With cancer incidence on the rise — and the cost of newer therapies keeping them out of reach of most — there has been a race to develop CAR-T cell therapies for Indian patients. Among researchers dedicated to lengthening the life span of survivors are those sitting in an unassuming building in the heart of Noida, who have been working tirelessly through the pandemic to develop therapies that are not just cost-effective but also innovative.CAR T cell therapies — or chimeric antigen receptor T cell therapies — collect a patient’s own immune T cells, re-engineer them in the laboratory, multiply them and then infuse them back into the patient. These engineered T cells can then identify the cancer cells, attach themselves to them, ultimately destroying them. The latest innovation is about making them more persistent against a relapse.AdvertisementCellogen Therapeutics is set to begin human trials soon for its novel CAR-T therapy at Christian Medical College-Vellore. It can not only fight a patient’s current cancer but also create a memory in the body’s immune system so that it can keep fighting it off whenever it emerges. The model has an Indian patent and a provisional US patent. This will work much like vaccines, to prevent relapse in cancer patients. Simultaneously, the researchers are also working on developing off-the-shelf CAR-T therapies — therapies that are not specifically designed for each patient.At present, there are two indigenously developed CAR-T therapies approved for the treatment of blood cancers in India — Immuneel’s Qartemi that costs around Rs 40 lakh and ImmunoAct’s NexCAR19 that costs around Rs 20 lakh.The first round of a battleWhen he came back from the UK, co-founder of Cellogen Dr Gaurav Kharya understood that India needed to develop its own cell therapies to ensure that these treatments became accessible. Cancer treatment was not his first interest, however. As a specialist of blood disorders, he wanted a way to cure sickle cell disease — a condition where the body starts producing red blood cells becoming rigid, sickle-shaped, and less capable of carrying oxygen. The shape of the blood cells can also lead to blockages in blood flow, leading to acute episodes of pain, chronic pain, organ damage, anaemia, infections, and strokes. He had been treating the children who suffer this pain with bone-marrow transplants.AdvertisementWhen his team did start working with lentivirus — the virus that carries modified cells back to the body — his interest grew using the same to treat cancers as well. “Researchers across the world were already working on this type of therapy,” he said.He reached out to everyone working in the field to gain knowledge. “T cells are the immune system’s foot soldiers. Most people do not get cancers because every day these foot soldiers identify thousands of cells that have acquired cancer-causing mutations and kill them. In some cases, however, some monster cells learn to dodge this identification mechanism and start proliferating,” explains Dr Kharya.While T cells are generalists, antibodies are specialised and can attach to specific receptors to defend the body against infections and cancers. In cancer, receptors are proteins on or inside cells that act like docking stations. When specific molecules in the body bind to them, they send signals that tell the cancer cell to grow and multiply. Knowing which receptors a tumour has is crucial for choosing the right treatment. The chimeric T cells are a combination of both — they are specialised foot-soldiers. They can be trained to attach to specific receptors found on the cancer cells but in large numbers.Dr Kharya explains why his approach is novel. “The first-generation therapies could target the cancer cell only one-on-one, meaning each modified T cell injected into the body could kill only one cancer cell. This is very disproportionate — a patient usually has billions of cancer cells while only two or three million modified T cells are administered. So, the cancer always had the upper hand and would relapse after a few months or years even in patients in whom it worked successfully. There was also no way to ensure that the body could start generating these cells on its own if and when the cancer relapsed,” he says.What can be a solution?Second generation therapies are trying to ensure that the modified T cells could start replicating within the body as per the need, increasing their persistence and thereby the time for which a patient remains cancer-free.First is adding more than one target. “Some of the second-generation therapies are bi-specific, meaning they target two receptors. There are only a minuscule number of cancer cells that can escape both the targets, reducing the chances of the therapy failing after some time,” says Dr Kharya.Second, ensuring that the immune system learns how to produce the modified T cells on its own. “This is where our innovation lies. We create a memory in the immune system. We added another co-stimulatory domain to our engineered T cells, which ensures that every time these cells replicate, a number of them go to the central memory. So, even after the cancer has completely been killed, the memory persists. And, if there is a relapse, say after a couple of years, the immune system immediately recognises the cancer cells and starts producing the modified T cell,” he explains.In layman terms, it would work like a vaccine, which trains the immune system to recognise various pathogens and produce specific antibodies against them.The phase I clinical trials of the Cellogen CAR-T therapy will start soon, probably within a month, at Christian Medical College-Vellore. The trial will be conducted on nine patients with acute leukaemia and nine with lymphoma. The phase II trial will be on 27 patients and in more than one trial site. These “living therapies” do not require phase III studies, so it should become available soon after these studies. The therapy is likely to cost around Rs 20 lakh.Cellogen is, however, working on another innovation that is likely to bring down the cost of the novel therapy further.Off-the-shelf therapiesWhat makes CAR-T therapy so costly is the fact that it cannot be mass-produced and needs to be created for each and every patient separately. Researchers are working to create CAR-T therapies that can multiply within the body, eliminating the need for extracting a patient’s T cells and modifying them in specialised labs. This novel method can bring down the cost of treatment to around Rs 8 lakh.“For in-vivo CAR-T therapies, instead of delivering the modified T cells using a virus vector, we deliver the genetic instruction for making them. This information reaches the DNA of the cells and then teaches it to make the modified T cells,” says Dr Kharya. What this means is the same product can be used by anyone without concern for any reaction.Dr Kharya adds that there is no risk of the virus, which is used to deliver the genetic instruction, becoming infective. The real challenge is not knowing whether the genetic information delivered will be used accurately. “With these types of therapies, the biggest fear is that once you insert it, you don’t know what will happen — how many on-target and how many off-target activities will take place. Now, we know that they are not that big of a concern and as an abundant precaution, monkey studies are being conducted instead of mice studies.”Cellogen has already received approval for conducting the animal studies and hopes to start the human studies for it by next year. Further, the team is trying to use this method to develop a therapy against a solid-tumour cancer that is a big challenge for India — triple negative breast cancer. This type of cancer not only affects younger people and is more aggressive, it also lacks all three receptors that are used by commonly used breast cancer therapies, making its treatment difficult.CAR-T treatment for solid cancers remains elusive — while several CAR-T therapies have been approved for the treatment of blood cancers, none has been approved for the treatment of solid-tumour cancers. This is because they come with their own set of challenges — the markers for solid cancers can be found on other healthy cells of the body as well, the molecular makeup of the cancer can be different within the same patient, and unlike blood cancers, they are not where the T cells are, making it difficult for these cells to enter the tumour micro-environment to destroy them. Dr Kharya is now looking to solve this challenge that, if successful, could help women survive aggressive breast cancers.