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

医学 淋巴瘤 TLR9型 免疫疗法 癌症免疫疗法 T细胞 癌症 免疫学 癌症研究 内科学 肿瘤科 免疫系统 生物 生物化学 基因表达 DNA甲基化 基因
作者
Tanaya Shree,Debra K. Czerwinski,Sarah Haebe,Anuja Sathe,Susan M. Grimes,Brock A. Martin,Michael G. Ozawa,Richard T. Hoppe,Hanlee P. Ji,Ronald Levy
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
标识
DOI:10.1158/1078-0432.ccr-24-2770
摘要

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 barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogenous T cell subpopulations, some of which may antagonize immunotherapy.

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