[co-authors: Dan Meckley, Preston Tran, and Heather Hatcher, Ph.D.]
Photo by National Cancer Institute on Unsplash
Innovative technologies are being deployed to address the Western world’s major killer: cancer. Traditionally, cancer treatment has included surgery, chemotherapy, and radiation, but recently, the development of targeted immunotherapies such as monoclonal antibodies and immune checkpoint inhibitors (e.g., PD-1, PD-L1 and CTLA-4 inhibitors) are showing considerable promise in immunooncology.
The fields of immunology and oncology have been linked since the late 19th century, when studies showed that killed and denatured bacteria injected into sites of sarcoma (a tumor that starts in the bone or muscle) resulted in tumor shrinkage. The intersection between immune surveillance and tumor biology has led to broad therapeutic advances, including the search for a cancer vaccine.
Traditional prophylactic vaccines work to prevent disease by preparing the body’s immune system against a pathogenic infection such as influenza or polio. Over the last decade, the US Food and Drug Administration (FDA) has approved prophylactic vaccines that prevent development of cancer by protecting against cancer-causing pathogens such as human papillomavirus (HPV) (GARDASIL ®9; Merck Sharp & Dohme Corp., Whitehouse Station, NJ) and hepatitis B virus (HEPLISAV-B®; Dynavax Technologies Corp., Emeryville, CA).
A cancer vaccine is a therapeutic vaccine that targets pre-existing tumors in cancer patients who have a fundamentally different immune response relative to that of healthy individuals. Cancer is characterized by an accumulation of genetic alterations, and every tumor has its own unique composition of mutations and novel surface antigens, or neo-antigens, with only a small fraction shared between patients. Not surprisingly, therapeutic vaccines have been challenging to develop; however, tumor neo-antigens present an antigenic target for pharmaceutical companies to design and develop cancer vaccines.
Within the past several years, there has been an explosion in early-stage clinical activity in gene-modified and cell-based immunooncology, which now encompasses about 58% of Phase I trials. The FDA’s Center for Biologics Evaluation and Research (CBER) provided sponsors with guidance on Clinical Considerations for Therapeutic Cancer Vaccines (October 2011) to determine optimal dosing, potential biological and clinical activity, and safety profile during early phase clinical trials, as well as endpoint selection in late phase clinical trials to support a subsequent Biologics License Application (BLA) for marketing approval. Many trials have shown potent therapeutic responses in a proportion of patients with late stage cancer, but it has been rare for trials to obtain more than a 5–10% partial or complete response. However, this limited success has not lessened the enthusiasm for development of potential cancer vaccines. In 2019, there were nearly 700 oncology clinical trials utilizing specific regenerative medicine and advanced therapy technologies to treat leukemia, lymphoma, and cancers of the brain, breast, bladder, cervix, colon, esophagus, ovaries, pancreas and others (ARM 2019 Annual Report, https://alliancerm.org/sector-report/2019-annual-report/). The 2010 FDA approval of the first cancer vaccine (Provenge (sipuleucel-T); Dendreon Corp., Seattle, WA), was supported by clinical trials showing that the vaccine prolongs survival in patients with metastatic, castration-resistant prostate cancer, though the effect was modest. In 2015, the FDA approved a therapeutic cancer vaccine for the treatment of advanced melanoma (IMLYGIC or T-VEC, talimogene laherparepvec; Amgen, Thousand Oaks, CA).
Despite the challenges, each translation of cancer vaccines to the clinical setting has yielded a deeper understanding of the immunologic response produced by cancer.
Several platforms for cancer vaccination are being tested, including peptides, proteins, antigen presenting cells, tumor cells, and viral vectors. Prior clinical trials have shown that cancer vaccines are well tolerated, target tumor neo-antigens and induce antigen cascade. Current trials seek to improve cancer vaccine efficacy either by targeting novel tumor antigens or employing vaccines in combination with other therapeutic approaches. Additionally, provisions in the 21st Century Cures Act have allowed the FDA to use an accelerated approval pathway for cancer vaccines that have been designated as “regenerative medicine advanced therapy” (RMAT).
Cancer vaccination comprises an array of approaches that seek to generate, amplify, or skew (or a combination thereof) antitumor immunity. Cancer immunotherapy may ultimately establish its position as the fourth pillar of anti-cancer therapy, complementing surgery, chemotherapy, and radiation.