Macrophage-driven CAR T cell resistance in B cell lymphoma

Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Molecular Biosciences

Major Professor

Marco Davila, M.D., Ph.D.

Co-Major Professor

Paulo Rodriguez, Ph.D.

Committee Member

Shari Pilon-Thomas, Ph.D.

Committee Member

Amer Beg, Ph.D.

Keywords

Cancer, Immunotherapy, Tumor microenvironment, Metabolism

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed/ refractory large B cell lymphoma (LBCL). Despite its promising efficacy, a subset of patients experiences primary resistance or relapse. In Chapter 2, we explore the tumor microenvironment (TME)-induced resistance mechanisms in patients with LBCL. Analysis of the intratumoral immune infiltrates in pre-infusion tumor biopsies revealed that the levels of immunoregulatory macrophages were elevated in patients who responded poorly to axicabtagene ciloleucel (axi-cel). Using preclinical mouse B cell tumor models, we found that the CAR T-cell-produced interferon-gamma (IFN-γ) enhanced the expression of inducible nitric oxide synthase (iNOS, NOS2) in tumor-associated macrophages (TAMs), impairing CAR T-cell effector function. Furthermore, metabolomics and stable isotope tracing showed that CAR T-cell metabolism was compromised by iNOS-dependent depletion of glycolytic intermediates and alterations in the TCA cycle. Inhibition of iNOS significantly improved CAR T-cell therapy outcomes in B-cell tumor-bearing mice, underscoring the importance of targeting iNOS in TAMs.

In Chapter 3, we explore how serum inflammatory proteins correlate with severe immune-mediated toxicities and adverse clinical outcomes in patients with diffuse large B-cell lymphoma (DLBCL) undergoing treatment with axi-cel. We developed a straightforward stratification model using pre-lymphodepletion levels of C-reactive protein (CRP) and ferritin to categorize patients into low, intermediate, and high-risk groups. This model effectively predicted clinical outcomes, indicating that patients at high risk were more likely to experience grade ≥ 3 toxicities and had worse overall and progression-free survival rates. Validation through two independent international cohorts verified that patients classified as low-risk achieved outstanding efficacy and safety profiles. These results demonstrate the effectiveness of our risk stratification model, which relies on easily accessible lab tests, in guiding the selection of patients for CAR T-cell therapy.

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