Effect on anti-tumor immunity and long-term memory CD8+ T-cell generation with a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine.

Abstract

e14016 Background: We are focused on developing and optimizing a next generation cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), into a single tumor cell line overexpressing a host of cancer associated neoantigens. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma cell line, stably transfected to express gp96-Ig, is being tested in a phase 1/2 clinical trial (NCT#02439450) for NSCLC. A similar line was generated that complements HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). Methods: To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines (mHS-110 and mHS-130) to activate and expand adoptively transferred ovalbumin specific T cells (OT-1) responding to tumor challenge with ovalbumin over-expressing, B16F10. To identify the best ratio of mHS-110 to mHS-130; multiple dose ratio and dose escalation studies were performed to measure T cell expansion (peripheral and intratumoral) in the context of tumor challenge. Results: CD8+ T-cell expansion was observed on day-7, post-priming, with greatest expansion seen for the 1 to 0.5 ratio. Animals were subsequently boosted 14-days post-priming; the 1 to 0.5 ratio combination gave the most consistent and robust expansion, peaking on day-21. Animals were then challenged with tumors s.c. and growth delay was monitored. Only the 1 to 0.5 and 1 to 4.5 ratio dose groups showed significant delay in tumor growth and weight. Spleen CD4+ and CD8+ T-cells, and CD8+ TILs all increased significantly, as compared to mHS-110 vaccination alone, for the 1 to 0.5 and 1 to 4.5 ratio dose groups. Conclusions: Only the 1 to 0.5 ratio dose group showed any long-term OT-1 expansion or longevity over all other dose ratios, strongly suggesting this is the best combination of gp96-Ig and OX40L-Ig expression for long-term anti-tumor memory generation. These results support the clinical translation of this approach of combining a T cell activation platform with costimulation.