In two mouse models of pancreatic cancer, Yasmin-Karim and Bruck et al. demonstrated that combination of intratumoral injection of CD40 agonist and single-dose (but not fractionated) stereotactic body radiation therapy (SBRT) led to complete regression of treated and untreated tumor sites, long-term survival, and development of immunological memory. The treatment increased the infiltration of CD8+ T cells in both treated and untreated tumors, and led to the development of vitiligo in long-term responders. Combination of SBRT and intratumoral CD40 agonist with systemic anti-TGFβ antibody led to local response, but reduced abscopal effect.
Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an in situ vaccine. In practice, this abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFbeta blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors.
Author Info: (1) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. Department of Radiation Oncology, Harvard Medical School, Boston, MA, United States.
Author Info: (1) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. Department of Radiation Oncology, Harvard Medical School, Boston, MA, United States. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States. (3) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. Department of Biology, University of Massachusetts, Lowell, MA, United States. (4) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States. (6) Electronic Materials Research Institute, Northeastern University, Boston, MA, United States. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, United States. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, United States. (9) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States. Department of Radiation Oncology, Harvard Medical School, Boston, MA, United States. Department of Biology, University of Massachusetts, Lowell, MA, United States.
