Skeptics may doubt the ability of pharma and biotech to develop an effective therapeutic cancer vaccine and can point to a long history of unsuccessful attempts, including the recent demise of the prostate cancer vaccine, PROSTVAC, which failed to demonstrate an improvement in overall survival compared with placebo. Some are even calling for a halt to investments in such efforts. Those critics would be remiss, however, to overlook recent advances in the field of immunotherapy that show tremendous promise toward bringing about a successful cancer vaccine in the near future.

Vaccines have been extremely successful in the prevention of diseases of viral origin, such as smallpox and hepatitis B. Unlike these prophylactic vaccines, which are generally administered to healthy individuals, therapeutic cancer vaccines are designed to eradicate cancer cells by bolstering the patient’s own immune responses.

The therapeutic cancer vaccine arena has been littered with late-stage failures such as PROSTVAC and NewLink Genetics’ pancreatic cancer vaccine, which not only failed to prolong survival, but may have curtailed it. Still, immunotherapy offers new hope.

Why past attempts have failed

Cancer grows continuously in the body, wreaking havoc on the immune system. Consequently, the body milieu of patients with cancer is very different than that of healthy individuals, rife with immunosuppressive elements that prevent them from responding briskly to vaccines. Immune system optimization is essential for finding, recognizing, and eliminating cancer cells. To unleash the latent power of the immune system in patients with cancer, it is important to both boost natural cancer-killing capabilities and degrade immune inhibitory processes that enable immune escape.

For cancer to be treated with a truly targeted approach, we must also enhance specific tumor trait recognition. Given its complexity, cancer needs to be treated with multiple therapies that counteract the mutational and externally induced survival traits of cancer cells.

Despite decades of research, most attempts at developing effective cancer treatment vaccines have failed at producing potent antitumor immune responses. One reason for the failure is that vaccines have generally been made with tumor antigens that are too similar to antigens on normal cells, leading to a process called immune tolerance where the body generates a weaker immune response to avoid harming normal cells. Advancements in genome sequencing have made it easier and more cost-effective to study antigens that are specific to cancer cells. These “neoantigens” open the door to promising personalized cancer vaccines.

Over the past 10 years, we have also seen a geometric increase in our knowledge of the immune system, tumor immunology, and the tumor microenvironment. We know that the inhibition of rapidly developing survival-benefiting mutations in cancer cells is critical to slowing cancer cell growth and triggering apoptosis, and that activation and targeting of the immune system may be essential to a cure. These advances have led to the development of immune checkpoint inhibitors and other immunotherapies that change the immunosuppressive milieu in the cancer patient. These therapies have revolutionized the treatment of cancer and are poised to breathe new life into the development of effective therapeutic cancer vaccines.

Critical success factors for developing a therapeutic cancer vaccine

With their renewed interest in the development of therapeutic cancer vaccines, pharma and biotech companies should consider the following factors to maximize the chances for success:

1. Develop a combination therapy. Slot cancer vaccines into combination regimens where each component addresses a different element of the disease. Cancer vaccines can take a long time to become effective within the body. However, if given as part of a combination therapy, where another therapeutic agent helps bring the disease under control, cancer vaccines could play a cleanup role. Currently, there are dozens of combination trials pairing cancer vaccines with immune checkpoint inhibitors or other immunotherapies, including studies sponsored by top cancer drug makers such as Merck, Bristol-Myers Squibb, and AstraZeneca.

2. Choose the right population. Selecting the tumor type and stage most likely to respond to a cancer vaccine is critical. Often, investigative cancer vaccines work, but just not well enough to satisfy the regulatory requirements for approval. One strategy is to select a disease for which there are no approved therapies, enabling a study design with no comparators.

Consider the example of venetoclax (Venclexta™), which was approved in April 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a 17p depletion and who have been treated with at least one prior therapy. Approval was based on a subset cohort of only 31 subjects with 17p depletion among the 106 total patients enrolled in a single-arm study. Venetoclax has since received multiple Breakthrough Therapy Designations for additional indications in both CLL and acute myeloid leukemia.

3. Think from a precision medicine perspective. An emerging area of cancer vaccine research involves neoantigens. Because they are cell surface molecules produced by DNA mutations present in cancer cells but not in normal cells, neoantigens may be better targets for immune therapy. In principle, neoantigen vaccines can potentially overcome two major obstacles in cancer therapy: the heterogeneity of tumors and off-target effects.

Recently, a study published in Nature provided proof-of-principle that a neoantigen vaccine tailored to a patient’s tumor can generate highly specific immune antitumor responses in melanoma patients. The vaccines used in this Phase I trial contained up to 20 neoantigens derived from an individual patient’s tumors. These study results warrant further development of neoantigen vaccines, both alone and in combination with other weapons in the immunotherapy arsenal.

Despite its struggles, the quest for cancer vaccines is finally turning the corner. The convergence of advances in cancer genome sequencing with our understanding of tumor immunology is bringing into focus the potential of personalized cancer therapy, and we are much closer now to achieving an effective therapeutic cancer vaccine than ever before.

Gerry Messerschmidt, M.D., FACP, is chief medical officer at Precision Oncology.

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