Immunotherapeutics is said to be the most likely field for the next major breakthrough in cancer. The first FDA-approved therapeutic cancer vaccine Provenge (Sipuleucel-T) recently made it to the market for treating prostate cancer, and many others have made their way to late phase trials, giving a sense of optimism to the field. Researchers expect new vaccines to be flooding through regulatory portals in the next decade.
Tumor cells are different from their normal counterparts in many ways, which would be expected to result in their immunological eradication. However, advanced tumors are highly immunosuppressive, giving the cancer the ability to avoid detection by the immune system. This combined with the importance of immune system at controlling and shaping developing tumors (“immuno-editing”) makes cancer a complex immunological disease and a challenging one to treat. It seems logical to treat such a disease with immunotherapeutics, that is, to teach the immune system to fight tumors. Only the immune system is so smart that it can find any cancer cell wherever it is in the body. Also, the fact that advanced tumors are highly immunosuppressive demonstrates that importance of the immune system in this context.
Viruses represent a masterpiece of natural selection and evolutionary fitness, and they can be used as a bioweapon against cancer. An important part of the mechanism of action of oncolytic viruses which kill tumor cells through lysis, i.e. breaking down the cell, relates to the immunogenicity of the phenomenon. This is especially true when viruses are armed with immunostimulatory molecules such as GMCSF, as with our lead clinical agent CGTG-102 (Ad5/3-D24-GMCSF). A big plus in these types of drugs is that they are usually not associated with life-threatening side effects and are well tolerated in comparison to most chemotherapeutics, for example. But even though understanding the mechanisms underlying tumor immunity has led to development of more efficient anti-cancer immunotherapeutics, a problem is that early phase clinical trials, including vaccine trials, tend to be in very late-stage disease. In this setting the immunosuppressive state of the tumors definitely has a negative impact on the treatment response. In addition, late stage cancer patients are often immunocompromised, and immunotherapy works best in patients with healthy immune systems. And the earlier the patient is treated, the smaller the tumor mass to be eradicated.
In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on advanced cancer. Recently, a number of clinical studies have reported clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. It is also noteworthy that the standard criteria used to define tumor response and progression may not adequately reflect patient responses to immunotherapeutic agents, since the responses can take a longer time than with traditional drugs. Also, immune response related inflammatory swelling can complicate tumor size measurements. Therefore, overall survival is expected to be a better endpoint in vaccine studies.
Rapidly accumulating clinical and immunological information enables rationale-driven vector design and improved treatment protocols. Given the recent advances and excitement in the field I expect it won’t be too long before some of the potential of oncolytic viruses as immunotherapeutics translate into clear-cut patient benefits.
Dr. Lotta Kangasniemi works as Resarch Director at Oncos Therapeutics, a biotech company developing novel cancer therapies based on its next-generation oncolytic viruses.