The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19

Abstract

Thirty years after initial publications of the concept of a chimeric antigen receptor (CAR), the U.S. Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell therapy. Unlike other immunotherapies, such as immune checkpoint inhibitors and bispecific antibodies, CAR T cells are unique as they are "living drugs," that is, gene-edited killer cells that can recognize and kill cancer. During these 30 years of development, the CAR construct, T-cell manufacturing process, and clinical patient management have gone through rounds of failures and successes that drove continuous improvement. Tisagenlecleucel was the first gene therapy to receive approval from the FDA for any indication. The initial approval was for relapsed or refractory (r/r) pediatric and young-adult B-cell acute lymphoblastic leukemia in August 2017 and in May 2018 for adult r/r diffuse large B-cell lymphoma. Here we review the preclinical and clinical development of what began as CART19 at the University of Pennsylvania and later developed into tisagenlecleucel.

Keywords: CART; CART19; CTL019, tisagenlecleucel; axicabtagene ciloleucel; chimeric antigen receptor T cells.

Figure 1.. Similar trajectories led to FDA approval of first two gene-edited cellular therapies for cancer.

Above timeline (blue): landmarks of tisagenlecleucel road to approval. Below timeline (red): landmarks leading to axicabtagene ciloleucel approval. UPENN, University of Pennsylvania. CART, chimeric antigen receptor T cell. CLL, chronic lymphocytic leukemia. FL, follicular lymphoma. NCI, National Cancer Institute. B-ALL, B-cell acute lymphoblastic leukemia. DLBCL, diffuse large B cell lymphoma. FDA, US Food and Drug Administration. R/R, relapsed-refractory. EU, European Union. Axi-cel, axicabtagene ciloleucel.

Figure 2.. Evolution of chimeric antigen receptors.

CAR, chimeric antigen receptor. a. First concept of chimeric gene constructs of T cell receptor (TCR) constant regions (C_α and C_β) fused to immunoglobulin (Ig) variable regions, V_H and V_L. In the “pre-CAR” concept formation of the antigen recognizing domain V_H-V_L required pairing of two individual constructs. b. Chimeras of CD4 and other surface molecules are engrafted onto the CD3ζ or Fcγ signaling domains originally with the purpose of elucidating the function of CD3ζ and Fcγ. c. The ”T-body” as proposed by Dr. Eshhar. The variable antibody domains V_L and V_H are put in serial connection via a linker creating a single chain variable fragment (scFv). The scFv is connected via a hinge to either a CD3ζ or the Fc receptor γ (FcRγ) activating domain. d. and e. Addition of a costimulatory molecule (e.g. CD28 or 4-1BB as shown in figure) established “second-generation CARs”.