CAR T therapies in multiple myeloma: unleashing the future

Abstract

In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with potent complement-dependent cytotoxic effects. Despite the challenges and obstacles associated with these treatments, the recent approval of the second FDA multiple myeloma CAR T-cell therapy has sparked immense promise in the field. Thus far, the results indicate its potential as a highly effective therapeutic solution. Moreover, ongoing preclinical and clinical trials are exploring the capabilities of CAR T-cells in targeting specific antigens on myeloma cells, offering hope for patients with relapsed/refractory MM (RRMM). These advancements have shown the potential for CAR T cell-based medicines or combination therapies to elicit greater treatment responses and minimize side effects. In this context, it is crucial to delve into the history and functions of CAR T-cells while acknowledging their limitations. We can strategize and develop innovative approaches to overcome these barriers by understanding their challenges. This article aims to provide insights into the application of CAR T-cells in treating MM, shedding light on their potential, limitations, and strategies employed to enhance their efficacy.

Fig. 1. Overview of autologous CAR T cell manufacturing.

The production of autologous CAR T cells begins with a patient’s leukapheresis, followed by T cell enrichment and activation. To promote the introduction and perhaps permanent integration of the CAR transgene, activated T cells are transduced (e.g., with a lentiviral vector). T cells that have been genetically engineered are then grown in either static or dynamic culture, cryopreserved, and reintroduced into the patient.

Fig. 2. Structure of five generations of CAR T-cells.

A The structure of CAR T-cells. B The first-generation CAR signaling domain has solely a CD3-derived signaling domain. A co-stimulatory domain is also present in second-generation CARs. CARs of the third generation have two co-stimulatory domains. Fourth-generation CAR T cells express chemokines such as IL-12 when activated. Fifth-generation CARs have a unique co-stimulatory domain that activates specific signaling pathways, such as JAK/STAT3.

Fig. 3. Potential target antigens.

Antigens associated with multiple myeloma, including CD19, CD38, CD138, BCMA (B-cell maturation antigen), Kappa (κ) light chain, SLAM7, NKG2D, and GPRC5D, can be exploited to create particular CAR-T cells efficiently.

Fig. 4. Challenges of CAR-T cell therapy for MM.

Challenges of CAR-T cell therapy for MM include: Tumor antigen heterogeneity, Immunosuppressive tumor microenvironment, and Trafficking and infiltration into tumor tissue.

Fig. 5. Strategies to overcome challenges to MM.

Dual CAR T-cell targeting is one of the essential strategies for targeting MM using CAR T-cell, which includes improvement in efficacy and specificity. (1) Efficacy improvement. A Dual CAR: depicts a myeloma cell expressing two antigens (Antigen 1 and Antigen 2); two separate CAR T cells, infused together or sequentially, each with a distinct CAR (CAR 1 and CAR 2), target each antigen; the co-stimulatory domain and CD3ζ domain in both CARs lead to complete activation of the T cells upon binding to their respective antigens, destroying the cancer cell. B Bicistronic CAR (1/2 construct): a single T cell with a bicistronic CAR construct can express two different CARs; full T cell activation occurs upon dual binding, suggesting improved efficacy through bispecific targeting. C Tandem CAR (scFv1/2 construct): a single T cell with a tandem CAR construct containing two binding sites (scFv1 and scFv2) for the two antigens; binding of both sites results in full T cell activation, suggesting another approach for enhancing efficacy through tandem CAR design. D ligand-based CAR construct: a T cell with a ligand-based CAR construct is shown to recognize and bind to the ligand; upon binding, full activation of the T cell occurs, indicating that ligand-based targeting can also improve the efficacy of CAR T-cell therapy. (2) Specificity improvement. A Bicistronic CAR/CCR construct: a T cell with a bicistronic CAR construct that includes a CAR and a co-stimulatory receptor (CCR) is shown; the T cell requires binding to both antigens for full activation, suggesting that dual antigen recognition can improve specificity and reduce off-target effects. B Inhibitory CAR (iCAR): shows a healthy cell with a TAA (tumour-associated antigen) and a self-antigen not present in the tumour cells; a T cell with a dual construct: a CAR for the TAA and an inhibitory CAR (iCAR) for the self-antigen; if the T cell encounters a healthy cell that expresses the self-antigen, the iCAR sends an inhibitory signal to prevent T cell activation, enhancing the specificity of the therapy by avoiding damage to healthy cells.

Fig. 6. Gene editing of T cells using of CRISPR-Cas9 strategy in cancer patients.

A cancer patient’s blood was used to isolate T cells. The CRISPR-Cas9 strategy was used for gene editing in normal T cells. After injecting the patient with the gene-edited T cells again, patients were observed to determine the efficacy and safety of the treatment.