Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Abstract

Chimeric antigen receptor-reprogrammed autologous T cells directed to CD19 are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas but still fail to cure most patients. Host inflammatory and tumor microenvironmental factors associate with CAR-19 resistance, but the tumor-intrinsic factors underlying these phenomena remain undefined. To characterize genomic drivers of resistance, we interrogated whole genome sequencing of 30 tumor samples from 28 uniformly CAR-19-treated large-cell lymphoma patients. We reveal that patterns of genomic complexity (i.e., chromothripsis and APOBEC mutational activity), and distinct genomic alterations (deletions of RB1 or RHOA) associate with more exhausted immune microenvironments and poor outcome after CAR-19 therapy. Strikingly, pretreatment reduced expression or sub-clonal mutation of CD19 did not affect responses, suggesting CAR-19 therapy successes are due not only to direct antigen-dependent cytotoxicity but require surmounting immune exhaustion in tumor microenvironments to permit broader host responses that eliminate tumors

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B‐cell non‐Hodgkin lymphoma

“…However, in a post hoc analysis of patients who had prior CD19‐directed therapies before receiving liso‐cel in TRANSCEND NHL 001, 92% achieved responses with no apparent effects on cellular kinetics 31 . Additionally, a study of genomic mechanisms involved in resistance to CAR T‐cell therapy in patients with LBCL found that neither reduced expression nor genomic alteration of CD19 was associated with poor outcomes 32 …”

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

“…The circulating tumor DNA profiling of samples from r/r DLBCL patients who underwent CD19 CAR-T treatment determined the association of SOCS1 , TNFAIP3 , and XPO1 mutations with a poor prognosis after that therapy [ 117 ]. Additionally, the whole-genome sequencing analysis of CD19 CAR-T-treated large B cell lymphoma patients indicated some tumor intrinsic aberrations, such as RHOA or RB1 deletions, APOBEC mutational activity, and chromothripsis events as characteristics for relapsed patients [ 118 , 119 ]. The aforementioned defects were accompanied by preserved CD19 expression.…”

Enrichment of TP53 alterations within GCB-like DNA subclassifications of diffuse large B-cell lymphoma after transition from de-novo to relapsed or refractory disease

“…DNA alterations included missense, deletion, frameshift, high-impact splice, and truncations. A GCB rrDLBCL validation cohort combining results from four sequencing studies was also assembled (N=54) [10][11][12][13].…”

“…2C) [10]. We added cases to this rrDLBCL validation population, integrating Greenawalt, Morin (N=25), Juskevicius (N=21), and Jain (N=24) (Supplemental Table 6) [10][11][12][13]. Significant enrichment of TP53 alterations within GCB cases were noted for both rrDLBCL populations (Fig.…”