Abstract
Memorial Sloan Kettering Cancer Center has teamed up with biotechnology company Advaxis to explore development of neoepitope-based immunotherapies. The partnership is just one of several such ventures in a promising area of research that uses advanced sequencing technology to customize vaccines based on altered proteins in individual patients' tumors.
New York, NY's Memorial Sloan Kettering Cancer Center (MSKCC) recently teamed up with biotechnology company Advaxis (Princeton, NJ) to investigate neoepitope-based immunotherapies. It is one of several ventures focused on developing personalized cancer vaccines that might be effective in shrinking tumors, alone and in combination with other therapies.
Neoepitopes are the mutated proteins produced by a patient's own tumors; neoepitope vaccines target these patient-specific proteins. In contrast, other vaccines have typically targeted self-antigens associated with distinct tumor types, such as prostate-specific antigen. The new vaccines effectively immunize patients against their own unique array of neoepitopes, driving the immune system to attack and kill cancer cells.
Preclinical studies are testing such vaccines alone and in combination with other immunotherapies, using high-throughput sequencing to identify mutations. The vaccines hold potential to enhance the effectiveness of checkpoint inhibitors and costimulatory molecules, which have been shown to work in some patients but not others. Drugs that inhibit the CTLA-4 or PD-1/PD-L1 pathways, for example, free up blocked T cells to multiply and attack the mutated tumor proteins.
“With the availability of high-throughput genomic sequencing and its applications, like whole-exome sequencing, we can now ask in a meaningful way what genetic changes in a tumor are being recognized by the immune system,” says Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service in the Department of Medicine at MSKCC. “We're now beginning to identify what mutations are or are not interesting to the immune system, and with that knowledge, beginning to create vaccines that encompass those mutated areas of the protein.”
Wolchok also works with Cambridge, MA–based Neon Therapeutics, which is among a handful of companies currently investigating neoepitope-based therapies. Others include Moderna Therapeutics, also in Cambridge; San Francisco, CA–based GritStone Oncology; and Dallas, TX–based Precision Biologics.
Advaxis developed its vaccine using bioengineered live attenuated Listeria monocytogenes (Lm) bacteria to deliver multiple antigens based on mutations in a patient's tumor.
“The vaccine effectively reteaches the immune system to view the tumor as a bacterially infected cell,” says Daniel O'Connor, CEO of Advaxis. “We are not targeting a generic cancer antigen which may or may not be present in a particular tumor but instead interrogating a specific patient's tumor, defining what mutations are translated into altered proteins, and using those as the targets for immunotherapy.”
Lm, a gram-positive bacterium, is a promising vaccine vector because it has a unique ability to present antigen targets from within dendritic cells and generate T cells that target these antigens. Generating T-cell responses against the neoepitopes focuses the immune attack on cancer cells and not normal cells, potentially lowering the risk of toxicity, says Wolchok. Because the bacteria activate the immune system via multiple pathways, they evoke a strong immune response.
Loading a single vaccine with hundreds of antigens based on mutations in a patient's tumor increases the chances of a robust immune response, says Robert Petit, PhD, Advaxis's chief scientific officer. As a result, researchers can observe which mutations incite an immune system response instead of trying to predict which ones are important.
Another advantage of the Advaxis approach is that patients can be treated multiple times to restimulate the immune system, if necessary, he adds.
“This allows us to keep chopping away at cancer until it's gone,” says Petit. “A system directed against neoepitopes could be a real game changer in the way cancers can be treated, and combining that with the enhancing power of checkpoint inhibitors and potentially costimulatory molecules may really allow us to personalize immunotherapy treatment against an individual's own cancer.” –Janet Colwell
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