A phase I clinical trial adding OX40 agonism to in situ therapeutic cancer vaccination in patients with low-grade B cell lymphoma highlights challenges in translation from mouse to human studies
Abstract
Purpose: Activating T cell costimulatory receptors is a promising approach for cancer immunotherapy. In preclinical work, adding an OX40 agonist to in situ vaccination (ISV) with SD101, a TLR9 agonist, was curative in a mouse model of lymphoma. We sought to test this combination in a Phase I clinical trial for patients with low-grade B cell lymphoma. Patients and Methods: We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody. The primary outcome was safety. Secondary outcomes included overall response rate and progression-free survival. Results: Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and 9 patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment. However, high baseline OX40 expression on T follicular helper and T regulatory type 1 cells, as well as high post-treatment soluble OX40, shed from these T cells upon activation, associated with progression-free survival of less than 6 months. Conclusions: Clinical results of T cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential…
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