Cell and gene therapies present an entirely new paradigm in drug development. Among these therapies, Chimeric Antigen Receptor (CAR)-T cell therapy has proven to be a game-changer in the field of cancer treatment. Over the past decade, CAR-T therapy has transformed the landscape of oncology by harnessing the power of the immune system to target and eliminate cancer cells. In this blog, we will explore the CAR-T therapy basics and its significant clinical impact on cancer patient outcomes.
What is CAR-T therapy?
CAR-T therapy involves engineering a patient's own T cells to express chimeric antigen receptors. These receptors are designed to recognize specific antigens present on cancer cells. Once the CAR-T cells are infused back into the patient, they seek out and destroy cancer cells. CAR-T cells are prepared in six steps which are illustrated in Figure 1, below. The patient’s peripheral blood is collected. Peripheral blood mononuclear cells are isolated by centrifugation. T cells are then enriched based on specific immunomagnetic beads and the CAR gene is introduced into T cells using a vector. Activation of CAR-T cells in vitro and expansion of CAR-T cells to the therapeutic dose is required, however, composition, purity, safety, and efficacy must be determined before being used in clinical trials. Finally, the patients are treated with CAR-T cells.
Most CAR-T cell therapies to date, including the FDA approved Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel), are generated using autologous (patient-derived) T cells. The challenge of autologous CAR-T cell therapy includes manufacturing, efficacy and leukapheresis (a procedure to remove white blood cells from the blood). Despite the inherent limitation of immunologic mismatch between donor and recipient, the allogenic (T cells derived from a donor who is not the patient) CAR strategies are actively being developed with the hope of quicker, more efficacious and more accessible CAR therapies. Figure 2 below compares pros and cons between autologous and allogeneic cells for use in CAR-T cell therapies.
GVHD: Graft-versus-host-disease, is an immune-mediated condition that occurs when donor cells attack the recipient.
CAR-T cells and next-generation CAR-T cell therapies
CARs can be broadly categorized into five generations based on their intracellular structural domains: the first generation of CAR-T cells have scFv (antigen recognition), transmembrane and the intracellular structural domain (CD3); the second generation has an added single co-stimulatory domain, such as CD28 or 4-1BB (also known as CD137), a member of the TNFR family and this enhances the expansion and tumor -killing effect of CAR-T cells in vivo the third generation has two or more co-stimulatory signals; the fourth generation is designed to release engineered genes, such as cytokines; and the fifth generation of CAR (universal CAR) uses gene editing technology to remove certain genes to prevent rejection and lengthen the survival period of CAR-T cells within the body, improving their capacity to eradicate malignancy. Today’s most widely used CAR-T technology is the second generation, which is more developed and is supported by a large body of clinical trial data (Figure 3).
CAR-T Clinical Applications
CAR-T therapy has shown exceptional efficacy in hematological malignancies, particularly in the treatment of B-cell malignancies. It has revolutionized the management of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL). Furthermore, CAR-T therapies have expanded to target other antigens, such as CD19, CD22, and BCMA, offering new treatment options for patients with multiple myeloma, chronic lymphocytic leukemia, and other B-cell malignancies. However, CAR-T therapies have to date only demonstrated limited efficacy against solid tumors. Compared with hematological diseases solid tumors present a unique set of challenges, including a lack of robustly expressed, tumor-exclusive antigen targets, as well as highly immunosuppressive and metabolically challenging tumor microenvironments (TME) which has limited treatment safety and efficacy in past trials. None the less a number of strategies are in development that may improve the efficacy of CAR-T therapies in solid tumors, including but not limited to, combining radiation, chemotherapy and other immunotherapies with the CAR-T to overcome the immunosuppressive TME and potentially reduce the adverse events.
The Future of CAR-T Therapy
Looking ahead, CAR-T therapy holds potential to extend into and transform cancer treatment of solid tumors as it has for hematological malignancies. Advances in genome editing techniques, such as CRISPR/Cas9, hold promise for enhancing CAR-T cell persistence and effectiveness. With ongoing advancement, we can expect to see increased precision, improved safety profiles, and expanded applications in various cancer types.
Conclusion
Over the past decade CAR-T therapy has transformed the field of oncology, offering new hope to patients. With its ability to activate and harness the power of the immune system to target cancer cells directly, CAR-T therapy has demonstrated remarkable efficacy and has the potential to shape the future of cancer treatment. As a scientist who has dedicated a career to oncology and molecular diagnostics, I am excited to witness the ongoing advancements in CAR-T therapy and its continued impact on patient outcomes. NeoGenomics’ pharma services division is engaged in partnerships with biotech and pharmaceutical companies to develop new drugs for personalized biological therapeutics. We offer the most broad and state-of-the-art molecular technology platforms for NGS, ctDNA, CTC (circulating tumor cell), qPCR, ddPCR, IHC, flow cytometry, and spatial multiplexed fluorescent assays. Please contact NeoGenomics’ pharma services team to see how we can support your CAR-T program.
REFERENCES:
- Caldwell KJ et al. Allogeneic CAR Cell Therapy-More Than a Pipe Dream. Front Immunol. 2021 Jan 8;11:618427.
- Bodmer W et al. Cancer Immunotherapy: Where Next? Cancers (Basel). 2023 Apr 18;15(8):2358.
- Safarzadeh Kozani P et al. Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero? Front Immunol. 2022 May 11;13:795164.
- Wang C et al. Gene Targets of CAR-T Cell Therapy for Glioblastoma. Cancers (Basel). 2023 Apr 18;15(8):2351.