Therapeutic cancer vaccines have been penned as the future of cancer treatment. But thus far we have seen a number of high profile late stage failures of cancer vaccines. So what is causing these late stage drop-outs? Below we list just a few of the common reasons cited for the poor performance we have witnessed of many therapeutic cancer vaccines when it came to Phase III trials.
|Leaving it too late|
|Cancer vaccine trials have so far tended to employ patients in the advanced stages of their cancer. The problem this undoubtedly poses for developers is that cancers can supress the immune system, and so the longer a patient has had cancer, the weaker their immune system may well be. Whilst the obvious answer may be to use patient samples with cancers at earlier stages, this poses a challenge when it comes to the planning times and the length of trials, not to mention that early stage patients are less likely to have been diagnosed and so available for trial participation.Along the same lines, late stage cancer patients are likely to have undergone some variety of chemotherapy which will have seriously impeded the immune system capabilities of those who received the treatment. This of course will limit any potential immune response the patient may exhibit as a result of the vaccine.|
|The wrong cancer|
|Many of the early disappointments came from vaccines targeting Melanoma (such as GSK’s MAGE-A3 and Vical’s Allovectin), perhaps this was due to a lack of effective treatment for melanoma patients, a high mortality rate among patients who are not diagnosed early, and because of spontaneous remissions noted to have taken place which perhaps indicate an immune response to the skin cancer.The problem is that melanoma are fast changing cells which can mutate faster than vaccine can initiate an effective immune response. It takes time for patients to develop an immune response, and with melanoma, as well as many other cancerous cells, able to mutate quickly, it is possible that the vaccines are being out paced by the cancer.|
Unhealthy immune systems
|Research performed by GSK during the development of MAGE-A3 in phases II and III showed that the health of a participant’s immune system affects the effectiveness of the vaccine. If we take suggestions of patient selection bias seriously for single-arm phase II studies, we can suggest that the immune systems of the generally healthy phase II participants produces a better response to the cancer vaccine than will be found amongst a randomly selected phase III patient pool.|
|Adjuvants: getting in the way?|
|Adjuvants are a staple in the majority of vaccines. Designed to in one way or another adjuvants stimulate the immune system to respond to a particular antigen.But a number of studies have shown that the commonly used incomplete Freund’s adjuvant (IFA) may actually be hindering the performance of cancer vaccines. Researchers found that T-cells, once stimulated, were congregating around the site of the injection where the non-biodegradable IFA lingers. After replacing IFA T-cells began to move towards the cancer cells without being held up at the injection site.
There was also the case of Megvax trial in melanoma which resulted in a disastrous Phase III after developers changed the adjuvant to one they believed would outperform the one used for their phase II trial.
|Against a backdrop of high profile cancer vaccine failures in stage three, as well as other treatments failing to gain approval, perhaps investors are right to have been a little conservative. But it is possible that this has led to a number of cancer vaccines being dropped in phase III trials due to a mere hint at ineffectiveness.For example, Angus Dalgleish, Professor of Oncology at St George’s Hospital, London, and founder of the UK Cancer Vaccine Institute and the vaccine biotech company Onyvax, believes that his prostate cancer Onyvax could well have performed better than Dendreon’s Provenge treatment had investors had the confidence to set store in the predicted nine-month survival rates. Instead, investors pulled the plug after Onyvax produce only similar results to Provenge.|
Down but not out…
Despite what may be seen as a long list of problems, researchers are already on their way to producing more advanced and efficient vaccines. Relatively, it is still early days for cancer vaccines and crucially developers are identifying new ways to improve the effectiveness of their vaccines.
Next week we will be looking at the future of cancer vaccines, and one things seems very clear: it’s not the theory that to blame, it’s the environment that needs to be changed.