Bhadrasain Vikram

Flt3L Therapy following Localized Tumor Irradiation Generates Long-Term Protective Immune Response in Metastatic Lung Cancer: Its Implication in Designing a Vaccination Strategy

Flt3 ligand (Flt3L) therapy that expands dendritic cells in vivo in combination with local tumor radiotherapy (RT) significantly improved survival and induced a long-term tumor-specific immune response in a murine model of Lewis lung carcinoma (3LL). The irradiated tumor cells were able to significantly restimulate the splenocytes of the RT + Flt3L cohort in vitro. The restimulated splenocytes demonstrated increased cytotoxic response, lymphocytic proliferation and elevated levels of Th type I cytokines (IL-2, IL-12, IFN-γ and TNF-α). The combination therapy of RT + Flt3L induced a long-term protective immunity in the disease-free animals. The protective effect was further enhanced when the disease-free animals were vaccinated with irradiated tumor cells. The vaccinated animals had significantly greater protection compared to the nonvaccinated group against subsequent challenge with 3LL cells. Taken together, these results indicate that the release of tumor antigens by irradiated dying tumors and concomitant administration of Flt3L was able to facilitate the generation of a tumor-specific long-term immune response against a poorly immunogenic tumor. This effect was further boosted by vaccination with irradiated tumor cells.

Harnessing the Potential of Radiation-Induced Immune Modulation for Cancer Therapy

The conventional use of radiotherapy is for local tumor control. Radiotherapy of the primary tumor can prevent the development of distant metastases, but this modality is generally not effective for treating preexisting systemic disease. However, radiation-induced tumor destruction may be considered a novel strategy for in situ cancer vaccination, in which tumor antigens released from dying tumor cells may be presented in an immunostimulatory context. Moreover, radiation has been demonstrated to induce immunogenic modulation in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell–mediated killing. Finally, radiotherapy typically has a favorable toxicity profile and is associated with the absence of systemic immunosuppression. Together, these properties suggest that radiotherapy may serve as an important component of combinatorial immunotherapies aimed at augmenting systemic antitumor immunity. Here, we provide an overview of the radiation-induced modulations of the immune system that may be harnessed for cancer therapy. Cancer Immunol Res; 1(5); 280–4. ©2013 AACR.