Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma

Abstract

B‐cell non‐Hodgkin lymphoma (B‐NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti‐CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B‐NHL. Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B‐cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti‐CD19 CAR T‐cell therapy, not only in B‐acute lymphoblastic leukemia but also in B‐NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte‐depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti‐CD19 CAR T‐cell therapy, with a focus on B‐NHL, and discuss the clinical implications and perspectives of CAR T‐cell therapy.

Crystal structure of B‐cell co‐receptor CD19 in complex with antibody B43 reveals an unexpected fold

“…B43‐pokeweed antiviral protein is a high‐affinity anti‐CD19 immunotoxin that is capable of causing apoptotic death in B‐lineage leukemic cells with a drug‐resistant phenotype . Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment of B‐cell leukemia and lymphoma . Blinatumomab, a bispecific antibody construct in the BiTE format, with B43 as a CD19 recognition arm, was approved for use in patients with relapsed or refractory B‐cell precursor acute lymphoblastic leukemia …”

Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy

“…Currently, more than 150 CAR‐T cell‐related clinical trials are on‐going (per http://ClinicalTrials.gov) to target diverse types of cancer including both hematological malignancies and solid tumors. The most successful results to date for CAR‐T cell therapies have been reported with anti‐CD19 CAR‐T cells used to treat B cell malignancies such as pre‐B cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non‐Hodgkin's lymphoma . Recently, the U.S. Federal Drug Administration (FDA) approved of Novartis' CAR T‐cell therapy CTL019 for the treatment of relapsed or refractory pediatric and young adult patients with B‐cell acute lymphoblastic leukemia (ALL) .…”

A dynamical systems perspective on chimeric antigen receptor T-cell dosing

“…Current CAR T cell dose determining studies are being designed as traditional phase I trials, using cell doses based on donor lymphocyte infusion (DLI) dosing schema. 20 While these have allowed gradual improvement in clinical outcomes, they do not lend themselves to personalized dose determination. These designs are inherently flawed, because CAR T cell and DLI are not comparable therapeutic modalities.…”