Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma

Abstract

Ciltacabtagene autoleucel (also known as cilta-cel) is a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) on the surface of cancer cells in B cell malignancies, such as multiple myeloma (MM). It is a second-generation CAR that is outfitted with an ectodomain comprising two BCMA-binding single chain variable fragment (ScFv) domains, a transmembrane domain, and an endodomain possessing CD3ζ and 4-1BB. Cilta-cel is an autologous, gene-edited CAR T-cell that is prepared by collecting and modifying the recipient's T-cells to create a patient personalized treatment in the laboratory to be infused back. This CAR T-cell product exceptionally entails CARs with two BCMA-targeting single-domain antibodies that detect two epitopes of BCMA expressed on the malignant cells of MM. Cilta-cel is the current addition to the treatment armamentarium of relapsed or refractory (r/r) MM after its approval by the FDA on February 28, 2022, based on the results of the Phase 1b/2 CARTITUDE-1 study. It was the second approved anti-BCMA CAR T-cell product after idecabtagene vicleucel (ide-cel) to treat myeloma patients. It induces early, deep, and long-lasting responses with a tolerable safety profile in r/r MM. Cilta-cel-treated myeloma patients may potentially experience adverse effects ranging from mild to life-threatening, but they are mostly manageable toxicities. Besides, it has a consistent safety profile upon a longer follow-up of patients. Cilta-cel generally outperforms ide cel in terms of efficacy in MM, but shows comparable adverse events. This review highlights the current updates on cilta-cel efficacy, adverse events, comparison with ide-cel, and its future direction in the treatment of MM.

Keywords: CAR T-cell therapy; adverse effects; cilta-cel; efficacy; multiple myeloma.

Figure 1

The structural construct of cilta-cel. It is a second-generation CAR T-cell containing an ectodomain, a TMD, and an endodomain. ScFv, short chain variable fragment; TMD, transmembrane domain; VH, variable heavy chain; BCMA, B cell maturation antigen; ITAM, immunoreceptor tyrosine-based activation motif.

Figure 2

A diagrammatic representation of the manufacturing process of cilta-cel. It is prepared in the laboratory using several procedures, including (1) Leukapheresis, (2) T-cell enrichment, (3) Gene transduction, (4) Expansion, (5) Lymphodepletion, and (6) Cilta-cel infusion.

Figure 3

Schematic illustration of the mechanism of action of cilta-cel against BCMA expressing MM. Cilta-cel produces pro-inflammatory cytokines and recruits other immune cells (such as NK cells and B-cells) to the tumor site and induces inflammation that destroys myeloma cells. It also mediates the cytolysis of cancer cells by using an apoptosis-inducing perforin-granzyme system and Fas-FasL-axis. BCMA, B cell maturation antigen; FasL, Fas ligand; GZM, granzymes; NK cells, natural killer cells; VH, variable heavy chain.