THE ELUSIVE CANCER VACCINE
Cancer vaccines have long been elusive, like unicorns, the fountain of youth, and calorie-free chocolate. But the emergence of a new crop of biotech companies makes it clear that a cancer vaccine is no myth. The latest advances in genomics have enabled scientists to focus on developing vaccines that train our bodies to recognize and fight an established tumor. In this article, we break down the science and technology of immunotherapeutic vaccines.
IMPORTANT TERM: NEOANTIGEN
An antigen is a protein (or portion thereof) that our immune system recognizes. Think of antigens as signal flags; some flags mean “all good,” and some signify “bad news.” An immune response occurs when attack cells, such as macrophages and cytotoxic T-cells, encounter a flag that spells trouble. The best-case scenario involves our immune system recognizing, targeting, and killing the cells displaying a bad antigen. In the worst cases, problematic cells evolve strategies to remain hidden from our immune systems. The ability of cancer to “disguise” itself with good antigens makes it possible for some cancers to go undetected until very late stages.
As a tumor grows, it can accumulate additional mutations. Scientists have found that some mutations produce new antigens that the immune system can recognize. These neoantigens are the secret sauce in cancer vaccines.
A precipitous DNA mutation rate is a hallmark of cancer cell development. Once a tumor establishes itself, it may produce dozens, even hundreds, of mutations that differentiate it from healthy cells. Identifying specific mutations is the first step toward creating a neoantigen vaccine. The whole process begins with a biopsy to collect tumor cells for study. Thanks to advances in genome sequencing technology, researchers can rapidly sequence the tumor’s entire exome—the portion of DNA that makes proteins. Since only the exome produces antigens, it provides the key to revealing the neoantigens’ distinctive characteristics. Scientists then compare tumor exomes to healthy cells to ferret out differences in the DNA sequences.
Not all proteins make good antigens. The most useful in terms of cancer therapy are displayed on the cell surface, where the immune system can get at them. To identify cell surface neoantigens, researchers feed their uniqueto-cancer DNA sequences into bioinformatics programs that predict surface location probability. Typically, around five percent of the mutated genes represent potential neoantigens.
The most promising neoantigens get synthesized in the lab and mixed with an adjuvant — a substance that boosts overall immune response. Research has shown that neoantigen-based vaccines with at least 20 different neoantigens are most likely to both prompt a strong immune response and reduce the likelihood of resistance. The multi-pronged approach stems from the fact that while a tumor may mutate and stop producing one neoantigen, it’s unlikely to stop producing several simultaneously.
Sometimes, several different patients share common neoantigens. In other cases, effective antigens may be unique to a single individual. Imagine a vaccine developed for just one patient. Now that’s truly personalized medicine. Such precision was unthinkable even just a few years ago. It’s possible now because genome sequencing has yielded tremendous efficiencies in both time and money.
Many companies are already conducting clinical tests of neoantigen-based vaccines. Currently, it takes about six to 12 weeks to identify neoantigens and produce a vaccine. Industry-wide, the goal is to reduce development time to one month. Here are some of the key players and their products:
- Marker Therapeutics (Houston, TX) is currently in Phase II studies for a neoantigen-based vaccine (TPIV 200) for triple-negative breast cancer. This strain is the most treatment-resistant type of breast cancer.
- Neon Therapeutics (Cambridge, MA) is testing a melanoma and glioblastoma neoantigen vaccine, NEO-PV-01, in Phase III clinical studies in combination with Bristol-Myers Squibb’s (New York, NY) approved checkpoint inhibitor therapy Opdivo.
- Gritstone Oncology (Emeryville, CA) has neoantigen-based vaccines in Phase I/II clinical trials for non-small cell lung cancer.
The success of just one of these companies will usher in a new era of truly personalized medicine.
EASILY CONFUSED: PREVENTIVE VACCINE VS. THERAPEUTIC VACCINE
The Gardasil (Merck; Kenilworth, NJ) and Cervarix (GlaxoSmithKline; London, U.K.) vaccines for human papillomavirus (HPV) are often referred to as “cancer vaccines.” This is because they prevent HPV infection, the leading cause of cervical cancer. In other words, they are preventive vaccines. Neoantigen vaccines are therapeutic vaccines to help fight specific cancer that has already emerged.