Explore the groundbreaking realm of CAR-T cell therapy, a revolutionary cancer treatment achieving remarkable results in haematological malignancies. Delve into challenges, recent advances, and India's milestone approval, shedding light on the promising future of precision gene therapy.

Chimeric antigen receptor (CAR)-T cell therapy has been one of the revolutionary treatments as it has produced remarkably effective and durable clinical responses, especially in haematological malignancies. CARs are engineered synthetic receptors that function to redirect lymphocytes, most commonly T cells, to recognise and eliminate cells expressing a specific target antigen. CAR binding to target antigens expressed on the cell surface is independent from the Major Histocompatibility Complex (MHC) receptor resulting in vigorous T cell activation and powerful anti-tumour responses.

Common target antigens and indications

Among haematological malignancies, the indications for the use of chimeric antigen receptor (CAR) T cells are rapidly expanding. CD19-targeted CAR T cells are now approved for relapsed and/or refractory B cell lymphoma and B cell acute lymphoblastic leukaemia, and B cell maturation antigen(BCMA) -targeted CAR T cells are approved for relapsed and/or refractory multiple myeloma.

Major limitations to CAR-T cell therapy that still must be addressed include life-threatening CAR-T cell-associated toxicities, limited efficacy against solid tumours, inhibition and resistance in B cell malignancies, antigen escape, limited persistence, poor trafficking and tumour infiltration, and the immunosuppressive microenvironment.

Limitations of CAR-T cell therapy

Antigen escape

One of the most challenging limitations of CAR-T cell therapy is the development of tumour resistance to single antigen-targeting CAR constructs. Although initially, single antigen targeting CAR-T cells can deliver high response rates, the malignant cells of a significant portion of patients treated with these CAR-T cells display either partial or complete loss of target antigen expression. This phenomenon is known as antigen escape.

On-target off-tumour effects

One of the challenges in targeting solid tumour antigens is that solid tumour antigens are often also expressed on normal tissues at varying levels. Therefore, antigen selection is crucial in CAR design to not only ensure therapeutic efficacy but also to limit “on-target off-tumour” toxicity.

CAR-T cell trafficking and tumour infiltration

Compared to haematological malignancies, solid tumour CAR-T cell therapy is limited by the ability of CAR-T cells to traffic to and infiltrate solid tumours as the immunosuppressive tumour microenvironment and physical tumour barriers such as the tumour stroma limit the penetration and mobility of CAR-T cells.

Side effects and safety considerations

High rates of toxicities with some fatalities have prevented CAR-T cell therapy from becoming first-line treatment. Critical factors that likely determine the incidence and severity of toxicities are the design of the CAR, the specific target, and the tumour type.

These toxic levels of systemic cytokine release and severe immune cell cross-activation in some patients result in the following toxicities: cytokine-release syndrome (CRS), which is associated with supraphysiologic cytokine production and massive in vivo T cell expansion, hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome (MAS) defined as a severe hyper-inflammatory syndrome characterised by CRS and combinations of elevated serum ferritin and hemophagocytosis, renal failure, liver enzymes, splenomegaly, pulmonary oedema, and/or absence of NK cell activity, and immune effector cell-associated neurotoxicity syndrome (ICANS), which is characterised by elevated cerebrospinal fluid cytokine levels and blood–brain barrier disruption.

CRS is a result of administered CAR-T cells becoming extensively activated resulting in the release of massive amounts of cytokines. Clinical manifestations of mild CRS are fever accompanied by fatigue, diarrhoea, headache, rashes, arthralgia, and myalgia and in more severe cases, patients may present with hypotension, cardiac dysfunction, circulatory collapse, respiratory failure, renal failure, multiorgan system failure, and with possible progression to death. Pathophysiologically, CRS is believed to be primarily mediated by IL-6 and therefore, management relies on the use of IL-6 receptor blockade with tocilizumab and corticosteroids. HLH/MAS secondary to CAR-T cell therapy can be refractory to IL-6 inhibition and instead may require chemotherapy.

Clinical manifestations of ICANS range from confusion, headache, attention deficits, word-finding difficulties, focal neurological deficits, or encephalopathy to life-threatening cerebral oedema, transient coma, or seizures. Neurotoxicity following CAR-T cell therapy is relatively common and can occur in up to 67% and 62% of patients receiving treatment for leukaemia and lymphoma, respectively. Management of neurotoxicity focuses on corticosteroids as IL-6 inhibitors are often not effective for neurotoxicity associated with CAR-T cell therapy.

In solid tumours

The similar success of CAR-T cell treatment for haematological malignancies has not been observed in solid tumours because of the hostile tumour microenvironment and tumour heterogeneity. Most strategies developed to combat these limitations emphasise combinatorial techniques that still require further testing. Preliminary results of multiple clinical trials, including GD2- and HER2-CAR-T cells, are encouraging but must be reproduced and validated on a larger scale.

Recent advances

This “first in India” gene therapy was developed as a result of clinical trials and the dedicated efforts and excellent collaboration between IIT Bombay and Tata Memorial Hospital, Mumbai. The central government’s National Biopharma Mission-BIRAC had approved 19.15 Cr crore to the team for conducting a first-in-human phase-1/2 clinical trial of the CAR-T cells. The clinical trials were done by Dr (Surg Cdr) Gaurav Narula, Professor of Paediatric Oncology and Health Sciences, and his team from TMC, Mumbai, and the novel CAR-T cells that act as drugs that were manufactured by Prof Rahul Purwar, Bioscience and Bioengineering (BSBE) department and his team at IIT Bombay. The design, development, and extensive pre-clinical testing were carried out by IIT-B as a collaborative project with Tata Memorial Centre, Mumbai.

With this development, it is expected that the cost of CAR T cell therapy in India will be around 50 – 60 lacs. This is substantially lower compared to the expected cost of 3-4 crores for internationally manufactured ones.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bipinesh Sansar, DM Medical Oncology, Associate Professor Medical Oncology at MPMMCC and HBCH, Varanasi.