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The Elusive Cancer Vaccine

The promise of cancer vaccines have proven to be elusive. A new crop of biotechs are hoping to change that by taking advantage of the latest advances in genomics. Scientists are working overtime trying to develop cancer vaccines that train the immune system to recognize and fight an established tumor. In this WEEKLY, we’ll break down the science and technology of immunotherapeutic vaccines.

Term Of The Week: Neoantigen

An antigen is a protein or portion of a protein present in a cell that is recognized by the immune system. Think of antigens as flags; some flags are “good” and some flags are “bad.” An immune response occurs when attack cells, such as macrophages and cytotoxic T-cells, encounter a “bad” flag. The best case scenario: cells waving the “bad” flag or antigen are recognized, targeted and killed.  Worst case scenario: cells waving the “bad” antigen have evolved strategies to operate in stealth mode. This cloaking mechanism is often used by cancer — it is the reason why it can be a silent disease until the very late stages.

As a tumor grows, it can accumulate additional mutations (changes in the DNA). Scientists have found some of these mutations are significant enough to produce new antigens which the immune system can recognize. These are called neoantigens, and they are the secret sauce in cancer vaccines.

Finding Neoantigens

One of the hallmarks of cancer cell development is a high rate of DNA mutation. Once a tumor is established, it may grow to have dozens or even hundreds of mutations that differentiate it from healthy cells. Identifying these cancer mutations begins with performing a biopsy to collect and study a small sample of tumor cells. Thanks to advances in genome sequencing technology, researchers can sequence the tumors entire “exome”— the portion of the DNA used to make proteins. Since only the exome is used to produce antigens, scientists look only at the exome to identify neoantigens. Tumor cell exomes are then compared to healthy cell exomes, and the differences in DNA sequences are identified.

It turns out not all proteins make good antigens, the best are those displayed on the cell surface where they can be recognized by the immune system. In order to identify cell surface neoantigens, the “unique to cancer DNA sequences” are fed into bioinformatics programs which predict the probability of surface location. Typically around 5% of the mutated genes are potential neoantigens.

Training The Vaccine

Once neoantigens are identified, they are synthesized in the lab and mixed with an adjuvant — a substance that boosts the overall immune response. Ideally, a neoantigen-based vaccine contains at least twenty different neoantigens, both to produce a strong immune response and to reduce the likelihood of resistance. A tumor may mutate and stop producing one neoantigen, but it is unlikely to stop producing several simultaneously.

Although in some cases, several different patients may share common neoantigens, others may be unique to a given patient. So it is likely that these types of cancer vaccines would be truly personalized medicine — designed just for one patient. This type of precision was unimaginable even just a few years ago, but is possible today because of the increased efficiencies in both time and money achieved with genome sequencing.

The Game Changers

Several neoantigen-based vaccines are already in clinical testing. Currently, the time taken to identify neoantigens and produce a vaccine is around six to twelve weeks; the goal is to bring this development time down to one month. Key players include:

  • TapImmune (Jacksonville, FL) began Phase II clinical studies for a neoantigen-based vaccine (TPIV 200) for triple-negative breast cancer, the most difficult type of breast cancer to treat using today’s therapies. TPIV 200 will be tested in combination with AstraZeneca’s (London, UK) durvalumab, a checkpoint inhibitor currently in Phase III clinical testing.
  • Neon Therapeutics (Cambridge, MA) is testing its melanoma and glioblastoma neoantigen vaccine, NEO-PV-01, in Phase Ib clinical studies in combination with Bristol-Myers Squibb’s (New York, NY) already approved checkpoint inhibitor therapy Opdivo.
  • Gritstone Oncology (Emeryville, CA) and Immune Design (Seattle, WA) have a partnership to discover and develop neoantigen-based vaccines, with clinical trials for a non-small cell lung cancer product expected to begin in 2017. Patients in the trial will be treated with a neoantigen vaccine in combination with an as yet unnamed immune-checkpoint inhibitor. Checkpoint inhibitor treatments relieve the natural inhibitions on cytotoxic T-cells, enabling the immune system to become fully activated in response to the vaccine.

If any of these companies succeed, we will be witness to truly personalized medicine at work.

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