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.

Keywords: Adoptive cell therapy; B-cell non-Hodgkin lymphoma; CAR T; CD19; chimeric antigen receptor.

Figure 1

Schematic structure of a chimeric antigen receptor. Chimeric antigen receptor (CAR) consists of a single‐chain variable domain derived from a monoclonal antibody, a transmembrane domain, and a signal transduction domain of T‐cell receptor (CD3ζ) (a). To improve the CAR T‐cell expansion capacity, CAR structure was refined gradually (b). VH, heavy chain variable region; VL, light chain variable region.

Figure 2

Cytotoxicity of CAR‐T against tumor cells. Normal T cells interact with antigen‐presenting cells (APCs) such as dendritic cells to be activated via the T‐cell receptor (TCR) and other costimulatory domains (a). TCR‐mediated antigen recognition depends on the peptides displayed on the major histocompatibility complex (MHC) molecules. Nevertheless, a CAR‐T can recognize target antigens via the antigen‐recognition domain and is not dependent on MHC (b). When a CAR‐T recognizes a specific antigen, the cell is activated via the intracellular signal transduction domain and exerts target cell toxicity. Ag, antigen; CAR‐T, chimeric antigen receptor T cell.

Figure 3

The outline of CAR T‐cell therapy. CAR, chimeric antigen receptor.

Figure 4

The grading system and treatment algorithm for CRS after CAR T‐cell infusion. CAR, chimeric antigen receptor; CRS, cytokine release syndrome.