Cancer is predominantly a disease of aging caused by genomic instability. Finding effective ways to prevent and treat cancer is therefore of great interest to those working in the field of aging research as well as those working in oncology.
Therapies that target combinations of neoantigens, distinctive markers on the surface of cancer cells that the immune system learns to identify, is one potential approach to treating cancer. These neoantigen combinations vary between one patient and another and this is the focus of a new study which we will talk about today.
Immunotherapy is an approach to cancer treatment that seeks to make the immune system better at detecting and destroying cancer. This has the advantage over traditional drugs in that there should be fewer side-effects from using the body’s own defences to fight cancer.
The researchers in this new study have reported the results of an early stage human trial testing neoantigen vaccines in melanoma patients, and the initial results do show promise. In particular the lack of any serious side-effects are indeed encouraging, though more robust testing is needed to confirm its ability to reduce tumors.
Most therapies are based on a one-size-fits-all model of medicine, but it has been known for a long time that tumors are different in each patient. With recent advances in technology, it is increasingly more plausible to create therapies that are tailored to an individual and their unique tumor.
In the study researchers used vaccines that contained up to 20 neoantigens in this phase 1 clinical trial which we derived from the patient’s tumor. The vaccines were given to patients to help train their immune systems to learn to recognize these particular neoantigens, the idea being to stimulate the immune system to seek and destroy cancer cells with these neoantigens.
There are other immunotherapy approaches, such as checkpoint inhibitors, that also trigger an immune response against cancer neoantigens but these are not patient specific. They can sometimes cause an immune response against normal healthy tissue antigens leading to the immune system attacking normal cells.
This new custom approach saw that the vaccine caused a focused response against several cancer neoantigens by T cells, beyond that which is normally observed in other immunotherapies.
A small phase 1 human trial
The researchers ran a small clinical trial where the vaccine was administered to six patients with melanoma whose tumors had been surgically removed but were considered at high risk of relapse.
The vaccinations were given 18 weeks after surgery and by 25 months four of the six patients showed no recurrence of cancer. Two patients, who had cancer spread to their lungs prior to treatment had a recurrence after vaccination.
The researchers treated these two patients with the drug pembrolizumab, an inhibitor of the PD-1 immune checkpoint. As a result both patients saw a complete resolution of their tumors and remained free of the disease. This suggests the therapy can be combined with other treatments to boost its effectiveness.
Overcomes two major challenges for treating cancer
The findings of the study suggests, a personalized neoantigen vaccines could be used to overcome two major challenges in cancer treatment.
The first challenge is the highly individual and varied nature of tumors, known as heterogeneity, no two tumors are alike and this is why cancers can often evade traditional drugs that use an one-size-fits-all approach.
This is especially so with drugs that target single genetic abnormalities in cancer cells which may or may not be present in all cancers and thus why some cancers do not respond to certain drugs and even vary between individuals.
Because the vaccine has a number of different neoantigens from a tumor it is able to target multiple genetic types of tumor cells. This results in a better outcome as the immune system is encouraged to detect and attack multiple target antigens increasing its utility.
The second challenge is encouraging an immune response that is focused only on the cancer cells and that does not target normal healthy cells and tissues. The vaccine appears to have achieved this by having few off-target effects.
A few minor side effects were observed such as flu-like symptoms, fatigue, rashes and some irritation at the injection site. This is hardly a problem when you consider its effect on cancer.
Decades of failures
Despite the many decades of research efforts attempting to create effective cancer vaccines, these have mostly failed to produce good antitumor immune responses. The researchers in this study believe this is because these vaccines have generally used antigens that are too similar to those found on healthy cells. As a result the immune response is much weaker to avoid harming normal cells, a process known as immune tolerance.
In direct contrast to this, the neoantigen vaccine the researchers have used here is customized to each patient and uses the antigens present in the unique mutations found in that patient’s cancer and that are only present in those cancer cells. This means the treatment is able to bypass the natural immune tolerance system that normally reduces other approaches effectiveness.
Creating the vaccine
The vaccines are custom made by taking samples from a patient’s tumor along with normal DNA from their blood. The samples are then sequenced to identify mutations that are only present in the cancer cells compared to healthy cells.
Immune T cells only identify neoantigens that are “presented” to them by HLA molecules of the immune system as we discuss here. The researchers used computer algorithms to predict which neoantigen peptides would bind to the HLA molecules so that T cells would detect them. They used this method on the six patients tumor samples and discovered dozens of unique neoantigens, this then allowed them to create a customized vaccine for each of them.
The final step in the process was to synthesize the neoantigen peptides from the cancer cells and mix them with an adjuvant – a substance that triggers the immune response. This finished vaccine was then administered to the patient in a series of doses.
The researchers monitored the vaccine’s effect on the immune system and discovered that the T cells in the immune system indeed been activated by the vaccine and could recognize the neoantigens presented to them.
Perhaps most interestingly, many of the T cells we also able to detect the tumor cells directly, showing the vaccine had induced a tumor-specific immune response. This means that the immune system would attack the cancer cells directly and leave healthy cells alone.
The researchers are now moving towards launching a larger trial of the vaccine with greater numbers as you would expect during the clinical trial process. They plan to test the therapy in patients with more advanced cancer stages and plan to refine the process of predicting antigen presentation to boost the number of effective neoantigens they can target. They are also planning to further test the vaccine for synergy with other immunotherapeutics.
Should this approach pan out in the following clinical phase it has the potential to be made into a custom vaccine to be used to treat any cancer that has enough unique neoantigens. Obviously this initial human trial was small and so we should be positive but also remain grounded at the same time.
Needless to say, if this does prove effective then this would be a huge step towards bringing cancer under effective control and also aging. If we are to have any hope of living healthier and longer lives through medical advances then a solution to cancer must be found.
Here’s hoping that the researchers enjoy continued success in bringing an effective cancer vaccine to the world.
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 Patrick A. Ott, Zhuting Hu, Derin B. Keskin, Sachet A. Shukla, Jing Sun et al. (2017). An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, doi:10.1038/nature22991