In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer

Abstract

Radiation has long been the standard of care for many types of cancer. It is employed to locally eradicate tumor cells as well as alter tumor stroma with either curative or palliative intent. Radiation-induced cell damage is an immunologically active process in which danger signals are released that stimulate immune cells to phagocytose and present locally released tumor-associated antigens (TAAs). Recent studies have indicated that radiotherapy can also alter the phenotype of cancer cells that remain after treatment. These cells upregulate TAAs as well as markers, including major histocompatibility complex and costimulatory molecules, that make them much more immunostimulatory. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. This review highlights preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.

308 Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

“…Enzalutamide and abiraterone are FDA-approved for ADT in patients with metastatic CRPC. Both enzalutamide and abiraterone have been evaluated in numerous clinical trials that resulted in improved overall survival in patients with metastatic CRPC [4][5][6]9].…”

“…Immunogenic modulation describes a cascade of phenotypic and molecular events occurring when conventional therapies alter the phenotype of tumor cells, rendering them more susceptible to immune-mediated attack [9]. The molecular mechanisms of immunogenic modulation include a) changes in the surface phenotype of cancer cells, including exposure of calreticulin on the outer leaflet of the plasma membrane, b) downregulation of antiapoptotic and/or prosurvival genes, and c) modulation of components of the APM [17][18][19][20][21][22][23].…”

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…Quite from various trials it results that radiation focused on the tumor can convert it into in situ tumor vaccine by implying antigen release at tumor cell death, so synergically acting with immunotherapy to enhance anticancer immune responses through additively triggering the activation of prostate cancer specific T-cells (13,72). Indeed, radiation can activate the major histocompatibility complex (MHC) upregulation together with the cancer cell surface antigen expression and, moreover, radiation-induced both DNA damage and ROS (reactive oxygen species) development may lead to tumor cell death as well as to significant proliferation of tumor specific antigen-correlated T-cells.…”

“…Ipilimumab, as a fully human IgG1k-based anti-CTLA-4 mAb -the first immune check point blocker taking role in oncology clinical trials -has been used either alone or in combination with conventional therapies (ADT, radiation, chemotherapy) in several clinical trials for metastatic castration-resistant prostate cancer (mCRPC) patients, it resulting a significant decrease in PSA serum levels (4,5,11,12). Moreover, from a trial concerning combination therapy of T-cell check point modulator ipilimumab with EBRT it was followed that the radiation exposure, besides not inducing immunosuppressive effects, can, instead, synergically act with ipilimumab to effectively increase the antitumor immune response (4,5,(11)(12)(13).…”

Enhancing the Efficacy of Radiation Therapy: Premises, Promises, and Practicality

“…Radiation can stimulate an immunologic response. [17][18][19] The use of radiation as part of immunotherapy is of intense interest on the basis of vaccine studies 20,21 and the striking demonstration of the abscopal effect with radiation plus immune modulation. 22 Damage produced in one cell can induce changes in its neighbors, a concept called nontargeted or bystander effects.…”