Two Indian biotech players have each announced an independent push to produce affordable CAR-T therapeutics for the domestic market. In August, the country’s largest biotech, Biocon, announced it had formed Immuneel Therapeutics, a startup with US founders, to bring chimeric antigen receptor (CAR) T cell therapies to Indian cancer patients. The previous year, a group from the Indian Institute of Technology in Bombay (IIT-B) also launched a company, Immuno-Adoptive Cell Therapy (ImmunoACT), to produce CAR-T therapies to treat blood cancers. With over 400 CAR-T cell clinical trials in progress globally, these ventures are designed to address the local failure of the Indian market to make adoptive T-cell therapies available domestically to patients with cancer; the additional wrinkle is that they will deliver these cellular treatments at a fraction of the cost of those in West. Initially, the founders behind these companies anticipate that their products will first serve cancer patients locally, but ultimately they expect to attract patients from around the world.

T cells attacking a cancer cell. When T cells are genetically engineered to equip them with chimeric antigen receptors (CARs), it dramatically boosts their cancer-killing efficacy. Credit: Science Photo Library / Alamy Stock Photo

Although two CAR-T cell products—Kymriah (tisagenlecleucel) from Novartis to treat children with acute lymphoblastic leukemia (ALL) and Yescarta (axicabtageneciloleucel) from Gilead for adults with large B-cell lymphoma—are already available on the US market, an annual course of treatment comes at a very high price: $475,000 for Kymriah and $373,000 for Yescarta. The high prices have meant that many patients cannot afford treatment, particularly if required to pay out of pocket. This has meant many cancer sufferers have flocked to trials in Israel and China, where the treatments are available at much cheaper prices. “As CAR-T cells are an effective option for these cancers, we urgently need this immunotherapy to be available in India at an affordable cost to save lives,” says Satya Prakash Yadav, director of the Paediatric Bone Marrow Transplant Program at Medanta hospital near Delhi. Though exact figures are not available, the estimated market size for CAR-T cell therapies in India—based on extrapolation of data in various cancer hospitals—is 20,000–40,000 patients with leukemia and lymphoma per year.

It is this need that the two new Indian startups seek to address. “We cannot afford to miss the bus,” says Kiran Mazumdar-Shaw, Biocon founder and managing director.

Bangalore-headquartered Immuneel Therapeutics was conceived over a breakfast that Shaw shared in New York with 5AM Ventures’ Kush Parmar and cancer researcher and Pulitzer prize-winning author Siddhartha Mukherjee of Columbia University. “Our aim,” Shaw says, “was to develop a low-cost model that could offer cutting-edge cell therapy at $50,000”— nearly 10-fold less than Kymriah’s and Yescarta’s US price tags. The trio visualized a CAR-T cell therapy that would operate in a decentralized way, in individual hospitals, akin to a bone marrow stem cell transplant.

The Immuneel model is based on in-licensing the CAR-T cell technology and then working on streamlining the engineering steps and the process of growing patients’ cells under current good manufacturing practice (cGMP) conditions. The platform will then be offered to individual hospitals that can operate independently “in a fee-for-service model,” says Shaw. The cGMP manufacturing facilities will be set up at each hospital, with Immuneel personnel offering access to processing know-how and training for clinical staff. The company’s first production facility, at Narayana Health hospital in Bangalore, is slated to be ready by January 2020. The startup expects to infuse the first patient by September.

All three founders believe the new business model will bring down the cost of these therapies first in India, and then potentially elsewhere. “We wish to jumpstart cellular and immunological therapies in India and create a platform to deliver the safest and most validated therapy,” says Mukherjee. “We expect to reduce the cost radically using local expertise in engineering, manufacturing and production.” What’s more, Immuneel’s ‘hub-and-spoke’ model, as Shaw describes it, will save time. To patients who have exhausted other treatment options and who are often very sick at that point, a shorter time frame could mean the difference between life and death.

The CAR-T cell therapy procedures approved in the United States are complex. They entail removing T cells from the patient’s blood by apheresis, engineering the T cells to attack the cancer cells, then growing them to the final numbers needed for reinfusion. This is accomplished by doing all the cell manipulation at a central, accredited location, which may be far from the medical center where a patient undergoing the procedure is located. Shaw believes that a production schedule that is hospital-based will do away with expensive logistics and ensure a much shorter turnaround time. Shortening preparation time will also allow Immuneel to intervene earlier in the patient’s course of treatment than is the case for the approved treatments in the United States and thus increase the therapy’s chances of success.

“We are really excited to drive this unique model,” says Shaw. The company “is not married to a given technology,” adds Parmar. The expectation is that Immuneel will shepherd multiple generations of therapies through the clinic and on to regulatory approval in India. With that, the partners hope to set “a global benchmark in affordable access to cutting-edge therapies that are beyond the reach of most patients in the world,” says Shaw. Immuneel has already raised 1 billion rupees ($15 million) from investors who include India’s major hospital chains and pharma companies, as well as venture capitalists and philanthropists.

Across the country in Mumbai, ImmunoACT is also intent on slashing costs to roll out CAR-T therapies to Indian patients. The startup, founded by IIT-B researcher Rahul Purwar together with his students Alka Dwivedi and Atharva Karulkar, has a considerable head start on Immuneel: it has been incubating at the institute for nearly six years.

Unlike the Biocon spinoff, ImmunoACT was nurtured with seed funds initially from IIT-B and subsequently from the philanthropic organizations Wadhwani Foundation in Bangalore and Tata Trusts in Mumbai. Purwar says implementing the process of CAR-T cell production in cGMP facilities and finalizing preclinical testing has taken his team the better part of four years. “Doing this in an environment of public academic institutes working on research grants has been challenging compared with the huge resources that private entities and industry [such as Biocon] can bring together,” says Gaurav Narula, Purwar’s collaborator and a pediatric oncologist at Tata Memorial Centre in Mumbai. Even so, progress has been fast.

ImmunoACT has already developed a CAR-T cell platform for treating patients with CD19+ B-cell malignancies. The indigenous CAR-T product has passed ethics and biosafety clearances and gained a go-ahead from the health ministry’s screening committee for human testing; Purwar expects it to go into clinical trials by June next year. “The sheer pressure of dealing with >500 newly diagnosed children with ALL a year—many of whom choose palliation and inevitably die—was the main impetus for our effort to develop this alternative to [bone marrow] transplant,” says Narula.

Purwar’s team has shown that the CD19-targeted T cells produced in his laboratory can kill 100% of CD19+ B cells. Once clinical validation for the processes are in place, Tata Memorial Centre plans to start clinical trials in the first half of 2020. Purwar says if the trial is successful that his company “will make the therapy available at 1 million rupees ($15,000), not including hospital expenses.” Savings will be pinned mostly to manufacturing. “About 50–65% of manufacturing cost of CAR-T in the US goes to skilled labor,” he explains. “Here, we will be training scientists on our platform. This, plus the indigenously developed CAR-T cell technology, makes our therapy less expensive.” ImmunoACT, Purwar says, is in conversation with a few established Indian pharmaceutical companies to bring this technology to the clinic as early as possible. The company’s pipeline also includes bispecific CARs and novel strategies for improving CAR efficacy. Narula acknowledges the “immense help” he and Purwar received from training at the US National Cancer Institute facilities of Terry Fry, Nirali Shah, David Stroncek and Steven Highfill under a scientist exchange program set up between NIH Global Health and the IIT-B.

Support for bringing CAR-T to India has also come, somewhat belatedly, from the Biotechnology Industry Research Assistance Council (BIRAC), an industry–academia interface under the Indian Department of Biotechnology (DBT). “CAR-T is a priority for us,” says Renu Swarup, DBT secretary and chairperson of BIRAC. “The startup [ImmunoACT] at present is not funded by us, but it is under consideration,” she says. “We will soon have a comprehensive action plan to make available a cost-effective, affordable solution.” Towards this end, Swarup says DBT will also harness scientists’ expertise from the National Institute of Immunology in New Delhi to facilitate the development of CAR-T cell therapies in India.

DBT is also making progress on the regulatory front. In July, together with the Indian Council of Medical Research, the department released the draft government guidelines for clinical trials of CAR-T cell products. This should pave the way for human trials from ImmunoACT and Immuneel next year.

Bernard Munos, founder of the InnoThink Center for Research in Biomedical Innovation at the Milken Institute, is optimistic that current “kinks can be ironed out” to make CAR-T cell manufacturing more efficient. Scaling up to achieve mass production and low cost could happen incrementally, Munos says. There is work ongoing to “miniaturize and automate the steps that are currently performed manually in the lab,” and if these steps can be packaged into a machine that can be installed in hospitals, he adds, this would equip the hospitals for on-site production—the strategy currently being pursued by Immuneel.

Indian pharmaceutical companies are well known for their affordable products in the small-molecule generics market place. Will they make the country a magnet for CAR-T cell tourism? “Absolutely yes,” says Purwar. Immuneel is also optimistic. “We expect to deliver to patients in need anywhere in the world, but with particular emphasis on patients in India,” says Mukherjee.