Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia

Abstract

CD19-specific chimeric antigen receptor T cell (CD19 CAR T) therapy has shown high remission rates in patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the long-term outcome and the factors that influence the efficacy need further exploration. Here we report the outcome of 51 r/r B-ALL patients from a non-randomized, Phase II clinical trial (ClinicalTrials.gov number: NCT02735291). The primary outcome shows that the overall remission rate (complete remission with or without incomplete hematologic recovery) is 80.9%. The secondary outcome reveals that the overall survival (OS) and relapse-free survival (RFS) rates at 1 year are 53.0 and 45.0%, respectively. The incidence of grade 4 adverse reactions is 6.4%. The trial meets pre-specified endpoints. Further analysis shows that patients with extramedullary diseases (EMDs) other than central nervous system (CNS) involvement have the lowest remission rate (28.6%). The OS and RFS in patients with any subtype of EMDs, higher Tregs, or high-risk genetic factors are all significantly lower than that in their corresponding control cohorts. EMDs and higher Tregs are independent high-risk factors respectively for poor OS and RFS. Thus, these patient characteristics may hinder the efficacy of CAR T therapy.

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

“…Moreover, accumulating evidence indicates that ALL-driven alterations in immune cells contribute to escape from immunosurveillance, leukemia progression, and thus affect treatment outcome. It has been recently demonstrated that the efficacy of chemo- and immunotherapies of ALL may be compromised by the accumulation of cells with immunosuppressive function, such as Tregs and non-classical monocytes [ 6 , 11 , 171 ]. However, more research is needed to assess the functional role of Tregs and to elucidate which properties of non-classical monocytes promote leukemic survival.…”

“…Notably, rare studies provide a correlation of the Tregs number with disease progression or a detailed explanation of how they elicit potent suppressive mechanisms; thus, more functional studies in this context are of great need. Furthermore, in recent studies, an increased circulating Tregs frequency has been linked with diminished potency of selected immunotherapies against BCP-ALL, such as blinatumomab [ 6 ] or CAR-T cells [ 171 ]. A more detailed explanation of immunosuppression mediated by blinatumomab-stimulated Tregs in BCP-ALL involves not only IL-10 production but also direct cell-to-cell contacts with other T cell subtypes.…”

Challenges and Clinical Strategies of CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments

“…found that a high antigen burden could promote the expansion of CAR T-cells ( 101 ). Moreover, some characteristics of patients, including extramedullary diseases other than CNS, increased levels of Tregs, and high-risk cytogenetic/molecular abnormalities such as E2A/PBX1, often lead to a low remission rate ( 113 ). Further studies are needed to unveil the underlying correlation.…”

Case Report: Combined Intravenous Infusion and Local Injection of CAR-T Cells Induced Remission in a Relapsed Diffuse Large B-Cell Lymphoma Patient

“…The CAR included a murine anti-CD19 single-chain variable fragment, 4-1BB costimulatory domain, and CD3z T cell activation domain. We followed a published CAR-T cell manufacturing process protocol (11).…”