From Human Oncology
Combining Radiation and Immunotherapies to Achieve In Situ Tumor Vaccination
T cell checkpoint inhibitors are a class of immunotherapies that modulate tumor tolerance among T cells and have demonstrated efficacy for many tumor types. Activation of an anti-tumor immune response is a complex process involving many immune cell lineages and, therefore, combinatorial targeted approaches seem likely to achieve cooperative effect. Illustratively, in some clinical settings dual checkpoint blockade is showing enhanced efficacy compared to single agent treatment, however increased toxicities are also encountered and these may limit further efforts to improve response through systemic immunotherapy combinations.
In situ tumor vaccination is a strategy that seeks to use local therapies to convert a patient’s own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify a systemic anti-tumor immune response without triggering toxicities associated with systemic immunotherapy administration. Radiation therapy may serve as a critical component of in situ vaccination by stimulating immunogenic cell death and release of tumor-specific antigens, phenotypic changes in surviving tumor cell immune susceptibility, and local eradication of suppressive immune cell lineages. We have identified a cooperative in vivo interaction between radiation and the immune response to local intra-tumor injection of tumor-specific antibody. This effect is enhanced with the combination of radiation and immunocytokine – a fusion of tumor-specific antibody and immune stimulatory cytokine, such as IL2 – resulting in complete regression of moderate sized tumors (~ 200 mm3) in most mice, limited toxicity, and a memory T cell response. In mice bearing larger tumors (~500 mm3) and micro-metastases, where combination of radiation and immunocytokine is no longer typically curative, we have observed improved animal survival and reduction in metastatic disease burden with the triple combination of local radiation and intra-tumor immunocytokine plus systemic T cell checkpoint blockade compared to dual combinations of these treatments.
Looking ahead, the research efforts of the Morris lab are focused on examining the mechanisms, pre-clinical testing, and clinical translation of treatment approaches that combine radiation and molecular-targeted therapeutics to drive anti-tumor immune response. The broad goal of this effort is to develop more effective, less toxic treatments for cancer patients. Preclinical studies demonstrate cooperation between radiation and checkpoint blockade and early phase clinical studies of such combinations suggest modest response. Preclinical studies of next generation strategies to augment response to checkpoint blockade are now warranted. In pursuit of this objective, our intention is to begin by using: 1) radiation to modulate the anergic tumor immune microenvironment and increase tumor susceptibility to immune recognition, 2) tumor-specific antibodies to enhance cell-mediated tumor destruction by NK and myeloid cells and antibody-facilitated antigen presentation by FcʏR-expressing cells, and 3) immune stimulatory cytokine to augment innate and adaptive immune responses - all for the purpose of eliciting in situ vaccination. Using in vitro, ex vivo, and in vivo methods in clinically relevant murine tumor models, we are exploring unique mechanisms and optimizing novel applications of this therapeutic strategy.