer. That is the potential to deliver a stronger effect at the tumour level, or the tumour microenvironment. Tumours, particularly those that are established and growing are very good at shutting down T cell responses once T cells arrive at the tumour.  This is true even when that T cell response is strong in peripheral blood. This is due to the fact that tumours have evolved to possess very powerful suppressive mechanisms.  Many of these suppressive mechanisms emerge from the tumour vasculature itself, which can attract immune cells that have a function of suppressing other immune cells. The structure of the tumour itself, the stroma, is also a barrier. Additionally, the inside of the tumour is a hypoxic environment which ends up attracting a variety of suppressive immune cells, that again cause immune suppression in the tumour microenvironment. As you can imagine, it is very difficult to get around all of these hurdles, and every day we learn more and more about additional evasion mechanisms that we didn’t know were at play.  

This is why the new checkpoint inhibitor compounds are so appealing.  They are designed to reset the balance within the tumour microenvironment and level the playing field for the immune system to fight tumours.  Without this rebalancing at the tumour level, cancer vaccines have struggled to successfully treat cancer.  With this rebalancing, we may be able to use cancer vaccines in more advanced cancer patients. From the failures in the field of cancer vaccine, we know that cancer vaccines when used as monotherapies cannot do anything meaningful to an established tumour.

That leaves two choices.  You can either utilize cancer vaccines in patients who do not have a lot of tumour bulk, those with minimal residual disease, where you’re trying to prevent micrometastases from occurring and delay progression.  Or you have to look at aggressive treatment combinations where you influence the tumour itself (checkpoint inhibitors) so it becomes more receptive to T cell infiltration (cancer vaccines). That is why you really need to consider a combination approach for effective cancer immunotherapy.

Do you see any major changes in the next 12 months within the vaccine landscape?

I think we’re on the cusp of some very dramatic things happening with cancer vaccines. The first step is the pharma industry rethinking the earlier stigma attached to cancer vaccines and recognizing the vast potential these treatments have in battling cancer.   I see this is already happening.  I’ve heard comments from some of the major pharmas that we need to throw away all our biases towards cancer vaccines and rethink about what makes sense to combine with our compounds, what are the right targets to go after, what’s the right vaccine design, what kind of clinical data is there to support the mechanism of action of these vaccines to give us confidence that we should jump in and try them.  There is a growing sentiment that the industry shouldn’t just assume that cancer vaccines are not going to work. The industry is beginning to acknowledge that these treatments have been used the wrong way, that we now know much more about cancer and how vaccines can impact the disease, and that we are now finally gathering convincing data to support that cancer vaccines may work, etc.

There is tangible evidence that this perception is starting to change. You’re seeing companies in early stage development doing combination trials with two vaccines, for example. We have been using metronomic low dose cyclophosphamide for some time, and I think we’re advertising cyclophosphamide very well to other companies.  In fact we’re seeing others use our regiment now, whereas a few years ago nobody was contemplating that approach.  And we’re starting to see biotech companies release intriguing clinical data. Aduro recently announced surprising clinical data in pancreatic cancer. Immunocellular reported a failure but one that included an interesting positive signal with progression-free survival.

The pharmas, GSK in particular, are marching on with their Phase III programs and they’re expecting to release data this year. So if GSK’s data comes back positive in any form, I think that will be a boost to the industry. Merck KGaA has recommitted to cancer vaccines and has positioned the class as one of the company’s top strategic areas of interest. Right now, there is so much momentum in immune therapy and the realisation that checkpoint inhibitors are probably going to be most effective if they’re combined with a cancer vaccine approach. Even if GSK failed, I don’t think the cancer vaccine industry is going to be set back very far. A failure could be attributed to the design of the vaccine, the fact that they’re not doing combination therapies – there are a lot of reasons why it might fail.  A failure with GSK’s vaccine might have some negative impact but I think people will look past it and see cancer vaccines as something we need to continue to look at aggressively.

There has been some concern among the general public about the safety and risk of vaccines. What positive steps can the industry take to improve public perception?

I think a lot of it could be attributed to a single researcher in the UK who was spreading a variety of false data on the association of vaccine preservatives and safety risks. So that has unfortunately caught on like wildfire and established a strong, yet inaccurate public perception.  This despite the fact that the researcher has been completely discredited, his papers have been pulled , and there’s been an education process to explain to the world that he was biased and his research was bogus and fabricated. Last year, I believe one of the leading scientific publications wrote an article covering the entire fiasco and attempting to correct the record publicly.  The article touched on one of the true tragedies of this scandal, namely that broad populations of people were not vaccinating their kids because they believed vaccines were risky.  This in turn resulted in some serious public health issues due to the non-compliance with vaccinations. It’s very unfortunate, because people forget what vaccines have done for humanity and how they’ve saved us from diseases like polio and smallpox. There’s no question in my mind that the benefit of vaccination outweighs any risk associated with those approved vaccines.

What was the last vaccine you had?


Dr Mansour is speaking at the 14th annual World Vaccine Congress where he will be delving further into this topic on March 25. For more information on the event taking place on March 24-26, please click here

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