Our immune system: Nature’s defense mechanism
Our body is capable of self-defense. Whenever we catch an infection, we become normal in the next few days. Many a time this happens without any treatment. The reason being internal immense capacity of the body to self-defend. Commonly it is known as immunity. It is our immense natural power. The most important cells of the body which are responsible for this defense are called T cells. They can detect foreign invaders. Creating its own army and then selectively attacking the enemy. It involves a process of detection, expansion of the army and killing. Not only this, but they retain the memory. So, God forbidden the infection or the enemy comes again they are already knowledgeable. The same should be true about cancer. Cancer cell in true sense is also foreign to the body. But cancer cells are smarter and they evolve escaping mechanisms.
In the ever-evolving battle against cancer, a new weapon has emerged—one that does not kill cancer cells through drugs or radiation, but through the patient’s own reprogrammed immune cells. T cells which are our defense are trained to detect and kill the enemy. This innovation, known as chimeric antigen receptor (CAR) T-cell therapy, represents one of the most profound medical advances of the 21st century. It is the culmination of decades of immunological research, genetic engineering, and clinical courage.
Every cell on its surface has various structures or proteins commonly called antigens. They are like identities of this cell. T cells have the capacity to differentiate them and diagnose them as self or foreign. Chimeric antigen receptor -CAR T- cell therapy is the process of training individuals own T cells in recognising these foreign surface markers present on cancer cells. The problem with these identifiable markers is, sometimes there presence on normal cells. In that case T cells may start killing normal cells. This is the reason for slow progress of science as it evolves. One must be sure about the target.
The CAR T Breakthrough: Reprogramming T cells to fight cancer
Today, CAR T-cell therapy stands at the intersection of hope and science. It has transformed the landscape of blood cancer and is now striving to conquer solid tumors. For the public, the name may still be unfamiliar, but its impact is unmistakable. Patients once given months to live now enjoy years of remission, sometimes even cure.
How it works?
CAR T-cell therapy is a type of immunotherapy. It starts with collecting a patient’s own white blood cells by a machine called cell separator. The process is like giving blood donation. From these white T cells, a type of white blood cell essential to immune defense, are separated called T cell separation. This is a very technically demanding process and costs a lot. If driven in a closed system, the cost goes up to Rs 10 lakhs. This is an important reason for the high cost of the product. Using open processes, the cost may be slightly reduced. These cells then need to be manipulated so that they start expressing receptors on the surface. This requires the introduction of genes inside these cells. Introduction of anything into cells is a technically serious proposition strongly regulated by law. Firstly, a new gene is designed which can produce required protein in t side the cell. Then an approved non dangerous virus is chosen which can take this gene inside the cell and place it at an appropriate place. This level of technology and genetic engineering has evolved over many years and is still being developed. Once new genes go into T cells, they produce CAR receptors on the cell surface. The process requires constant monitoring as only the desired number of viruses should enter a cell, otherwise it may do harm, it requires a quality check at all stages, including sterility of the product. This is done in the lab. Once the product is ready it is introduced back to the patient. These T cells are genetically engineered to express a chimeric antigen receptor (CAR a synthetic molecule that allows them to recognise and attack cancer cells expressing a specific antigen, such as CD19. This new receptor is a fusion of several parts: an antibody fragment that targets cancer, a transmembrane domain, and intracellular signaling domains that activate the T cell. Once these “trained” cells are infused back into the patient, they seek out and destroy cancer cells, expanding in the body and providing long-term immune surveillance.
We can use different genes to put different molecules on the cell surface. This would allow T cells to reach different cancer cells. Every cancer cell and type will have a different molecule unique to that type of cancer.
CAR T- cells are living drugs. Unlike chemotherapy, which diminishes over time, CAR T- cells can multiply and persist, providing ongoing protection.
The first success of CAR T therapy was in acute lymphoblastic leukemia (ALL), particularly in children and young adults. The ELIANA trial, a multinational study, led to the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-ALL in 2017.
In large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), Yescarta (axicabtagene ciloleucel) was approved based on the ZUMA-1 trial, which demonstrated an overall response rate of 82 per cent with a 54 per cent complete response. Other approved indications include follicular lymphoma, mantle cell lymphoma, multiple myeloma.
These therapies have shown remarkable results where all other treatments had failed. Median survival has increased substantially, and in some cases, durable remissions suggest potential cure.
Solid tumors present a different challenge. Unlike blood cancers, which have freely circulating cells, solid tumors are embedded in a hostile microenvironment. They may express antigens less uniformly, hide from immune cells, or suppress them through checkpoint molecules.
Despite these hurdles, early trials have shown promise:
- Glioblastoma: EGFRvIII-targeted CAR T cells have been studied, though results were mixed.
- Pancreatic cancer: Mesothelin-targeted CAR T cells are in trials, with early signs of activity.
- Ovarian cancer: MUC16 and mesothelin targets are under evaluation.
- Prostate cancer
- Lung cancer
More recent innovations such as armored CARs (which secrete cytokines), dual-specific CARs (targeting two antigens), and logic-gated CARs (which activate only in tumor-specific contexts) are addressing the immunosuppressive nature of solid tumors.
While first-generation CAR T-cell therapies were revolutionary, scientists quickly recognised the need to address their limitations, especially when tackling complex solid tumors. This has led to the evolution ofnext-generation CAR T-cell platforms, incorporating advanced engineering features to enhance efficacy, reduce toxicity, and broaden clinical utility.
Armored CAR T Cellsare engineered to secrete pro-inflammatory cytokines such as IL-12 or express ligands that counteract the tumor’s suppressive microenvironment. These modifications help the CAR T cells resist tumor-induced exhaustion and enhance their survival in hostile solid tumor niches.
Dual and Tandem CAR T Cellsexpress two different CARs targeting separate tumor antigens or one CAR that can bind two antigens simultaneously. This approach addresses antigen heterogeneity and reduces the risk of tumor escape due to antigen loss.
Logic-Gated CARsemploy synthetic biology to construct T cells that activate only in the presence of specific combinations of antigens. This precision reduces off-tumor toxicity and improves safety, particularly critical when targeting antigens also expressed on normal tissues.
Switchable or ON/OFF CARsallow external control of T-cell activity using small molecules or antibodies, enabling clinicians to modulate therapy post-infusion—a major leap in safety.
Allogeneic “Off-the-Shelf” CAR T Cellsare created from healthy donors and edited to eliminate graft-versus-host and rejection risk. Products Allogene Therapeutics aim to reduce production time and cost, making therapy more accessible.
CAR T-cell therapy’s remarkable efficacy comes with distinct toxicities, particularly: Cytokine Release Syndrome (CRS): A systemic inflammatory response resulting from rapid T-cell activation and cytokine secretion. Symptoms range from fever and hypotension to life-threatening organ dysfunction. The incidence varies across products and indications. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Manifesting as confusion, aphasia, seizures, or cerebral edema. Though often reversible, ICANS can be fatal without prompt treatment. Prolonged Cytopenias and Hypogammaglobulinemia: Common in heavily pretreated patients. Requires long-term monitoring and supportive care including IVIG for infection prevention. Secondary Malignancies: Rare but potential risk due to integration of viral vectors used for gene transfer. Long-term registries are underway. Rigorous protocols, early intervention algorithms, and enhanced manufacturing processes have significantly reduced the severity and duration of toxicities in recent trials.
CAR T – cell therapy redefined the cancer treatment and where does India stands?
CAR T-cell therapy has already redefined cancer treatment in select hematological malignancies. However, its future lies not in remaining an exception but becoming a foundation of oncologic care across all tumor types and patient groups. Current use is limited to relapsed/refractory settings. However, combining CAR T cells with first-line regimens—chemotherapy, radiation, or checkpoint blockade—may enhance complete response rates and potentially reduce relapse. Trials inminimal residual disease (MRD)settings are underway, particularly in multiple myeloma and lymphoma. Instead of waiting for disease to relapse, CAR T cells may serve as consolidation post-transplant or after induction therapy. For instance, in myeloma, combiningCAR T with immunomodulatory drugs (IMiDs)post-response could prolong remission. Tumors often express PD-L1 to suppress T cells. Combininganti-PD-1 or CTLA-4 inhibitors with CAR T therapycan overcome this, leading to deeper and sustained responses, especially in solid tumors.
Ongoing clinical trials in glioblastoma, lung cancer, and mesothelioma are evaluatingPD-1–resistant CAR T cellsor administeringanti-PD-1 post-CAR infusion.
AI and machine learning are being deployed to: Predict immunogenic antigens. Optimise TCR and CAR construct design, forecast cytokine storm risk, Stratify responder’s vs non-responders via gene expression signatures. This will result innext-gen CARs tailored to each patient, significantly improving outcomes and reducing toxicity.
CAR T-cell therapy has already cured relapsed pediatric B-ALL. Pediatric solid tumors—likeneuroblastoma (GD2),sarcomas, andmedulloblastomas—are under exploration with antigen-specific CARs. Long-term follow-up is assessing growth, development, and fertility impacts.
For countries like India, indigenous development and frugal engineering hold the promise of global democratisation of cell therapy. The challenge lies in building the necessary clinical infrastructure, training a new oncology workforce, and ensuring ethical and affordable delivery of these advanced treatments.
CAR T therapy reminds us that the future of oncology lies not just in attacking the tumor, but in empowering the immune system to remember, adapt, and overcome. As we move forward, CAR T cells will likely form the core of personalised cancer immunotherapy—engineered not only to cure disease, but to prevent it from ever returning.