Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation

Abstract

Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n = 6), double-hit high-grade B-cell lymphoma (n = 1), and Burkitt lymphoma (n = 2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance.

Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis

“…[15][16][17][18][19] CAR T-cell product properties, such as kinetics and dose, can also be taken into account, 20 along with tumoral intrinsic factors. [21][22][23] Chow et al previously reported a poor outcome in 61 patients presenting progression or relapse after CAR T-cell treatment. 24 The DESCAR-T registry offers a unique opportunity to gather data about a large European cohort.…”

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

“…Disease relapse can occur by 12 months after infusion of CAR-T cells in up to 50% of patients [197]. Relapse connected with CD19 antigen loss is also observed in the case of NHLs but is less frequent than in ALL [198].…”

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

“…The broad analysis of samples from patients with lymphomas (mainly DLBCL) before and after CD19 CAR-T therapy displayed a tremendous phenotypic shift in tumor cells after CAR-T infusion. These genomic changes included downregulated expression of B cell markers (CD19, CD20, CD22, CD79a), an increased methylation profile, and mutations affecting immune suppressive mechanisms, such as the PI3K pathway [ 116 ].…”