Checkpoint blockade therapy of cancer has had tremendous impact; still, only a subset of patients experience remissions. One hypothesis is that resistant tumors lack sufficient somatic mutational burden and thus, targetable tumor-associated antigens (TAA). To the contrary, we described that Hodgkin’s lymphoma, despite a high anti-PD1 response rate (~65-87%), has significantly fewer mutations (Reichel et al., Blood 2015) than highly mutated tumors, such as lung cancer (anti-PD1 response rate ~20%). Recent, seminal work confirms that the presence of dendritic cells (DC) capable of cross-presenting TAA correlates with tumor immunogenicity (Spranger et al., Proc Natl Acad Sci USA 2016). Our hypothesis is that checkpoint blockade is limited by the tolerogenic microenvironment, specifically, suboptimal cross-presentation of TAA by suitably activated dendritic cells (DC). If so, then checkpoint blockade will be potentiated by optimal recruitment, loading, and activation of cross-presenting DC at the tumor site. We and others have recently found that tumors—including lymphomas—evade immune clearance by active exclusion of DC. Despite progress in mechanistic understanding of this immune evasion, we still lack means to modulate the phenomenon and facilitate T-cell entry and destruction of tumors.
We developed an early-phase trial (funded by Damon Runyon CRF) testing a unique, rationally designed in situ vaccine (ISV) comprising 1) Flt3L to recruit DC, 2) radiotherapy (XRT) to load Flt3L-mobilized DC with TAA, and 3) Toll-like receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. Strikingly, we observed partial and complete systemic tumor regressions, including distant and untreated tumors, improving months after therapy, and even elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic antitumor immune response. The trial is based on our preclinical dat,a which recapitulate the clinical findings and also show that the ISV cure rate (~40%) increases markedly by combination with PD1 blockade (80-90%). These data prompted a new trial combining ISV with PD1 blockade opening in 2018.
Though PD1/PDL1 blockade is potentiated by in situ vaccination, it is possible that there may be other, even more effective checkpoints for combination. We have developed two separate, complementary screening approaches using a novel EGFP-specific, murine CD8 T cell to enrich or probe for novel tumor-expressed (“PD-L1-like”) checkpoint molecules and have identified candidates for validation. Ultimately, the screening can be performed in vivo in the context of various immunotherapies, including in situ vaccination, stem cell transplantation, or PD-1 blockade.
Citation Format: Joshua D. Brody. Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA32.