In recent years, chimeric antigen receptor (CAR) T-cell therapy has changed outcomes for patients with aggressive blood cancers that no longer respond to standard treatments. In some acute leukaemias, CAR T-cell therapy has led to remissions lasting months or even years. Early-stage trials have explored its use in severe autoimmune diseases like lupus as well, where it may help reset a misfiring immune system.
Originally developed in the early 1990s, the central idea behind CAR T-cell therapy is to retrain the body’s own immune cells to recognise and destroy rogue targets. T cells — the patrolling white blood cells — often fail to identify cancer cells. So scientists extract a patient’s T cells and insert genetic instructions that make them express the synthetic molecule, CAR. It gives T cells the ability to detect a specific ‘tag’ — most often CD19, which is found on nearly all B cells — that are the primary culprits in these cancers.
Once these reprogrammed T cells are infused back into the body, they expand, circulate, detect, and eliminate. The process is targeted and potent — but also slow, expensive, and complex. It requires personalised cell harvesting, lab-based genetic engineering using viral vectors, and chemotherapy to prepare the body to receive the modified cells.
Vishwanath S., a senior consultant in medical oncology, Apollo Hospitals, Bengaluru, estimated from personal practice that CAR T-cell therapy in India typically costs around ₹60-70 lakh. “Roughly ₹30-35 lakh goes toward manufacturing the personalised CAR T-cells through complex ex vivo processing,” he said. “The rest covers hospitalisation, supportive care, and monitoring for two to three weeks — including side effects, infections, and post-infusion care.”
Engineering T-cells inside the body
A study in Science on June 19 by researchers from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases, Capstan Therapeutics, and the University of Pennsylvania takes the core idea of CAR T-cell therapy and moves it entirely inside the body.
Instead of extracting T cells and engineering them in a lab, the researchers delivered messenger RNA directly into circulating immune cells using tiny, fat-based molecules known as lipid nanoparticles (LNPs). Commonly used in mRNA vaccines, they help genetic instructions enter target cells. To make sure the message reached the right cells, the researchers added a kind of biological address label: antibodies that bind specifically to CD8+ T cells, the immune system’s frontline killers. This targeted formulation, called a CD8-targeted lipid nanoparticle (CD8-tLNP) allowed the instructions to be delivered with precision.
When injected into mice, tLNPs carrying instructions for a CD19-targeting CAR successfully reprogrammed circulating CD8+ T cells, while in cynomolgus monkeys, a CD20-targeting version was used. Within days, B cells were depleted across multiple tissues, and tumours regressed in mice — all without personalised cell processing, viral vectors or chemotherapy. In monkeys, the treatment turned most CD8+ T cells (up to 85%) and nearly all related immune cells (95%) into cancer fighters after the second or third dose, showing strong results.
Bypassing bottlenecks
The key advantage of this platform is that it avoids several of the most restrictive components of current CAR T-cell therapy, and without compromising function.
Since the CAR instructions were delivered using mRNA rather than viruses, the changes to the immune cells were temporary, lowering the risk of permanent genetic side effects. The therapy also worked without lymphodepleting chemotherapy — a preparatory treatment that wipes out a patient’s existing immune cells to make space for the modified T cells. This step carries risks of serious secondary infections due to low immunoglobulin levels, necessitating prolonged and recurrent hospital admissions. And because the entire process took place inside the body, there was no need for custom lab-based cell manufacturing. Dr. Vishwanath noted that the ability to bypass both complex in vitro manufacturing and chemotherapy-based lymphodepletion could make CAR T-cell therapies safer and more accessible for frail, elderly, and comorbid patients.
The researchers also introduced a newly developed component, Lipid 829, a biodegradable carrier designed for improved tolerability. It showed faster clearance from the liver and lower inflammatory markers than earlier nanoparticle formulations while still delivering the CAR instructions effectively to T cells.
Signs of an immune reset
Beyond cancer, the study also explored whether the same platform could target B cells in autoimmune settings, where they mistakenly attack the body’s own cells.
In monkeys, the treatment led to near-complete depletion of circulating and tissue-resident B cells, including in the spleen, lymph nodes, and bone marrow. Over the following weeks, fresh B cells gradually returned — and when they did, they were mostly naïve, like new recruits with no memory of having turned against their own body. This mirrored observations from human trials of conventional CAR T-cell therapy in lupus, where long-term remission has been linked to repopulation by naïve B cells.
The researchers also tested the platform on blood samples from patients with lupus and myositis. In laboratory assays, CD8-tLNPs successfully reprogrammed the patients’ own T cells, which then eliminated their B cells in vitro.
While these findings remain preclinical, they reinforce that transient CAR expression might offer a way to reset the immune system without long-term immunosuppression.
What the safety data say
The risks associated with conventional CAR T-cell therapy include cytokine release syndrome (CRS), neurological complications, and, in some cases, long-term effects from random integration of viral vectors in the patient’s genome.
A patient who received CAR T-cell therapy for primary mediastinal B-cell lymphoma at Tata Memorial Centre in June 2024 said it was her fourth line of treatment after three earlier regimens had failed.
“It finally put my cancer into remission,” she said. “But recovery hasn’t been simple. I stayed 27 days in the hospital because of sepsis. I’ve had pneumonia and still get secondary infections due to low immunoglobulin levels. Another friend is facing something similar. One of the others who had the treatment with us — she had leukaemia — passed away recently, possibly from the same. I’m better; cancer free, but I wouldn’t say I have been able to get back to how life was before my diagnosis.”
She does however call herself an outlier and that others have had easier recoveries.
The new study aimed to minimise some of these risks by using non-integrating mRNA and the new lipid nanoparticle.
In monkeys, the treatment was mostly safe. Inflammation markers rose slightly after infusion but normalized with standard premedication of antihistamines and corticosteroids. Liver side effects, a concern with nanoparticles, were minimal with Lipid 829.
However, one monkey developed a serious immune overreaction resembling hemophagocytic lymphohistiocytosis — a known CAR T-cell therapy risk — after the last infusion and had to be euthanised. While this was a single case, it underscored the importance of careful dosing and clinical monitoring.
Dosing like a drug
In monkeys, two or three intravenous infusions, spaced 72 hours apart, were enough to induce CAR expression in circulating CD8+ T cells and achieve near-complete depletion of B cells across multiple tissues.
Because the formulation was standardised, not patient-specific, and required only intravenous dosing, the procedure resembled a biologic drug infusion more than a cell therapy protocol. In principle, this delivery model could reduce the need for specialised infrastructure.
The platform represents one of the most developed in vivo CAR T-cell systems tested to date. It showed functional results in mice and non-human primates, used a defined dosing regimen, and included safety modifications such as enhanced CD8 targeting and premedication.
Dr. Vishwanath said, “Robust human trials will be essential to confirm safety, efficacy, and long-term outcomes”. How the body will react to the engineered T cells and repeat dosing remain open questions as well.
“Reproducibility will be another major issue,” Pankaj Prasad, who has worked extensively in cell and gene therapy in India and Singapore, cautioned. “When pilot experiments are performed in the R&D lab by humans and when they are reproduced by automated machines, there is always variability. The small-scale results do not match with the automated machine-generated results and usually require another loop of standardisation.”
The study lays the technical groundwork for translation, but the safety, efficacy, and scalability of this approach in humans remain to be established. If future trials succeed, it could expand the scope of CAR T-cell therapy beyond what current platforms allow.
Matters for India
India faces a high burden of B cell-driven cancers. Regional cancer registries show that diffuse large B-cell lymphoma (DLBCL) — one of the most aggressive types — makes up 34-60% of non-Hodgkin lymphoma cases, followed by follicular lymphoma. Acute lymphoblastic leukaemia is the most common cancer in Indian children accounting for 75% of all cases. All of these conditions are candidates for conventional CAR T-cell therapy.
India’s burden of autoimmune disorders is also rising, with one study suggesting a 30% increase in prevalence since the COVID-19 pandemic.
The approach described in the new study avoids many of the constraints that have limited the therapy’s use in India. If proven safe and effective in humans, it could be ideal for settings where specialised infrastructure is limited and patient volume is high. Furthermore, a simplified, infusion-based platform like this could make advanced immunotherapy more widely feasible, especially in places where few cell therapy units and trained specialists limit access.
If it passes all the quality checks, this platform could shift not just how we deliver CAR T-cell therapy but also who can benefit from it.
Anirban Mukhopadhyay is a geneticist by training and science communicator from Delhi.
Published – June 20, 2025 07:00 am IST
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