It is 2015. Alka Dwivedi, is striving to develop patient-focused therapy for cancer. This leads her to join Rahul Purwar, a Professor at the Indian Institute of Technology Bombay (IIT-B), who is working on developing affordable CAR-T cell therapy in India.
Chimeric Antigen Receptor (CAR) T cell therapy involves genetically modifying a patient’s T cells to fight malignant tumor cells. T cells are a type of white blood cell developed from the stem cells in the bone marrow and are a vital part of the immune system, defending the body against infections.
Dr. Purwar returned to India in 2013 after completing his post-doctoral programme at Harvard Medical School and realised that India lagged behind the West in CAR-T research. The US was already working on it by then, and in 2017, it had approved the first commercial CAR-T cell therapy, which cost anywhere between ₹3 and 4 crores, excluding hospitalisation to treat side effects, rendering it unaffordable to middle and low-income countries, including India.
He was driven by a vision to provide accessible treatment to Indians. It took ten years to flesh out his vision in research that included his students Alka Dwivedi and Atharva Karulkar. “When I saw what he was doing, I decided to give it my 100% to make it successful,” says Dr. Dwivedi, the former doctoral student who now works at the National Cancer Institute (NCI) in Bethesda, Maryland.
He would soon be joined by Gaurav Narula and Hasmukh Jain, haemato-oncologists from Tata Memorial Hospital (TMH), Mumbai, who spearheaded the clinical trial phases of NexCAR19. “We were just getting to know that [CAR-T therapy] is something that is going to potentially change the treatment paradigm,” said Dr. Jain.
How are CAR-T cells made?
T-cells (a type of white blood cell) are collected from the patient through a process called leukapheresis. They are then modified in the lab to express proteins called chimeric antigen receptors (CARs) on their surface. The gene responsible for encoding CAR is developed synthetically in the lab, and a vector acts as a vehicle to deliver CAR into the patient’s T-cell. Commonly, viral vectors, such as lentiviral vectors, are used, as seen in NexCAR19. The re-engineered T cells are then multiplied by millions in the lab and sent back to the hospital, where they are infused into the patient. The patient usually undergoes chemotherapy before receiving the CAR-T cells.
The CAR comprises several components that enable it to identify cancer cell antigens and stimulate an immune response. Each CAR spans across the cell membrane, with a portion extending outside the cell and a portion inside. The exterior segment is made of fragments of laboratory-generated antibodies selected for their affinity to bind to the targeted antigen. The internal segment of CAR consists of two components responsible for transmitting signalling once the receptor interacts with an antigen.
The FDA has approved six CAR-T cell therapies till now, and four of them target CD19, a protein produced on the surface of leukemia and lymphoma cells. NexCAR19 is similar in this aspect. A key difference between the CAR-T cell therapies developed in the US and NexCAR19 lies in the composition of antibody fragments. While those developed in the US originate from murine (mice) sources, NexCAR19 has human proteins added to the mouse antibody, resulting in a ‘humanised’ CAR. This modification might have contributed to its reduced toxicity.
Collaboration with NCI
The researchers were trying to develop a therapy unexplored in India, and it was not an easy path. “We tried multiple times and had multiple failures and successes,” says Dr. Dwivedi. “The process is very lengthy and requires skill. When I was trying, the process was not working.”
Recognising the need for expertise, the team decided to seek help from the NCI and brought on board Nirali Shah, M.D., who collaborated with Dr. Jain and Dr. Narula on the clinical trial phase of the treatment. “They knew what they wanted to do and how to develop it in India for India,” says Dr. Shah.
They visited NCI during a conference at the American Association for Cancer Research (AACR). The team met researchers at NCI who helped them troubleshoot and provided insights on protocol and the challenges they were facing. Upon returning to India, they implemented the suggestions provided, and it worked well. “NCI had a great impact on our development,” says Dr. Dwivedi. The visit helped the team design an effective therapy. A smile spreads across her face as she reminisces about the day the CAR construct worked not only in vitro but also in mice.
Clinical Trial
After successfully developing CAR-T cell therapy, the team had to approach the Central Drugs Standard Control Organization (CDSCO) for clinical trial approval. “I think getting approval to conduct the study was a second critical milestone,” says Dr. Shah.
On June 4, 2021, the first patient was treated at Tata Memorial Hospital, and the CAR-T therapy worked. “We were super happy that whatever we saw in the laboratory was working on the patient. It was a huge thing,” says Dr. Dwivedi.
In October 2023, based on the data emerging from the clinical trial, CDSCO approved the first CAR-T cell therapy to treat relapsed or refractory B-lymphomas and B-Acute Lymphoblastic Leukemia (B-ALL), where all other lines of treatment had failed. Thus emerged a Made-in-India product, built by a team that persevered despite numerous challenges.
Risks of CAR-T therapy
While CAR-T therapy has shown remarkable progress in cases that looked hopeless, its efficacy varies from person to person, and it remains too early to declare it a complete cure. Moreover, it entails several side effects, the cytokine release syndrome (CRS) being the most common — an inflammatory response triggering immune system hyperactivity.
Neurotoxicity is another common side effect but it wasn’t observed in any early-stage clinical trial patients, potentially because of the ‘humanised’ antibody fragments used. Additionally, infections and low blood cell counts are other side effects doctors anticipate.
“We had to keep in mind that complications, which we may not be aware of now, might appear as you go along. That is something we have to be careful about,” says Dr. Jain.
Despite the promise of CAR-T therapy, access to primary healthcare remains a challenge in many parts of India, with cancer treatment primarily concentrated in metropolitan areas. Given the therapy’s side effects, proximity to a hospital is paramount. As a clinician and scientist, Dr. Shah points out that her biggest worry with CAR-T cell implementation is managing its side effect profile linked to inflammation, particularly in cases requiring intensive care support, and the possibility of patients being heavily immunocompromised.
“You have to be really mindful when you try to adopt a therapy from one country to the next. You have to also think about the clinical parameters where this therapy is going to be implemented,” says Dr. Shah
Relatively costly therapy
The project started with Dr. Purwar’s dream of developing an affordable treatment. While NexCAR19 is priced at a fraction of its US counterpart, it remains relatively high for many Indians, ranging from ₹40 to 45 lakh. “It’s still one of the most expensive therapies that we have in the entire field of cancer therapy,” says Dr. Jain.
The manufacture of NexCAR19 involves multiple steps that affect its cost. Labour, logistics, materials, and facility expenses as well as marketing, distribution, and intellectual property development all play a significant role in pricing according to Shirish Arya, Co-founder and Director-Corporate Strategy and Business Development at ImmunoACT, a startup founded by Dr. Purwar and backed by Laurus Labs to commercialise the therapy.
The good news, though, is the price can be further reduced. “We are working hard to increase access further”, says Mr. Arya. “As purchasing power improves, scale up of manufacturing will help reduce cost of production”. Also, the low toxicity means a patient doesn’t have to bear the cost of hospitalisation.
NexCAR 19 is the result of collaboration, teamwork, and a professor who dreamt of developing an affordable treatment. “I think a big takeaway is you learn from one another’s expertise. They knew what expertise they were seeking and sought support to try to gain that expertise,” says Dr. Shah.
It is a product with a good safety profile and a huge population of patients who need it despite being approved only for relapsed or refractory patients says Dr. Jain. “ At present, I think what is important is how we will be able to increase access to patients who are in need. That is I think is the biggest challenge that we have.d”
