August 1, 2008
Oncology.
No. 9
Synergizing Radiation Therapy and Immunotherapy for Curing Incurable Cancers
Opportunities and Challenges
James W. Hodge, PhD, MBA
Senior Scientist
Director, Recombinant Vaccine Group
Laboratory of Tumor Immunology and Biology
Center for Cancer Research National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Chandan Guha, MB, BS, PhD
Associate Professor
Department of Radiation Oncology
Vice Chairman
Department of Radiation Oncology
Albert Einstein College of Medicine
Bronx, New York
Jacques Neefjes, PhD
Head, Tumor Biology Division
The Netherlands Cancer Institute
Amsterdam, The Netherlands
James L. Gulley, MD, PhD, FACP
Senior Clinician and Director
Clinical Immunotherapy Group
Laboratory of Tumor Immunology and Biology
Center for Cancer Research National Cancer Institute
National Institutes of Health
Bethesda, Maryland
The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics. Evidence suggests that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (eg, radiation) later in the disease process. Indeed, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. As monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in crosspriming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research. This review examines mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses as well as preclinical systems demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy.
Radiation is often considered immunosuppressive, an activity that is most likely a result of the complex interplay of hormesis and the abscopal effect. The abscopal effect, also called the “distant bystander” effect, is a paradoxical effect of radiation on cellular systems whereby local radiation may have an antitumor effect on tumors distant from the site of radiation.[1] Indeed radiation’s ability to enhance distinct immune responses by inducing a “danger” signal that excites and activates the immune system has recently come under investigation. In the context of tumors, radiation has been hypothesized to cause tumor disruption and a type of “danger” signal that could be successfully exploited to improve the effectiveness of immunotherapy.[2]
Radiation therapy is conventionally used for local tumor control. Although local control of the primary tumor can usually prevent development of subsequent systemic metastases, tumor radiation fails to control preexisting systemic disease, which may be present only as micrometastatic (and therefore undetectable) deposits. Combining radiation therapy with immunotherapy allows one to exploit two broad areas: (1) radiation-induced tumor-cell death as a potential source of tumor antigens for immunotherapy, and (2) postirradiation tumor-cell modulation that allows more efficient immune-cell access and increased sensitivity to T-cell killing. These tumor-specific T cells could arise endogenously or be induced from active vaccination strategies.
Many clinical trials exploring the use of radiation and vaccines in the treatment of cancer are currently underway. As knowledge of the synergistic effects of radiation and immunotherapy increases, the translational use of this strategy for a variety of carcinomas will become more feasible.
