Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma

Abstract

CD19-directed chimeric antigen receptor (CAR-19) T cells are groundbreaking immunotherapies approved for use against large B-cell lymphomas. Although host inflammatory and tumor microenvironmental markers associate with efficacy and resistance, the tumor-intrinsic alterations underlying these phenomena remain undefined. CD19 mutations associate with resistance but are uncommon, and most patients with relapsed disease retain expression of the wild-type receptor, implicating other genomic mechanisms. We therefore leveraged the comprehensive resolution of whole-genome sequencing to assess 51 tumor samples from 49 patients with CAR-19–treated large B-cell lymphoma. We found that the pretreatment presence of complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species predict CAR-19 resistance. In addition, the recurrent 3p21.31 chromosomal deletion containing the RHOA tumor suppressor was strongly enriched in patients for whom CAR T-cell therapy failed. Pretreatment reduced expression or monoallelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are related to multiple mechanisms. Our study showed that tumor-intrinsic genomic alterations are key among the complex interplay of factors that underlie CAR-19 efficacy and resistance for large B-cell lymphomas.

A tour de force provides novel insights into CD19-CAR T cell resistance mechanisms

“… 2 Mechanisms of resistance are likely multifactorial and relate to tumor cells and the microenvironment, CAR T cells, and native non-engineered immune cells. While many potential mechanisms of resistance to CD19-CAR T cell therapies have been described, 3 , 4 , 5 comprehensive analyses that include tumor cells as well as CAR T cells are in its infancy.…”

A unique hub‐and‐spoke model to optimize patient management in lymphoma using novel CAR‐T cell therapy in Southeast and South Asia

“…Genetic markers such as myc translocations may also have predictive value; however there is no consensus to date 18 . Nonetheless, it appears likely that there are multiple mechanisms involved in determining treatment outcomes, including tumor‐specific alterations to the genome 19 . Future research will no doubt shed more light on the complex interplay of the various factors involved in the patient response to CAR‐T cell therapy.Although analysis of data from clinical trials can identify characteristics of patients most likely to have positive treatment outcomes, clinical trial populations may not fully represent patients who can benefit from CAR‐T cell therapy in the real‐world setting.…”

“…Genetic markers such as myc translocations may also have predictive value; however there is no consensus to date 18 . Nonetheless, it appears likely that there are multiple mechanisms involved in determining treatment outcomes, including tumor‐specific alterations to the genome 19 . Future research will no doubt shed more light on the complex interplay of the various factors involved in the patient response to CAR‐T cell therapy.…”

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

“…Furthermore, 19CAR-T cell exhaustion under an immunosuppressive tumor microenvironment (TME) leads to disease progression or relapse. Chronic TAA exposure in the TME results in constitutive activation of 19CAR-T cells, differentiation, epigenetic alteration, and upregulation of immune checkpoint molecules [46][47][48]. Recently, numerous novel strategies have been developed to modify T cells to overcome TME and tumor heterogeneity TAA.…”