Cancer treatment has traditionally relied on surgery, chemotherapy, and radiation therapy. However, recent advancements have led to the emergence of targeted therapy and immunotherapy as new dimensions in cancer treatment. Immunotherapy focuses on boosting the patient's immune system to fight cancer, with immune checkpoint inhibitors as the foundation. CAR-T cell therapy, which genetically modifies T-cells to target specific cancer cells, has gained substantial interest but are extremely costly. NexCAR19, developed by IIT Bombay under ImmunoAct, is India's first indigenous anti-CD19 CAR-T cell therapy, solidifying India's position as a global leader in advanced cell and gene therapies with significantly reduced cost and adverse effects.
The advent of CAR-T cell therapy
Radiation therapy, chemotherapy, and surgery have been the cornerstones of cancer treatment for many years. While they remain essential therapy pillars, recent advancements in the field have significantly changed the treatment landscape for cancer patients. While chemotherapy targets both cancer and normal cells, recent advances in radiotherapy created better targeted versions of it, but the risk of radiation exposure cannot be eliminated. Surgery, on the other hand, always has a psychological impact associated with fear of undergoing knife. Targeted therapy targets the proteins that regulate the growth, division, and metastasis of cancer cells. Tumor growth is caused by cells dividing too quickly due to genetic mutations and the accompanying changes in cellular proteins. Researchers uncover probable genetic abnormalities and resulting aberrant proteins that fuel the growth of specific cancer types in order to develop a tailored therapy. Whereas chemotherapy is nonselective and affects all rapidly proliferating cells, the targeted therapy medication targets only the defective protein. Though tamoxifen, that targets the estrogen receptors on ER-positive breast cancer, is considered the first targeted therapy, therapies like as imatinib (Gleevec) and trastuzumab (Herceptin) garnered great popularity in the 2000s. Targeted therapy is primarily classified into small-molecule inhibitors and monoclonal antibodies. Currently all the approved targeted therapies can either be clubbed into growth inhibitors or angiogenesis inhibitors. These drugs locate and destroy cancer cells by focusing on specific molecular alterations that are particularly present in those cells. Many malignancies are currently treated with dozens of targeted medicines as routine care. Although there were expectations that there would be minimal adverse events following targeted therapy, due to their specific target, we still have a range of adverse drug reactions with these targeted therapies because though these drugs target receptors overexpressed in cancers, many of these receptors are crucial for normal functioning of the body.
Immunotherapy, that emerged after targeted therapy, primarily releases the brakes from the immune cells that could attack the tumour cells more precisely. The immune system identifies and eliminates abnormal cells as part of its regular work, and it probably stops or slows the growth of many malignancies. For example, immune cells have been observed in and surrounding tumours on occasion. Tumor-infiltrating lymphocytes, often known as TILs, are cells that indicate the immune system is reacting to the tumor. Individuals with TIL-containing tumours typically have better prognoses than those without them. Cancer cells have strategies to evade the destruction by immune system, despite the immune system's ability to stop or delay the progression of cancer. Genetic alterations in cancer cells may hide their appearance to the immune system. Certain cancer specific proteins on the surface of cancer cells have the ability to inhibit immune cells or escape those immune cells. The initial therapeutic modality under cancer immunotherapy consists of immune-checkpoint inhibitors (ICIs). These drugs, blocks the immune escape signal that arises from the interaction between a protein on T-cell surface and its corresponding ligand expressed on the surface of tumours. Blocking this interaction reactivates the T-cell to recognise and kill the tumor cells. Currently, PD-1, PD-L1, CTLA4, and LAG-3 are the preferred target against which we have approved antibody-based drugs. However, ICIs face various serious challenges such as antigenic loss on the cancer cells creating the resistance against some ICIs, while secretion and upregulation of immunosuppressive metabolites such as adenosine hinders the action of ICIs. Besides these direct actions, cancer cells and the resident immune cells show a various abnormality in important regulatory pathways while cancer heterogeneity play a very crucial role in resistance. On the other hand, cellular therapies such as T-cell transfer therapy, CAR-NK cell, and CAR-M cell are the new players on the block among which currently we have only CAR-T cell therapy approved. In Chimeric Antigen Receptor-T cell therapy popularly known as CAR-T cell therapy, T-cells isolated from the person suffering from cancer are genetically modified to express CAR on their surface and infused back into the patient following a certain level of in vitro proliferation, whereby these engineered T-cells respond more actively and precisely against the cancer for which they are armed. After a successful injection, the patient's body begins to produce more of the modified T-cells, where the chimeric antigen receptor is instructed to seek out and eliminate any cancer cells that have the corresponding antigen protein. The chimeric receptor is an engineered antigen-binding domain of antibody that is deliberately expressed in these isolated T-cells so that after being expressed on the surface they can interact with the tumor cells that express the corresponding antigen (ligands) on their surface. Since most of these tumor antigens are tumor specific antigens, these engineered CAR-T cells precisely attack only their target cancer. These engineered expressed proteins are called chimeric because they have been assigned two functions viz. binding to the specific cancer antigen and inducing the effector function of these engineered T-cells to release cytotoxic cytokines. There are four major domains of these chimeric receptors viz. the extracellular domain, the hinge region, the transmembrane domain, and the intracellular domain. The antigenic or extracellular domain confers the antigenic specificity to the engineered T-cell and binds to the specific antigenic protein present on the surface of the cancer cell. This domain is primarily derived from the variable heavy and light (VH and VL) part of the specific immunoglobulin structure connected via a linker creating the single chain variable fragment structure. The transmembrane domain works as the anchor while the intracellular region initiates the cascade of intracellular signalling resulting in activation of the engineered T-cells. This interaction is MHC-independent, and therefore, highly specific to the cancer specific antigen targeted. In the life-cycle of CAR-T cell development, the second, third, fourth, and fifth generation of engineered cells contained CARs that had “extra” co-stimulatory signalling sub-domains that can potentially modulate the cytokine populations being released. This co-stimulatory feature was absent in the first-generation CAR-T cells. Further, addition of extra sub-domains that activates the JAK-STAT pathway in these engineered cells make the fifth generation CAR-T cells well equipped to kill the cancer cells in the strongest possible way currently.
In the treatment of cancer, chimeric CAR-T therapy has become a ground-breaking new pillar, especially for relapsed/refractory (r/r) B-cell malignancies that have relapsed or are resistant to treatment. The FDA authorised six CAR-T cell products for hematological malignancies, including lymphoma, leukemia, and myeloma, after witnessing remarkable clinical outcomes. Currently, the six approved CAR-T cell therapies target CD19 or B-cell maturation antigen (BCMA). Table 1 summarizes the approved CAR-T cell therapies.
Table 1: Currently approved CAR-T cell therapies
Year of approval
B-cell acute lymphoblastic leukemia (ALL) and B-cell non-hodgkin’s lymphoma (NHL)
B-cell non-hodgkin’s lymphoma (NHL) and Follicular lymphoma
Mantle Cell Lymphoma (MCL) and B-cell acute lymphoblastic leukemia (ALL)
B-cell non-hodgkin’s lymphoma (NHL)
B-cell lymphoma and leukemia
*Approved by CDSCO in India
As with all the therapeutic modalities, CAR-T cell therapy has its own share of challenges and adverse drug reactions (ADR). Cytokine Release Syndrome (CRS) is the most frequently encountered ADR in this treatment modality, where there is unregulated burst release of cytokines following the CAR-T infusion. This CRS is often accompanied by neurotoxicity known as immune-effector cell associated neurotoxicity syndrome (ICANS). B-cell aplasia, hypogammaglobulinemia, and anaemia are often reported too following CAR-T cells infusion. Antigen escape is another major challenge where the single targeting CAR-T cells are rendered ineffective because of change in the structure of the target or loss of the target antigen expression. Tumor relapse is yet another factor that is currently commonly seen with treating the solid tumors, though still in various stages of pre-clinical and clinical trial. Moreover, many antigenic targets for solid tumors are often expressed on normal cells too (there could be difference in expression levels though), CAR-T cells targeting such antigens often show “off-target effect”. These off-target effects destroy normal tissue as well expressing these antigens. Another major structural limitation in targeting solid tumors is their immunosuppressive microenvironment and stroma that limit cellular infiltration but allow infiltration of immune cells aiding in immunosuppression.
Besides these technical challenges, one major challenge is the cost of the treatment that limits its commercial use in most of the countries especially developing and underdeveloped. A single dose of the initially approved six CAR-T cells range from 300,000 USD to 500,000 USD. Several reasons, principal among them the labor-intensive and intricate manufacturing process, add to the therapy's expensive cost. The multi-step process of developing CAR-T cells is carried out in a GMP facility and calls for highly qualified workers, GMP-grade consumables, and facilities. Manufacturing failure is a prevalent issue that hinders the advancement of a strong CAR-T platform. This is because a lot of cancer patients who get CAR-T cells have already had a lot of pre-treatment such as radiation therapy. When non-targeted medicines like radiation and chemotherapy are administered repeatedly, the T-cells become exhausted, which leads to subpar efficacy and manufacturing failure.
NexCAR19: A ray of hope
India, a country with a high cancer load, requires such path-breaking treatment at affordable cost. Currently approved CAR-T cell therapies are practically unaffordable to India and to almost all the developing country, and therefore, developing its own cellular therapies is the best possible method India can have. NexCAR19, the first indigenous CAR-T cell therapy containing the humanised CAR protein against CD19, has been developed by the team headed by Dr. Rahul Purwar, Associate Professor, Department of Bioscience and Bioengineering, IIT Bombay, India. It completed its clinical trials under the supervision of Dr. Gaurav Narula, Professor at Pediatric Oncology at Tata Memorial Centre, Mumbai, India, and recently received approval from the Central Drug Standard Control Organization (CDSCO) India. Since most of the previously approved CAR-T cells contained the mouse derived single-chain variable fragment domain, development of anti-mouse antibodies is reported in many patients following the infusion of these CAR-T cell therapies. In this context, NexCAR19 is the first such therapy containing the humanised CAR receptor that mitigates the chances of development of development of immune response against the treatment. Phase I/II pivotal clinical trial with r/r B-cell lymphomas and leukaemia involved sixty individuals across many centres. The clinical data shows an overall response rate of about 70%. Comparing the safety profile to other commercially licensed CD19-directed CAR-T cell treatments, there is a noticeable improvement in terms of cytokine release syndrome (CRS) and lack of neurotoxicity. As per the reports, the cost for nexCAR19 will be approximately 30-40 lakhs INR which is about 1/10th of the cost of the currently approved CAR-T cell therapies.
Cost effective immunotherapies are essential for high cancer load nations such as India, and also for other developing and under-developed countries. Cellular therapies hold great promise in specific targeted treatments. CAR-T cell therapy is a ground-breaking treatment currently approved for haematological malignancies, while being tested for few solid tumours as well. The exorbitantly high cost of six CAR-T cell therapies approved by US-FDA are practically unaffordable in developing and under-developed countries. The recently approved first indigenous CAR-T cell therapy in India named NexCAR19 is the first therapy containing humanised CAR which has shown great results in r/r B-cell lymphoma along with significantly reduced adverse events such as CRS and neurotoxicity. Moreover, another Indian biotechnology start-up Immuneel Therapeutics, Bengaluru, India has also released initial Phase-II trial data for its anti-CD19 autologous CAR-T cell therapy (Varnimcabtagene Autoleucel) and holds a lot of promise. These indigenous products give a great hope for cost-effective CAR-T cell therapies in India, and to the developing/under-developed nations that may look at India with lots of hope for such treatments.