Abstract 2382: Development and testing of the first in class immunotherapy targeting immuno-suppressive δ1 containing γδ T cells for the treatment of pancreatic ductal adenocarcinoma and other solid tumors

Abstract

Abstract Background: Targeting and engineering γδ T cells has recently emerged as an orthogonal therapeutic approach in oncology with capacity to effectively modulate both innate and adaptive immune properties. We and others have shown that in solid tumors such as pancreatic ductal adenocarcinoma (PDA), melanoma, glioblastoma, breast cancer etc., γδ1 T cells express immunosuppression-related molecules and possess a pro-tumorigenic capacity. Previously, we have shown that intra-tumoral γδ T cells from patients bearing PDA, colorectal cancer (CRC) and hepatocellular carcinoma (HCC) potently inhibit patients’ αβ T cells, rendering them immunosuppressed. We hypothesized that anti-δ1 monoclonal antibody would be a potent and effective, novel therapeutic. In order to harness the therapeutic potential of γδ1 T cell blockade we have developed a set of highly specific, fully human anti-δ1 T cell receptor (TCR) antibodies. Methods: We have sequenced δ chains from 19 cancer patients with primary PDA, primary CRC and gastric cancer (GC) to identify tumor-specific δ1. A proprietary synthetic, human antibody library was screened via phage display to identify high-affinity antibodies. Surface plasmon resonance and bead-based assays were used to measure binding affinity. We used a panel of ex-vivo experiments to assess the immunosuppressive features of γδ T cells. Antibody efficacy was assayed using patient-derived organotypic tumor spheroids (PDOTS) which recapitulate complex tumor architecture. PDOTS of n = 20 patients (PDA, CRC and liver metastases, HCC) were treated with the antibodies and resulting immune profiles analyzed by flow cytometry. Results: Because the δ1 chains in patients showed diverse CDR3 sequences, we used a selection strategy to identify antibodies that bind diverse δ1 TCRs. Our first-in-class anti-δ1 antibodies have low nanomolar affinity to human δ1 TCRs and show no binding to δ2 TCRs. Furthermore, we chose the lead clinical candidate that showed no preference for the γ chains of the TCR, as patients may harbor a diverse set of γδ heterodimers. Importantly, we show that our lead anti-δ1 antibody achieves reproducible and robust efficacy in the PDOTS system as shown by the up-regulation of pro-inflammatory T cell markers (IFNγ, TNF-α, CD44). Ongoing experiments in γδ knockout mice will investigate the efficacy of combination of γδ1 T cell targeting and existing checkpoint inhibitors (anti- PD1, PDL1, and CTLA4). Conclusion: We have defined a novel therapeutic immuno-oncology strategy and translated it to develop and characterize a lead clinical candidate anti-δ1 monoclonal antibody. Overall, our results demonstrate that we have an efficacious, novel immunotherapy that has the potential to be transformative for the treatment of cancers where γδ1 T cells drive a pro-tumorigenic, immunosuppressive environment. Citation Format: Tatyana Panchenko, Wei Wang, Eric Denbaum, Takamitsu Hattori, Akiko Koide, Aleksandra Filipovic, George Miller, Shohei Koide. Development and testing of the first in class immunotherapy targeting immuno-suppressive δ1 containing γδ T cells for the treatment of pancreatic ductal adenocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2382.