India's Oncological Milestone: Nexcar19 Unveils First Homegrown CAR T-Cell Therapy
Undoubtedly, cancer stands as one of the most terrifying diseases known to humanity. Its grip on our collective fear is rooted in the ongoing quest for a definitive cure. As cancer treatment methods evolve, so do the various types of cancer since cancer itself mutates and adapts over time. Yet, amidst this daunting reality, a glimmer of hope emerges with the introduction of CAR T-cell therapies. Although first introduced in the USA in 2017, CAR T-cell therapy arrived in India only in late 2023, embodied in NexCAR 19, heralding a new chapter in the fight against cancer. Let us delve into the intricacies of this groundbreaking therapy and the promise it holds for those battling this relentless foe.
The Evolution of Cancer Treatments
Traditional cancer treatments like surgery, chemotherapy, and radiation therapy have been around for a long time. But now, there are new treatments, like targeted therapies and immunotherapy, that are changing how we fight cancer.
Then, a new type of immunotherapy—CAR T-cell therapy—emerged. It is very promising for treating advanced blood cancers like leukemias and lymphomas. CAR T-cell therapy is a new immunotherapy for cancer therapy in which a patient's immune cells are engineered in the lab to fight cancer. Since 2017, the US FDA has approved six CAR T-cell therapies, which are mainly used for blood cancers.
Even though CAR T-cell therapy is exciting, it doesn't work for everyone and can be very expensive. Nevertheless, after a lot of research, it is now a standard treatment for aggressive lymphomas in many countries.
NexCAR 19 In India
On October 13, 2023, the Central Drugs Standard Control Organisation (CDSCO) in India approved the first CAR T-cell therapy (NexCAR 19), a groundbreaking immunotherapy developed by ImmunoACT, a company associated with the Indian Institute of Technology Bombay. This therapy is designed to treat leukemia and refractory or relapsed lymphoma, which are cancers of the lymph system.
As mentioned above, CAR T-cell therapy was initially approved for specific cancer types in the US in 2017. Since then, six therapies by different drugmakers have been authorized by the US Food and Drug Administration (FDA). This therapy is termed a "living drug" because it utilizes a patient's own genetically engineered cells to target cancer.
The Living Drug
CAR T-cell therapy is often described as a "living drug" because it involves modifying a patient's own immune cells to fight cancer.
T cells, which are crucial to the immune system, are used in CAR T-cell therapy. These cells are collected from the patient and then engineered in a lab to produce special proteins called chimeric antigen receptors (CARs). These receptors are designed to recognize specific proteins, or antigens, found on the surface of cancer cells.
Once the T cells are modified to express CARs, they are multiplied in the lab and then infused back into the patient. The hope is that these CAR T-cells will continue to multiply within the patient's body and target and kill cancer cells that display the antigen recognized by the CAR.
The FDA-approved CAR T-cell therapies mainly target antigens found on B cells, such as CD19 (Cluster of Differentiation 19) or BCMA (B-cell maturation antigen).
CAR T-cell therapies involve various components, including external domains made from lab-made antibodies, which help the receptor recognize tumor cells, as well as internal signaling and co-stimulatory domains, which transmit signals into the cell after interacting with an antigen. These components can affect the overall function of the engineered cells.
Here is the simple flowchart of how CART T-cell Therapy works
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| Collection of T-cells from patient's blood sample |
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| Engineering of T-Cells |
(Lab Work)
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| Production of CAR T-Cells |
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v
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| Infusion of CAR T-Cells into Patient |
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v
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| Recognition & Targeting of Cancer Cells |
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v
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| Activation & Killing of Cancer Cells |
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v
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| Proliferation & Persistence of CAR T-Cells |
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v
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| Monitoring & Evaluation |
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| Long-term Immune Memory |
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Understanding the Side Effects of CAR
CAR T-cell therapies show promising results in fighting cancer, but they can also come with serious reactions. Like with any cancer treatment, there's a risk of side effects, such as a drop in antibody-producing B cells and a higher chance of infections. One significant concern is cytokine release syndrome (CRS).
CRS happens when infused T cells release cytokines (small proteins that control inflammation in the body) into the bloodstream, causing high fevers and drops in blood pressure. It can be dangerous, but it also indicates that the therapy is working, especially in patients with extensive cancer.
Another side effect to watch out for is neurologic effects, like confusion and impaired speech. These effects, known as immune effector cell-associated neurotoxicity syndrome (ICANS), are still not fully understood.
What Makes Nexcar 19 Unique Among Car T-Cell Therapies?
CAR T-cell therapies are very expensive, typically costing around $400,000 in the US. Fortunately, the NexCAR 19 (Actalycabtagene autoleucel), developed by ImmunoACT in collaboration with the Tata Memorial Centre (TMC) within India, offers it to Indian patients at a significantly lower cost, around Rs 30-40 lakhs.
Clinical data from phase 1 and 2 trials indicate a nearly 70 percent overall response rate among approximately 60 tested patients, including young adults and adults. The therapy also improved the safety profile, particularly in terms of cytokine release syndrome (CRS) and the absence of neurotoxicity, compared to other commercially approved CD19-directed CAR T-cell therapies.
This approval represents a significant milestone in India's cancer care landscape, offering new hope and potential advancements in treatment options for patients.
Expanding Horizons: Exploring New Targets
As research on CAR T-cells advances rapidly, hundreds of ongoing clinical trials are uncovering new possibilities. One exciting avenue of exploration is the identification of additional antigens on tumor cells that could serve as targets for CAR T-cells.
While CAR T-cell therapies targeting CD19 and BCMA have gained FDA approval, researchers have also developed therapies targeting other antigens commonly found in blood cancers, including those targeting multiple antigens simultaneously.
But what about using CAR T-cells to treat solid tumors like brain, breast, or kidney cancer? Progress in this area has been slower. Efforts to identify antigens unique to solid tumors have faced challenges, with many attempts yielding little success.
Solid tumors also present challenges in their microenvironment, such as physical barriers preventing CAR T-cells from reaching tumor cells or immune-suppressing molecules hindering their function.
Another hurdle is tumor heterogeneity, meaning tumors of the same type can vary greatly between patients and even within the same patient. This variability can make it difficult to find suitable targets for CAR T-cell therapies.
Despite these obstacles, researchers are persistently exploring ways to overcome them. Some are developing "armored" CAR T-cells capable of navigating the hostile tumor microenvironment by secreting specific molecules. Others are focusing on standard CAR-engineering techniques to target single-surface antigens on cancer cells.
"Off-the-shelf" CAR T-Cell Therapies
Researchers are rethinking the approach to CAR T-cell therapies by exploring alternative sources of immune cells, moving away from patient-derived cells to those from healthy donors. The aim is to develop "off-the-shelf" CAR T-cell therapies readily available for use, rather than needing to be custom-made for each patient.
While FDA-approved CAR T-cell therapies utilize a disarmed virus to deliver genetic material into patient-derived T cells, off-the-shelf CAR T-cells in clinical trials are employing gene-editing technologies like TALON and CRISPR to induce donor-derived T cells to produce CARs.
Moreover, some off-the-shelf CARs utilize a different immune cell type called natural killer (NK) cells. Some employ nanotechnology and mRNA-based approaches, allowing CAR T-cells to be generated inside the body.
A Second-line Treatment Option?
Initially, CAR T-cell therapy has been considered a last resort for cancer treatment, typically administered when other treatments have failed. However, recent large clinical trials have shown that CAR T-cell therapy can be more effective than standard treatments for certain types of cancer, such as non-Hodgkin lymphoma that has relapsed after initial chemotherapy. This has prompted experts to consider CAR T-cell therapy as a potential second-line treatment option, particularly for high-risk patients.
For children with acute lymphoblastic leukemia (ALL), using CAR T-cells as a second-line treatment could offer significant benefits, especially for those at high risk of disease recurrence after initial chemotherapy. Clinical trials are underway to evaluate CAR T-cell therapy in children with ALL who do not respond optimally to initial chemotherapy.
The Bottom Line
In essence, ongoing research and advancements in cellular therapies offer hope for improving cancer treatment outcomes and expanding therapeutic options for patients. NexCAR19 in India stands out for offering affordable CAR T-cell therapy, a stark contrast to the high costs in the US. With plans for manufacturing facilities across India, they aim to treat 1,200 patients annually. This achievement not only marks India's first CAR T-cell therapy but also sets a model for global collaboration, showing that low- and middle-income countries can build similar therapies from scratch.
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