Designing Chimeric Antigen Receptor Therapies to Overcome Treg Suppression

Stanford University, Stanford CA

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Abstract

PROJECT 2: PROJECT SUMMARY/ABSTRACT Autologous T cells engineered to express chimeric antigen receptors (CARs) have transformed the management of patients with relapsed/refractory large B cell lymphoma (LBCL). Approximately 40% of patients treated with commercial CD19-CAR T cells as a third-line therapy, and approximately 50% of patients treated as a second- line therapy, experience durable disease control. While these outcomes have had substantial clinical impact, more than half of the patients receiving these expensive therapies do not benefit. We have utilized a bench-to- bedside-to-bench approach to identify mechanisms of LBCL resistance to CD19-CAR therapy and to develop new approaches to improve outcomes. During the previous funding period, this Project identified three major mechanisms of resistance following CD19-CAR therapy for LBCL, which have informed the current Project. First, we identified CD19 loss and inadequate CD19 expression density as major drivers of relapse and demonstrated activity of a novel CD22-CAR to address this problem, with long-term disease control in approximately 50% of patients with LBCL refractory to CD19-CAR therapies treated on our investigator-initiated trial. The CD22-CAR is now undergoing pivotal testing with an industrial sponsor, and thus this renewed Project will not further address antigen modulation. Second, we demonstrated the utility of pre- and post-therapy circulating tumor DNA to predict outcome following CD19-CAR therapy, and these results confirmed the potent adverse impact of high tumor burden on patient outcome following CD19-CAR therapy. This Project seeks to address this challenge by delivering a novel two-dose regimen of CD19-CAR therapy to patients with high-burden disease with the goal of improving disease control (Aim 1-1). Third, we, and the Maus group at Massachusetts General, implicated CAR regulatory T (Treg) cells in disease progression following CD19-CAR therapy for LBCL. This discovery provides a new axis for targeting to improve outcomes for patients with LBCL, and in addition, these findings are of great scientific interest as they were the first to implicate CAR Tregs in resistance to any CAR therapy. Here, we propose to deeply interrogate the biology of CD19-CAR Tregs using methylation analysis to characterize them as natural vs. induced Tregs (Aim 1-2), and fate mapping to identify their cell of origin within the pre-treatment apheresis and manufactured product (Aim 1-3). In Aim 2, we develop CD19-CAR manufacturing approaches that diminish the risk of expanding/inducing CAR Tregs and in Aim 3, we undertake spatial profiling to explore the biology of CAR Tregs within the LBCL TME. Aim 3 further tests the hypothesis that CAR Treg trafficking to the LBCL TME can be prevented through CCR4 blockade as a prelude to clinical testing of this approach. Together, these studies will further inform the basis for LBCL resistance to CAR T cell therapies and will provide new testable approaches to improve outcomes for patients receiving CAR T cell therapy for LBCL. These studies will also deliver fundamental insights into the biology of CAR Tregs, which may very well be generalizable to other diseases, such as solid tumors, wherein genetically engineered T cells have not manifested similarly potent effects as in LBCL.