CAR-T Cell Therapy and NexCAR19: India’s first indigenous CAR-T cell therapy

CAR-T Cell Therapy and NexCAR19: India’s first indigenous CAR-T cell therapy

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 have 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 the fear of undergoing a 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 cancer, many of these receptors are crucial for normal functioning of the body.

Immunotherapy, which 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 destruction by the 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 from 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, block the immune escape signal that arises from the interaction between a protein on the T-cell surface and its corresponding ligand expressed on the surface of tumours. Blocking this interaction reactivates the T-cells to recognise and kill the tumor cells. Currently, PD-1, PD-L1, CTLA4, and LAG-3 are the preferred targets against which we have approved antibody-based drugs. However, ICIs face various serious challenges, such as antigenic loss in cancer cells, which creates resistance against some ICIs, while secretion and upregulation of immunosuppressive metabolites such as adenosine hinder the action of ICIs. Besides these direct actions, cancer cells and the resident immune cells show various abnormalities in important regulatory pathways, while cancer heterogeneity plays a very crucial role in resistance. On the other hand, cellular therapies such as T-cell transfer therapy, CAR-NK cell therapy, and CAR-M cell therapy are the new players on the block, among which we currently 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: 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: the extracellular domain, the hinge region, the transmembrane domain, and the intracellular domain. The antigenic or extracellular domain confers 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) parts 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 signaling, resulting in the 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 generations of engineered cells contained CARs that had “extra” co-stimulatory signalling sub-domains that could potentially modulate the cytokine populations being released. This co-stimulatory feature was absent in the first-generation CAR-T cells. Further, the addition of extra sub-domains that activate the JAK-STAT pathway in these engineered cells makes the fifth generation CAR-T cells well equipped to kill 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.

Read more: https://www.pharmafocusasia.com/articles/car-t-cell-therapy-and-nexcar19

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