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Business News/ News / India/  NexCAR 19 cancer therapy: Conceived at IIT Bombay, delivered in Tata Memorial

NexCAR 19 cancer therapy: Conceived at IIT Bombay, delivered in Tata Memorial

  • CAR T-cell therapy involves modifying a patient’s T-cells—white blood cells that are integral to the immune system. The lab-modified cells are then infused in the patient to multiply and fight cancerous cells. The therapy costs $400,000 in the US and tenth of that in India. But, does it work?

Rahul Purwar, founder of ImmunoACT. Purwar portioned off most of his office space to create a lab where he could conduct research on CAR T-cell therapy.

Mumbai: Sheeba Verghese, 60, the founder of a disability-focused non-governmental organization in Faridabad, had always had a beautiful, thick shock of hair. Three years ago, however, she noticed something that would eventually take a toll on her scalp—there was a growth on her tonsils. Tests revealed that she had diffuse large B-cell lymphoma (DLBCL), one of the most common types of lymphoma (cancer of the lymph nodes). She tried naturopathy in Kerala, and then chemotherapy at the All India Institute of Medical Sciences (AIIMS) in New Delhi. After eight rounds of chemotherapy through much of last year, Sheeba had lost all her hair, even her eyebrows. But for a while, the treatment seemed to be working.

Mumbai: Sheeba Verghese, 60, the founder of a disability-focused non-governmental organization in Faridabad, had always had a beautiful, thick shock of hair. Three years ago, however, she noticed something that would eventually take a toll on her scalp—there was a growth on her tonsils. Tests revealed that she had diffuse large B-cell lymphoma (DLBCL), one of the most common types of lymphoma (cancer of the lymph nodes). She tried naturopathy in Kerala, and then chemotherapy at the All India Institute of Medical Sciences (AIIMS) in New Delhi. After eight rounds of chemotherapy through much of last year, Sheeba had lost all her hair, even her eyebrows. But for a while, the treatment seemed to be working.

In November, the final reports came in, and the news was not good—the cancer had returned. Sheeba’s doctors suggested a stronger dose of chemotherapy, saying she had only weeks to live. Instead, she and her husband decided to try a different approach. “The next day, we were at Amrita Hospital in Faridabad, to ask if CAR T-cell therapy was possible in our case," recounts Sanjay Verghese, her husband.

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In November, the final reports came in, and the news was not good—the cancer had returned. Sheeba’s doctors suggested a stronger dose of chemotherapy, saying she had only weeks to live. Instead, she and her husband decided to try a different approach. “The next day, we were at Amrita Hospital in Faridabad, to ask if CAR T-cell therapy was possible in our case," recounts Sanjay Verghese, her husband.

CAR T-cell therapy involves modifying a patient’s T-cells in a lab (a T-cell is a type of white blood cell integral to the immune system). The modified cells are then infused back into the patient so that they can fight the cancerous cells, multiply in the body, and prevent the resurgence of cancer. The treatment is offered to patients suffering from certain forms of cancer who do not respond to chemotherapy, immunotherapy by monoclonal antibodies, or a bone marrow transplant.

This February, 28 days after the first infusion of the CAR T-cell treatment, Sheeba’s reports came in. Her cancer had been arrested.

NexCAR 19 effect

A researcher works on CAR T-cell therapy in IIT Bombay.

Sheeba received a new kind of CAR T-cell therapy that is infused intravenously. This home-grown version, called NexCAR 19 (the formal name is actalycabtagene autoleucel), was designed and developed on a shoestring budget in a tiny room at the Indian Institute of Technology (IIT) Bombay by professor Rahul Purwar with his PhD students Alka Dwivedi and Atharva Karulkar, with support from Dr Gaurav Narula, Dr Hasmukh Jain and other doctors from Tata Memorial Hospital, Mumbai.

According to an article published on the website of the National Cancer Institute, the US government’s principal agency for cancer research, the therapy modifies T-cells with a chimeric antigen receptor (CAR) to target CD19, an antigen/protein usually seen in large amounts on the surface of B cells. A B-cell is a type of white blood cell; an antigen warns the body that something is foreign and is capable of stimulating an immune response. After being refined in the lab for years, the NexCAR 19 therapy was first tried out on a patient on 4 June 2021 at Tata Memorial Hospital, as part of a human trial. NexCAR 19 costs a tenth of the treatment in the US, so it is cheaper in relative terms. According to the doctors, CAR T-cell therapy costs $400,000 in the US, whereas in India, where the therapy became commercially available in November 2023, it can currently be done for 40-45 lakh.

So far, NexCAR 19 has been administered to 98 patients (including 76 during clinical trials) across 45 hospitals. The response rate is 60-70%, according to data provided to Mint by ImmunoACT, a startup founded by Purwar and incubated at Society for Innovation and Entrepreneurship (SINE) at IIT Bombay to commercialize the therapy. About 50% of the patients were completely cured after three months. The remainder showed a partial response, indicating they may need additional treatment, such as a bone marrow transplant or chemotherapy, ImmunoACT told Mint.

Millions of people suffer from the kind of cancers CAR T-cell therapy addresses but the treatment is inaccessible for most people because of its prohibitive cost. The team sought to develop a therapy that would make a difference in India and other developing countries, and proving its efficacy was the first step to that end. “We have done what the biggest pharma firms have not managed," Purwar told Mint. “When we started out, there were countless discussions with companies but no one was convinced. They did not believe that a therapy developed by academia would bring them commercial success. Now that we have succeeded, things have changed," he added.

Not a silver bullet

To be sure, CAR T-cell therapy is not a silver bullet—success is not guaranteed. As the Stanford Medicine website noted in 2021, in a review of a Stanford study, “CAR T-cell therapy works for many types of blood cancers, but more than half of patients relapse."

And, although it is far cheaper than being treated abroad, the cost of CAR T-cell therapy is still exorbitant by Indian standards, at 40-45 lakh. In comparison, chemotherapy in a government hospital costs about 4.5 lakh, which is a fortune in itself for most Indians. Worse, CAR T-cell therapy is not covered by insurance and the costs will financially cripple most families. But for patients like Sheeba, who are told they have only weeks to live, CAR–T cell therapy is akin to a Hail Mary pass in American football, when a team is on the brink of defeat with seconds left on the clock.

A team effort

Purwar, an alumnus of Lucknow University, earned a doctorate in molecular medicine from Medizinische Hochschule Hannover (also known as Hannover Medical School), Germany in 2006, and then pursued a post-doctoral programme in immunology at Harvard Medical School from 2007 to 2012. The following year, he returned to India and joined IIT Bombay’s bioscience department, where he began his research on CAR T-cell therapy.

Initially, it started as an academic project and was supported through research grants. Purwar worked with his students Dwivedi and Karulkar. Dwivedi, who is from Mirzapur in Uttar Pradesh, had joined IIT Bombay in 2015 as a PhD student under Purwar. Her PhD project focused on developing indigenous CAR T-cell therapy for blood cancer patients. She finished her PhD in 2021 and is currently working at the National Cancer Institute, under the National Institutes of Health (NIH), in the US. NIH is US government’s medical research agency.

A file photo of IIT Bombay.

Soon, their work attracted the attention of Dr Narula, a paediatric haematologist-oncologist at Tata Memorial Hospital. Narula recalls how he got in touch with Purwar. “Why was CAR T-cell research being done by an IIT Bombay professor in the bioscience department, I wondered. So, I met up with him. ‘I need a car and you need a driver,’ I told Purwar. He said he’d need two years but was ready in six months," Narula told Mint over a call from Madrid, where he had gone for a seminar on CAR T-cell therapy. Thereafter, the IIT Bombay team and Tata Memorial doctors started working together.

Dr Hasmukh Jain, an oncologist at Tata Memorial Centre, would join the team later. “At Tata hospital, 30% of the patients under 15 years did not respond to treatments and at times had barely six months left to live. Bone marrow transplantation or chemotherapy did not work on them and there were one or two such patients on a daily basis," Dr Jain told Mint.

A roadblock and US help

A number of therapies were developed and tested on animals.

However, the going was far from easy. The researchers were trying to develop CAR T-cells that would be able to withstand attacks from the immune system but those efforts did not succeed. “The initial years we had many failures," Dwivedi told Mint. So, the team turned to experts in the US for help, including those at the NIH.

One of the specialists they consulted with extensively at NIH over the next decade was Terry Fry, executive director of the Gates Institute at the University of Colorado Anschutz, who is also a professor of paediatrics, haematology and immunology. Clinical trials of CAR T-cell therapy had by then demonstrated the ability to induce a remission in 70-80% of children who were treated.

“In my many years in this profession, being associated with Dr Gaurav (Narula) and Dr Rahul (Purwar) and their CAR T cell programme has been one of the most humbling and satisfying opportunities in my career," Fry told Mint over a call from the US.

After gleaning insights from the Americans, the Indian team renewed its research efforts. “The challenge here is working on live cells. How thousands of modified cells, which show a positive response under a microscope, work in the human body, and at what pace they multiply. It is different for each human body," said Jain.

A number of therapies were developed and tested on animals. The team noticed that one set of modified T-cells performed well in destroying cancer cells without triggering a full-blown immune reaction that would do harm. This would eventually become NexCAR 19. The next step was to get approval for human trials.

The road to the trials

The process to apply for clinical trials for NexCAR 19 was not simple and had to be done in batches for acute lymphoblastic leukaemia (ALL) and DLBCL, blood cancers found in children and adults.

In 2020, IIT Bombay and Tata Memorial Hospital filed for phase-1 clinical trials on paediatric ALL with the Central Drugs Standard Control Organisation (CDSCO). In 2021, ImmunoACT applied again to the CDSCO for an adult DLBCL phase-1 trial. Both applications were approved in 2021. Dr Narula oversaw the pediatric ALL trial, while Dr Jain supervised the adult DLBCL trial.

Narula, 57, recounts that getting through to regulators was an exhaustive and nerve-wracking experience since larger pharma firms have an army of researchers, lawyers, patent experts, and regulatory officers, whereas in this case it was a clutch of professors, doctors and PhD students. “We had two volumes with 50 annexures each, which we placed with the regulator and ethics committee...they grilled us for hours and over days," said Narula.

Initially, the ALL and DLBCL patients were given low doses of the therapy and this was gradually increased. Subsequently, the clinical trials were expanded to other indications such as B-Cell Leukaemia and Lymphoma. The phase-1 trial went on until 2022 and the results showed a good safety profile.

Encouraged, the team submitted an application before the CDSCO for approval of phase-2 clinical trials, which was received in 2022. The phase-2 trial, in patients aged 15 and above, commenced in December 2022 and ran till August 2023.

The results of phase-2 showed a 70% overall response rate—proportion of patients who had a partial or complete response to the therapy—the company claimed.

The celebrations after each success were muted. “We celebrated the phase I trial success by going to a rooftop restaurant near IIT Bombay and next morning we were back in the hospital treating patients," said Dr Jain.

Buoyed by the positive response from the trial, Purwar’s startup, ImmunoACT, applied for market authorization of the treatment and received approval from the CDSCO in October 2023, for patients aged 15 and above. The paediatric phase-2 trial (named ESHA) is currently being conducted by Tata Memorial Centre, the parent body of Tata Memorial Hospital, and is expected to be concluded shortly. Jain told Mint that patients will be monitored over the next 15 years at least to keep track of any changes.

Challenges continue

The newness of the therapy is causing hesitancy among patients. There are also monitoring issues.

While many hospitals across India have signed up with ImmunoACT to offer this treatment, the newness of the therapy is causing hesitancy among patients. Then there are monitoring issues, which pose a challenge in developing countries. “I was less concerned with the challenges of manufacturing given the scientific expertise of the team in India than the ability to monitor the patients after they have received the treatment. The doctors in India treat a large number of patients and many do not have access to healthcare near their home once they are discharged," Fry pointed out.

The global shortage of lentiviral vector, a virus strain used for gene therapy and CAR T-cell therapy, is causing concern regarding the scalability of the operation. Lentiviral vectors are the critical starting material for most CAR T-cell therapies. “The cost of the lentiviral vectors is one of the biggest issues. The vector is derived from HIV. Regulators in India and elsewhere have very high standards on the safety of the vector used for manufacturing a clinical product and scaling it for a large number of patients is a challenge," Fry told Mint.

It remains to be seen if this small team will succeed in its goal to take CAR T-cell therapy to the masses and conquer cancer. For now, their efforts have given Sheeba Verghese new hope. The survivor has kept her locks of hair. “She has kept them as a reminder of what she went through and the strength that it takes," said her husband. Sheeba’s next scan is in April.

ABOUT THE AUTHOR

Devina Sengupta

Devina tracks and writes on workplaces, human resources and education for Mint. She also occaisionally writes an opinion column. She hosts a podcast on interesting HR trends in corporate India called The Working Life.
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