Oncologist Dr Siddhartha Mukherjee on the crisis in the health economic system in India, attempting to cure blood cancer through sophisticated cell therapy, deploying strategies to prolong remissions and keeping costs down
Kaunain Sheriff: Can you take us through the breakthrough therapy that you are introducing in India and the science behind it?
Let’s begin with immunotherapy against cancer. It comes in many variations but there are three main ones. First are monoclonal antibodies (MABs) which have been in use for a long time. The second is T-cell therapy. This does not involve transfer of T-cells but uses your own native cells. In order to prevent your own T-cells from attacking themselves, you inactivate them so that you don’t get autoimmunity. Some examples of autoimmunity would be Type 1 diabetes, lupus and arthritis. So, your body basically keeps a check on these T-cells and inhibits them. These drugs are called checkpoint inhibitors, some of which are available in India. Obviously, if you activate your T-cells against cancer, they can also be activated against your normal cells. So, checkpoint inhibitors are necessary. The third variant is the CAR T-cell therapy, where we extract T-cells from a cancer patient’s body and we use a virus, which is a modified and inactivated version of the HIV virus but doesn’t cause HIV, to deliver genes into them. These genes then weaponise the T-cells to attack cancerous cells. In other words, we remove the T-cells from the body through apheresis, they go into an extremely sterile laboratory, are activated with gene therapy and harvested in incubators until they expand to a very large number and are frozen. This process usually takes about 10 to 14 days before the cultured cells are transfused back into patients.
Originally, when this was done in the US by several people, including Michel Sadelain at Memorial Sloan Kettering and very successfully by the UPenn group, led by Carl June and Bruce Levine, there was scepticism about whether these highly activated T-cells would attack the tumour which had spread considerably. The results were quite remarkable and almost miraculous. These patients were on the verge of death and mostly had liquid cancers or leukaemia as their tumours had stopped responding to multiple cycles of chemotherapy. We also tried to ensure that the activated T-cells, that would release cytokines or chemicals that T-cells use to communicate with each other and with the immune system, wouldn’t generate a cytokine storm. We controlled it with medicines. Since then, we’ve already dosed several patients. A group in IIT is also dosing patients using the same formula. Theirs is a phase one trial, ours is a phase two trial. Theirs is a new product, ours is a clinically exposed product that has already been proven to be successful in humans. We have in-licensed it from Barcelona, it has already completed trials in Spain and has been proven to be both safe and extremely effective. We are giving the doses of T-cells in not one shot but in three or four shots, depending on how we do at the trial.
Uniquely in India, we’ve been able to reduce the cost, which is a very difficult process because the input costs are already very high. You need an army of scientists, a specialised facility, several machines, manipulations and so on. In India, we have the innovative capacity to administer the dose to patients at a much earlier stage of the disease. If successful, it will be a great contribution to medicine internationally because we will be able to show that we can actually keep longer remissions and keep patients better for a longer period of time.
Kaunain Sheriff: This treatment has been there for almost a decade in the US, parts of the UK and now also in China. What does the global data tell us about its efficacy?
The global data looks very good. The tumours that respond are lymphoma, leukaemia and myeloma, all refractory tumours. I also have another company in the US called Vor Biopharma, which is one of the first companies to attempt this in myeloid leukaemia. This occurs mostly in children though some adults do get it, too. The effectiveness of CAR-T therapy in children has been 90 per cent. In other words, five to seven years of survival in 80 to 90 per cent of patients. Remember, these patients were initially refractory or relapsed. It was a very difficult population to treat, the only other treatment available to them being a bone-marrow transplant. But there the effectiveness is much lower, there’s a much more toxic regimen and the side effects could go on for four decades. In contrast, this would be a 14-day process, followed by two or three days of infusion, and the cure rates could be 80 to 90 per cent, depending upon the kind and intensity of leukaemia. In myeloma, the cure rates are 80 to 90 per cent, too.
The effectiveness of CAR-T therapy in children has been 90 per cent. In other words, five to seven years of survival in 80 to 90 per cent of patients. And remember, these patients were initially refractory or relapsed
We have many strategies at Immuneel, which is the Bengaluru-based company, through which we are trying to determine if we can prolong the remissions, increase the percentage of remissions, and potentially even cure myeloma, using novel strategies. And again, this would be a contribution from Indian medicine to the rest of the world. Once we’ve completed clinical tests, we will start working on the product for a clinical trial, which will be a phase two trial.
Safety is paramount at Immuneel. We’re following international standards, DGCI and other appropriate guidelines of the Indian ecosystem. So far, there have been very mild adverse effects, nothing to stop the phase two trial.
Scientists here are of the highest calibre. Clinical, manufacturing and scientific teams are world-class. They work with my lab at Columbia University. There’s no difference in the quality of conversation or innovation
Kaunain Sheriff: The first participant was a child. How was the experience? Can this be used as a first line of treatment for children?
It was a very big learning experience. A huge amount of training and quality control protocol was involved. We don’t want to just throw the drug at someone, we want a full ecosystem, a partnership, and the achievement of that was the first child was appropriately treated.
Part of the protocol involves infusing chemotherapy into the spinal cord, part of the therapy for some high-risk patients involves giving radiation, which causes all sorts of downstream effects. When they grow older, they have cognitive, post-traumatic, psychiatric and psychological disorders. They are growth-limited at times because of the chemotherapy. Who would not like their child to receive one-day therapy, after 14 days of growing T-cells, without being first battered by two years of chemotherapy? But it’s impossible to do that in the US if the cost is going to be $400,000, plus all the associated care. Remember that $400,000 is coming after two or three years of chemotherapy, which itself is another $400,000- $500,000. So, that child is being treated now with nearly a million dollars of chemo plus CAR-T therapy. This is why innovation and tech transfers are very important in this field to lower costs and deliver this therapy upfront.
Kaunain Sheriff: In the US, the cost is around Rs 3-4 crore and that’s just the drug itself. Then you have hospitalisation and medicine. How will you bring this cost down in India?
We are attacking every potential pinch point. We are now ramping up the production of our own virus facilities, which will again be of international standards. We have decreased the labour costs enormously, partly because they are intrinsically cheaper. Hospitalisation costs are also intrinsically cheaper. All the associated drug costs are cheaper. We are using all the innovation that is available to decrease the costs dramatically. We cannot change the intrinsic costs of certain goods because the patient’s safety comes first. We’ve already lowered the costs dramatically but are aiming to lower them further, partly by producing some of these products or goods in India, partly by identifying 10 pinch points.
In the early days of cancer therapeutics, risk assessment was basically clinical. Now, we use the patient’s own genetic data. In other words, we study how they will metabolise or change responses to drugs
Kaunain Sheriff: Are you thinking of collaborating with the IIT Bombay team, which is working with Tata Memorial, to bring the cost down?
We’ve been in touch with the IIT team. But again, the entire ecosystem has to be appropriately deployed such that these are not competitive products but collaborative products. It’s fair to say that this industry needs to be appropriately regulated. This is a very sophisticated therapy and the last thing we want is to contaminate the field with actors who don’t have the sophistication and the knowledge to develop CAR-T therapies.
Kaunain Sheriff: How was it working with scientists here?
Scientists here are of the highest calibre. There are clinical, manufacturing and scientific teams and they are world-class. The research team works with my laboratory at Columbia University. There’s no difference in the quality or the level of conversation and innovation.
Kaunain Sheriff: You’re very close to bringing at least two potentially very significant drugs. One is related to untreatable leukaemia and the other addresses stem cells linked to arthritis, which is very common among women in India. When can these be rolled out?
The first one has started its clinical trials. It’s a very complex twist on cellular therapy. My lab discovered it, we patented it and we’ve now sent it off to Vor Biopharma. We are waiting for an outcome signal. In osteoarthritis, we were the first, along with another group, to identify the stem cells or the progenitor cells that form cartilage. In animal models, these cells can be stimulated to grow using a drug. Potentially, they can also be transplanted. So we’re using a variety of mechanisms to grow these cells. This is a regenerative medicine study and if the cells are already dead, then you can’t bring them alive. You have to intervene at a stage where you’re seeing damage or injury but the cells haven’t completely died. The challenge in regenerative medicine is to find the Goldilocks spot, don’t go in too early or too late.
We have a third study, which is probably one of the most interesting studies in cancer, which is combining diets with drugs. This is not voodoo nutritional science but is based on extremely rigorous scientific experiments in which we’ve shown that particular diets, which lack certain substances, or have the addition of other substances, are synergistic with drugs. Targetted therapies make them much more effective. Our last study was published in Nature and trials will begin. That’s what we call the independent pillar. Not chemotherapy, not radiation, not surgery, not immunotherapy — the four pillars of anti-cancer therapy — but a fifth pillar, where we treat diet as a drug.
Kaunain Sheriff: In India, we are looking at 30 million cases by 2025. Global data says that around 30 to 50 per cent of cancers are preventable. Do these figures worry you?
It worries me a lot. Cancers being treated by CAR-T don’t seem to be preventable. Lymphoma has certain carcinogens that are preventable. But childhood leukaemia is a genetic accident. There’s a pyramid-like basis for cancer therapy. At the bottom, where you get the most effect for the least cost, is prevention. Preventable carcinogens include tobacco, triggers include obesity while some cancers are caused by viruses. The Human Papilloma Virus (HPV) causes cervical cancer and there’s a very effective vaccine against it. We are in the process of discovering new carcinogens. Large studies are on to find the link between industrial and particulate pollution and cancer. The centre of the pyramid is early detection and screening. Finally, there’s the top of the pyramid and the most expensive: treatment.
Anonna Dutt: What would cancer therapy look like in 10-20 years and why did you choose to work in India?
Each cancer is treated differently. We haven’t been able to be very successful with cellular therapy against solid tumours, such as ovarian cancer and colorectal cancer. For such cancers, we’ll have to use some other inventive mechanisms or new drugs. You can’t imagine how complicated Vor Biopharma is in terms of delivering its therapy for myeloid leukaemia. I have made a series of other inventions that are also going on trial. Those will be for solid tumours. So, it will be a mix. Some parts of it will be personalised for a patient. In the early days of cancer therapeutics, risk assessment was basically clinical. Now, the risk assessment is clinico-pharmacogenetics, which means that we use the patient’s own genetic data. In other words, we study how they will metabolise or change responses to drugs, and track the genetic data from the cancer. Our risk assessment is far more sophisticated than it was 50 or 60 years ago. Then there are the five pillars I talked about. But the emphasis on prevention will continue.
I chose India because the clinical and the scientific ecosystem, particularly in tech hubs like Bengaluru, were sufficient and sophisticated enough to develop this.
Harish Damodaran: So much is happening in cell therapy in human biology. Why is there so much resistance to plant biology, be it in gene editing or modification?
In medicine, we’re treating sick people. In the entire genetically-modified (GM) food industry, we’re giving products to healthy people, so the regulatory concerns are totally different. In one case, the patient would die if you didn’t give them the therapy. In the other, you are exposing someone who is physically healthy to unknown GM foods. That said, I’m perfectly sanguine with GM foods as long as they have passed safety paradigms and have been ecologically evaluated. Some of them have also led to monoculture of plants, which is a big problem because evolutionary and ecological diversity are important. If a plant species goes extinct, you can’t revive it from the dead. Besides, all species, plants and animals, are mutating all the time which is also genetic modification. The other alternative is to chemically modify plants, which is more harmful.
Liz Mathew: During the African Genome Project, there was one finding that established race as a social construction and not a genetic reality. Any scope for such a study in India?
There’s a very large Indian genomic study, which is being conducted to figure out what the diversity of the Indian genome, broadly speaking, is. I can’t tell you what the answer is going to be. There has been a lot of endogamy in India and that will have genetic consequences.
Rinku Ghosh: Can your new therapy arrest the aggressive Acute Myeloid Leukaemia (AML)? Also, how rigorous should we be about self-screening?
AML is really a tough disease to treat. In fact, we are still treating AML as we used to about 10 or 15 years ago, with standard chemotherapy followed by, in some patients, bone marrow transplantation, which is very toxic and difficult to administer. Vor Biopharma is one of my companies, which arises from the work done at Columbia University. It is a completely new way of treating AML and potentially a curative way, but it’s on trial. I’m very hopeful.
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Everybody should be aware of screening guidelines as they are available on highly regarded public websites and are constantly upgraded. The WHO, the National Cancer Institute and the European Cancer Institute have very clear guidelines. The epidemiology of India and many countries like India is shifting away from death as a result of infectious diseases towards death from chronic non-infectious diseases. For countries like India, it’s like dividing mammals into cows and non-cows because there are now so many non-communicable diseases that are responsible for death, including cardiovascular disease, hypertension, and, of course, cancer. It’s advisable to keep up with the new epidemiology. Appropriate screening, including colonoscopies, should be performed at the right age at the right time for the at-risk population. Upper endoscopy must be performed at the right age at the right time for at-risk people. Don’t miss mammography.
Aakash Joshi: How does the cost of a life-saving drug for children, like the one that’s being developed, pan out in a country like India?
In India, we will probably end up with a triple-hybrid model, with some cost displacement through the government, some cost assessment through private insurance and some through individuals. This is a health economics problem. I think the health economic system in India is in a crisis. It is a mishmash. Even within a single colony, you have a private hospital, a government hospital, you have a partially government hospital, someone’s privately insured, someone’s half-insured. It’s a complete mishmash.
We need to create a system. My father was ill, and unfortunately passed away. He was in a hospital but the hospital didn’t have a pharmacy. I had to go across the street to a private pharmacy to buy the medicines that had been prescribed for him. This is an absurd system.
Why SiddharthA Mukherjee
Dr Siddhartha Mukherjee is an eminent oncologist and Pulitzer award-winning author. He’s rolling out a significant clinical trial on treatment of cancer, called the Chimeric Antigen Receptor (CAR) T-cell therapy, which has already been used in several countries. If his phase II clinical trials at Immuneel, the Bengaluru-based company he’s founded with Biocon chairperson Kiran Mazumdar Shaw and Dr Kush Parmar, are successful, then this therapy would be India’s contribution to the rest of the world. He’s also developed an independent pillar of treatment. Not chemotherapy, radiation, surgery or immunotherapy but using customised diet as drug.