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.