The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead

Abstract

Immunotherapy is the upcoming trend in cancer treatment. Traditional cancer treatment methods include surgical resection, radiotherapy, chemotherapy, small molecule targeted drugs, monoclonal antibodies, and hematopoietic stem cell transplantation (HSCT). Surgical resection is useful for early-stage patients but not for metastatic cancer cells; radiotherapy and chemotherapy are more common but produce substantial damage to normal tissues and have poor selectivity. Targeted drugs, including monoclonal antibodies, have better comprehensive efficacy but can also encourage gene mutation of tumor cells and drug tolerance. HSCT is effective, but choosing a donor is often difficult, and the graft is also prone to rejection. Thus, chimeric antigen receptor (CAR)-T cell therapy, a form of cellular/adoptive immunotherapy, is at the forefront of cancer therapy treatments due to its sustained remission, fewer side effects, and a better quality of life. CAR-T cell therapy involves genetically modifying the T cells and multiplying their numbers to kill cancer cells. This review article gives an insight into how the CAR-T cells have evolved from simple T cells with modest immune function to genetically engineered robust counterparts that brought great hope in the treatment of hematological malignancies. Much research has been undertaken during the past decade to design and deliver CAR-T cells. This has led to successful outcomes in leukemias, lymphomas, and multiple myeloma, paving the way for expanding CAR therapy. Despite tremendous progress, CAR-T cell therapies are faced with many challenges. Areas for improvement include limited T cell persistence, tumor escape, immunosuppressive components in the tumor microenvironment, cancer relapse rate, manufacturing time, and production cost. In this manuscript, we summarize the innovations in the design and delivery of CAR technologies, their applications in hematological malignancies, limitations to its widespread application, latest developments, and the future scope of research to counter the challenges and improve its effectiveness and persistence.

Keywords: adoptive immunotherapy; car-t cell design; car-t cell therapy; car-t cells in hematological malignancies; fda approved car therapies; hematological malignancies; immunotherapy and hematological malignancies; next generation car-t cells; safety strategies in car therapy; side effects of car therapies.

Figure 1. The different generations of CAR-T cells. (In addition to hematological malignancies, some fourth generation CAR T cells have also shown progress in the treatment of solid tumors, autoimmune diseases, and allergic diseases such as asthma. Antigen-specific Tregs and gene-edited T cell therapy have also shown encouraging results in controlling inflammation in allergic asthma.)

CD: cluster of differentiation; UniCAR: universal CAR-T cells; Treg: regulatory T cells; NFAT: nuclear factor of activated T cells; CD3ζ: cluster of differentiation three zeta; CAR: chimeric antigen receptor

Figure 2. PRISMA flow diagram showing the data selection process.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Figure 3. Overview of CAR-T cell treatment being administered to a patient.

CAR: chimeric antigen receptor [3].

Figure 4. Summary of some of the strategies to overcome challenges in CAR-T cell therapy.

TRUCKs: T cells redirected for antigen unrestricted cytokine‐initiated killing; CARs: chimeric antigen receptor