^*Ritika Sud

^*Professor, Lady Hardinge Medical College, New Delhi

 

Traditionally Chemotherapy and radiation have been the standard of care in the management of haematological malignancies for decades. Advances in the field of immunology have led to better understanding of the body’s defense mechanisms and ways to harness it to treat blood cancers. Chimeric antigen receptor (CAR) T-cell therapy also known as “immunotherapy” has recently garnered pace in the management of hematological malignancies. CAR-T therapy uses the patient’s own T cells to recognize and attack cancer cells. B-cell lymphomas and leukemias begin when normal B cells mutate and become cancerous. Immunotherapy improves the body’s ability to detect and attack these cancer cells.

Autologous CAR T-cell therapy involves engineering a patient’s own T cells to recognize and attack cancer cells. White blood cells are taken from a patient’s blood in a procedure called “apheresis” or “leukapheresis” and sent to a laboratory where the T cells are separated and then modified so they have artificial receptors on their surface. The receptors direct the engineered T cell to find and attack the cancer cells. These artificial receptors are called “chimeric antigen receptors.” The number of engineered CAR T cells is multiplied in the laboratory and are frozen and sent to the hospital or treatment center. When the patient is ready for treatment, the CAR T cells are thawed and given to the patient in the form of an intravenous (IV) infusion.

The antigen used for CAR-T cells is a primary design consideration. CAR-T cell therapies target tumor-specific antigens or tumor-associated antigens that are upregulated on the surface of cancer cells. The CAR-T cell recognizes and binds to the target antigen, which is usually a specific protein or glycoprotein upregulated on the surface of cancer cells, through a single-chain variant antibody (scFv) on the CAR protein. The scFv binds to the target antigen enabling recognition by the CAR-T cell. Once CAR-T cells recognize the target antigen, signaling domains within the CAR, such as D3ζ, are activated and initiate an intracellular signaling cascade. The activated CAR-T cells then target tumor cells expressing the target antigen through multiple mechanisms, like: i) Direct cytotoxin release which directly lead to tumor cell lysis and apoptosis ii) cytokine release where activated CAR-T cells secrete cytokines, to stimulate immune cell activation and inflammatory responses and iii) immune cell alliance where activated CAR-T cells can activate and recruit other immune cells, such as natural killer (NK) cells and macrophages, to form an immune cell alliance to jointly attack tumor cells. The CAR T cells in addition to eradicating the cancer cells in the body, also remain in the body for months after the infusion has been completed thus resulting in long-term remissions for some patients with certain types of blood cancer

At present there are six approved CAR T-cell therapies in the USA Tisagenlecleucel (Kymriah®) is a CD19-directed genetically modified autologous T-cell immunotherapy USFDA approved for relapse/refractory B-ALL or large B-Cell lymphomas in Patients up to 25 years of age Axicabtageneciloleucel (Yescarta®) CD19-directed genetically modified autologous T-cell immunotherapy, FDA approved since 2017  for use in Adult relapse/refractory  large B-cell lymphoma. Brexucabtageneautoleucel (Tecartus®) a CD19 directed immunotherapy received FDA-approval in 2020 for adult with Relapsed / refractory mantle cell lymphoma (MCL) and B-ALL. Lisocabtagenemaraleucel (Breyanzi®)used in relapse/refractory large B-cell lymphoma, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Idecabtagenevicleucel a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy. Ciltacabtageneautoleucel (Carvykti™) is FDA approved for use in adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In October 2023, Central Drugs Standard Control Organization, approvedNexCAR19 India’s first CAR-T cell therapy.

 

Though CAR-T cell therapy has proven efficacy in management of haematological tumours, it also has many treatment-related undesirable effects and safety concerns and still faces challenges in clinical application thus limiting its widespread use. CRS (cytokine release syndrome) occurs in 20-50% of recipients of CAR-T. When CAR-T cells kill tumor cells, they release large amounts of cytokines, causing activation of the immune system and systemic inflammatory response .The efficacy of CAR-T cell therapy is limited by the selection and heterogeneity of target tumor antigens. Antigen expression varies between tumor types and patients, and a number of tumors may even lack specific antigens Patients may experience relapses or drug resistance, resulting in a less durable efficacy after treatment. Solid tumors have a complex tumor microenvironment, due to the production of immunosuppressive factors and the interaction of tumor cells with other cells causing the tumors to sometimes suppress the activity of CAR-T cells thus limiting its use in solid tumors.

CAR-T cell therapy is a revolutionary therapy with notable efficacy in treating B cell-associated malignancies. By targeting specific antigens on the surface of tumors, CAR-T cells are able to identify and destroy malignant cells, making available a new treatment option for those patients who have failed conventional treatments. Despite this CAR-T therapy poses a fair number of challenges. Serious adverse effects like CRS and neurotoxicity limit its use. Immune escape mechanisms and suppression of the tumor microenvironment too limit the effectiveness and durability of CAR-T cells. Improvement in the safety, specificity and durability of CAR-T therapies is one of the current research priorities.  Further development and application of CAR-T cell therapy is expected to expand its use to include a wider range of diseases, like other types of cancers, autoimmune and infectious diseases.