# Mechanisms of Resistance to Novel Immunotherapies in B-Cell Lymphomas: Focus on CAR T and Bispecific Antibodies

## TL;DR

This paper reviews how B-cell lymphomas develop resistance to new immunotherapies like CAR T cells and bispecific antibodies, highlighting molecular mechanisms and the need for improved treatment strategies.

## Contribution

The paper systematically outlines molecular resistance mechanisms specific to CAR T cell therapy and bispecific antibodies in B-cell lymphomas.

## Key findings

- Resistance to CAR T therapy includes CD19 epitope loss, genomic alterations, and T cell exhaustion.
- Bispecific antibodies face resistance through antigen loss, T cell dysfunction, and tumor-intrinsic mutations.
- The immunosuppressive tumor microenvironment contributes to resistance in both therapies.

## Abstract

B-cell lymphomas are blood malignancies derived from B lymphocytes and associated with decreased survival rates if recurrent or refractory to treatment. Novel immunotherapies approaches, including CD19-CAR T cell therapy and bispecific antibodies, are improving patients’ survival after failure of standard-of-care treatments. Despite these promising results, the onset of molecular resistance to these cutting-edge therapeutics limits their efficacy. This review aims to describe the molecular mechanisms of resistance to CAR T cell therapy and bispecific antibodies in B-cell lymphomas, with a focus on CAR T cell fitness, T cell exhaustion, tumor-intrinsic determinants, and the role of the immunosuppressive tumor microenvironment.

Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g., CD19 mutations, chromothripsis, APOBEC mutational activity, and deletions of RHOA). Additional genomic and epigenetic events, including mutations, alternative splicing of CD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance.