Indian-American oncologist and Pulitzer prize-winning author Dr Siddhartha Mukherjee has joined hands with Biocon Chairperson Kiran Mazumdar Shaw to bring innovative Chimeric Antigen Receptor (CAR) T-cell therapy to cancer patients in India.
CAR T-cells stands for a kind of immunological cell that is derived from your own body and is engineered or weaponised to go and kill cancer cells in your body.
At present, CAR T-cell treatment isn’t available at any price in India. A company formed this year in Bangalore by Mukherjee, Shaw and Kush Parmar plans to pioneer care delivery models at a much lesser cost that could change the way CAR T and other cell therapies are developed around the world.
In a free-wheeling interview with CNBC-TV18, Mukherjee talks about the cutting edge treatment and its implications on cancer care in the country.
“A part of the reason that I began to collaborate with Kiran was that if we can have one of those most viable telecom and software sectors on the planet, we should be able to make cellular therapies; we should be able to make CAR T-cell, T-cell. There is no fundamental reason that Indian engineers and Indian scientists and of course ultimately Indian patients cannot get access to these therapies,” Mukherjee pointed out.
Edited excerpts from the interview. I want to talk to you about your visit here to India – there is an announcement that you are making with Kiran Mazumdar-Shaw. So tell me a little bit more about that?
We are announcing the formation and launch of a company that will deliver cell therapies in India. Cell therapies are therapies in which cells – your own body cells – are used as drugs to fight cancer.
One example of this is a so-called CAR T-cell. The name stands for a kind of immune cell, immunological cell that is derived from your own body and is engineered, weaponised to go and kill cancer cells in your body.
This therapy has been in development in many countries for several years but was finally launched as an FDA-approved drug a couple of years ago against certain cancer zones. Different ones work for different cancers but it was not available in India at all. So we, Kiran, I and Kush Parmar partnered up and our goal is to deliver the first in human cellular therapy in India for cancer.
When are we going to be seeing this commercialised?
So, these are extraordinarily complicated. They are called living drugs. They are drugs but they are alive. So you can imagine, producing them, making them available is an extraordinarily complicated process and also you have to be extremely careful because it is not like manufacturing aspirin or penicillin. It is taking cells, weaponising them usually with a virus and then re-injecting them into the body. So the whole process to develop this – we are hoping – will take about six to eight months. We hope to be in human patients in India within 8 months.
Do you have all the regulatory clearances here in India?
A completely new regulatory framework needs to be created so that it is not just free for all as it were because these are toxic therapies, they are reserved for cancer patients, you have to know how to use them – these are living drugs, these are living things. You can imagine that if you don’t control them properly, they can go out of control. So you require not just the scientific framework, which is important, but also the regulatory framework. What are the circumstances that an individual hospital or a medical centre can be allowed to use them, what are the safety precautions.
We don’t have that yet in India?
We have the broad framework but it has to be made specific for the use for cellular therapies. India has a very powerful regulatory framework for the use of drugs but for living drugs - there are some special things that need to be addressed, safety needs to be addressed, you can get contamination. So you cannot just decontaminate a living drug like you decontaminate a chemical.
So for instance just to give you a very practical example, imagine if I am growing a patient’s T-cells in an incubator and that incubator gets infected with a bacteria or a virus, that whole batch has to be destroyed, the whole incubator has to be cleaned, maybe the entire facility has to be cleaned to ensure that the next one doesn’t get infected. So it is a very different process. It fits under the broad umbrella but it is fundamentally a different process.
It is all going to happen out of Bangalore, how is this going to work?
The best way we thought about doing this, Kiran and I have had extensive discussions. The best way to do this is to do it at one facility to start with. The closest analogy that we have to living drugs is drugs that are made out of living cells, insulin being one of them and as you know, Biocon which is making insulin and other molecules like insulin – other molecules such as Herceptin (Trastazumab) is also an antibody that is made by living cells. So we decided to start off with a facility where we could have exquisite control. We need to have exquisite control so that we can deliver the therapy to the first needy patients. These are extraordinarily effective drugs, we wouldn’t be doing this if these weren’t extraordinarily effective drugs for particular cancers.
Would these be affordable and accessible?
The challenge is affordability. Just to give you a sense of what the numbers are in the US, there are two T-cell drugs that are now approved in the US and the ticket price for them – they are called Yescarta and Kymriah – is around $400,000 per person. Part of the problem is that – if some of this is the companies are making profits -- but part of the problem is that they are intrinsically expensive to make. It is not like making aspirin, it is not like making insulin, it is not like making penicillin, you have to take the cells out of someone’s body, as I said weaponise them with a virus, grow them in incubators, ensure the safety and then return them back into patients. So I think that the real trick and the real advantage is we will be taking advantage of the ingenuity of Indian engineers and Indian bio-engineers.
We are pretty convinced, we have done very detailed analysis of this, this is my fourth visit and we are confident that we can reduce that $400,000 price tenfold.
Even that lies beyond affordability but it is on the order of a bone marrow transplant in most countries outside the west.
The goal is to make it affordable but this is never going to be an insulin or a penicillin or an aspirin, this is reserved for patients who are very needy, very desperate. We will almost certainly have programmes for the most needy and the most desperate that will allow them to afford it. These are intrinsically very difficult to make.
I want to pick up this latest collaboration that you have with Kiran who is part of the healthcare system in India. You have also got a similar venture where Johnson & Johnson is an investor and that’s venture you started about 3 years ago. Do you see more of these collaborations picking up pace? Global pharma has tried to reinvent itself post the backlash that it faced a few years ago. That backlash has now shifted to the technology companies. So do you see more of a collaborative approach being taken and what does it mean for research and development (R&D) going forward?
There is no other option. The maturation of a living drug, the natural cycle is exactly this. So usually drugs are born in laboratories; I am a laboratory investigator, I am a research scientist. I own the patterns that lead to the companies called Vor. I have another one called Myeloid, there are about 6-7 of them. These originate in the ideas of my ideas or in the ideas of very young investigators who are really driven to solve basis problem. How do you fight cancer with cell or with other therapies but that is their skillset. Now to convert that into a real therapy to run a human study to be able to deliver that therapy, safely, effectively to humans, you have to collaborate.
So the way we collaborate now is that we form a biotech company. This company is ceded by investors, it’s ceded on the basis of science. These investors are extremely savvy, they are extremely thoughtful, they before making an investment will make deep analysis of the product itself, is it viable, is it effective, what data do we provide etc. and then you form that company and at that stage you begin to attract companies like Johnson & Johnson, Novartis and open your asset to them, open what you have invented and ask the question – would you partner with us in bringing this thing which is just an idea to becoming a real medicine and this is a tried and tested process and this is what is happening.
I know that your research approach has been to understand the micro environment as you call it, to understand cause and co-relation. So given the approach that you have taken and with the likes of Johnson & Johnson, Novartis, Biocon etc. partnering with you, what could it mean for costs? Do you see this becoming more accessible and hence affordable for a country like India?
There is a pipeline process. A part of the reason that I began to collaborate with Kiran was that if we can have one of those most viable telecom and software sectors on the planet, we should be able to make cellular therapies; we should be able to make Chimeric Antigen Receptor (CAR) T-cell, T-cell. There is no fundamental reason that Indian engineers and Indian scientists and of course ultimately Indian patients cannot get access to these therapies. This is not as it were rocket science.
We have mastered that too…
We have almost mastered that, but it requires that kind of effort. It requires a certain sense of audacity, it requires an ambition but that is what we are in for. We know the challenges but we have a kind of deep confidence that we can reduce the cost 5-10 fold and still deliver effective therapies. The engineers that I have met here, the scientists that I have met here, the board that we formed is of the bluest chip quality. They involve some of the inventors of these therapies in the United States and in the UK. There is no lack of quality and determination. Operationalising it, making sure that the government partners with us in an appropriate way. Those are the challenges that we are facing right now and we will solve them.
I want to ask you this because you meet people who are backing or funding healthcare. You talk to regulators, you talk to governments around the world. What is the priority for instance for the government of India at this point in time. How do you deal with the cancer problem? It is a crisis that this country is also dealing with? What will it take for the government to prioritise it or how should they prioritise it?
The problem of cancer or the crisis of cancer is some ways the side effect or cross effect of a population that is living longer – that’s one reason; in India that is compounded by the fact that smoking is still a major problem, cigarette smoking, and pollution is a major problem. We are not effectively vaccinating for cancer such as cervical cancer that’s caused by human papillomavirus. Vaccine is available and that should be eradicated. So there are many arenas in which you could handle the cancer problem but to take a step back – cancer, for a government to handle a cancer - that strategy is built on a pyramid. The bottom of the pyramid is prevention and that is the deep bottom pyramid.
And that is where there isn’t enough attention?
That requires a vast amount of attention and prevention, I gave you some examples that’s why I used those examples first. I used the example of stopping of cigarette and tobacco, the effects of various pollutants particularly in the air and the water and finally vaccination against cancers that can be vaccinated against, not many but some certainly and especially some cancers of women. The second layer of that is early detection. This would include finding cancer at the earliest possible phases, the very effective ones there are Pap smearing, colonoscopy, less so mammography but still effective to find breast cancer and in general cancer health screening – that would be the second layer of the pyramid and the final layer of the pyramid is of course cancer treatments, therapies including chemotherapy, things like Tamoxifen which is actually quite inexpensive. Tamoxifen is an inexpensive drug and a very effective for breast cancer and all the way to the things that we have been talking about cell therapies, CAR T-cell therapies.
It’s important to realise that this pyramid is part of an ecosystem. It feeds back on itself. So you begin with prevention, there is an early detection and there is a final treatment, you only create a strategy against cancer by creating this entire ecosystem, you don’t slice out one piece of it and certainly you don’t slice out the most expensive piece of it which is treatment. Cancer treatment is at the top of the pyramid, the narrowest edge of the pyramid, the base as far as the government is concerned is to focus on prevention and that is an important idea for the Indian government and all other governments to internalise and it has to some extent; there are now finally anti-smoking, anti-pollution, vaccination campaigns all across India.
But do you see that happening at a pace that will ensure that we are being able to deal with this issue?
So for schizophrenia and depression – two major forms of metal health that process has happened. So we now understand very well that schizophrenia is not just a kind of random madness but rather is a genetic disease that has an environmental component to it but has a genes and environment component to it so that is one example.
Second example is depression again. For schizophrenia in fact, some of the genes are now being identified and we are trying to understand the circuits, the metal circuits that interact with the environment and thereby cause schizophrenia. We are beginning to understand similarly for depression.
In some cases, it has to do with the destigmatisation of things that were called illnesses but in fact are not illnesses at all. Homosexuality is one of them. 50-70 years ago a mental health handbook would define homosexuality as a mental illness. It has been a striking mark of progress to understand that that is not the case and more recently another striking mark of progress to identify the fact that there are in fact biologic and genetic factors in addition to environmental factors - but certainly biologic and genetic factors that makes a person’s sexual orientation in one direction or another.
So we have seen a lot of this happen already in many countries, we are seeing that happening in India and it was a very proud moment for the Indian courts to recognise this fact, to recognise that there is biology behind all sorts of health and some things that were called illnesses 10-15-20 years ago are really not illnesses, they are states of human behaviour.
What is it that is exciting you in the work that you are doing or the research that you are doing today?
We are doing a lot of work on gene therapy. We have a completely exciting new programme to try to cure a previously incurable form of leukaemia and we are going to run that first in human study next year.
We have invented a new way to try to cure leukaemia, it is the most exciting thing I have ever done in my life and I am basically so anxious to get this study off the ground. It will be the first time that we will get a gene therapy linked cure for leukaemia.
We have a lot of work that we are doing on stem cells. We identified a stem cell that contributes to osteoarthritis, one of the most common diseases of women around the world but also men.
We are doing a lot of work on pancreatic cancer and breast cancer, finding new medicines and again going through this process – I think of myself as an inventor. I invent drugs, all the programmes in my laboratory are now focused on making human medicines. If you are working in my laboratory and you cannot tell me how your work relates to the development of a new human medicine, for me it is a failure. Everything in my laboratory is directed towards absorbing the research from others but trying to make new human medicines.
I was reading this interview that you have done a few years ago where you spoke of how the research that was done for prostate cancer came up with ideas on how to deal with breast cancer for instance. So how much of that kind of cross-pollination are you seeing happen?
It is among the richest arenas of cross-pollination going on right now. We are borrowing as – the word for a person like me is translational scientist. I am a translator. I take insights from basic researchers, people who work on enzymes and bacteria and genes and genetics. I take those insights and ask the question how can I make a human medicine out of that? I take that all the way into a human clinical trial or human clinical study, the invention of the new drug. This can only happen if there is very deep cross-pollination. If the two camps as it were – basic scientist and translation scientist are not fighting each other but are reading each other and talking with each other constantly.
Is more of that happening today? Are the two camps more aligned?
The camps have decided to become more aligned because there is no other choice. This is the only way that we know to make medicine move forward. There is a third camp, clinicians but it is more like a relay race. There is a handoff between the basic scientists of insights to the translation researchers who then hand off that towards the clinicians. Now all of this process – right from the beginning till the end – has to come together and requires -- it is an ecosystem -- it requires governments to provide regulations, it requires philanthropists, of course it requires patients, it requires venture funds – it is a risk-taking process but nothing moves in the world of science without risk. So all of this has to come together and that is the only way it moves forward.
As you try to get this ecosystem to work together, what is the biggest challenge that you foresee today and my second question because our last chat was in Davos, as Bill Gates was trying to make a pitch for The Global Health Fund, do you see people now reacting differently to the needs to healthcare and putting more money behind research and development because that was a concern that Bill had that maybe you have got good numbers to show and so maybe people are going to think we have achieved what we needed to and then drop off. What do you believe is a big challenge?
This is sort of far away from the pinnacle or the summit, we are sort of in that middle of the road and this is the time that requires the most energy because the middle of the road is when people get the most tired. Bill and I have had many conversations together, we have tapped many conversations together in Seattle, in Davos and other places. The challenges of global health are extraordinarily acute today. They include a vast spectrum from arenas that the Gate Foundation has focused traditionally on which are contagious or infectious diseases all the way to chronic non-infectious disease such as hypertension, diabetes, obesity and of cancer. So, the challenges are great, they are not solved. We are living longer as a population, we now also need to learn to live healthier and we need to learn to live more fulfilling, robust and ultimately more dignified life. Right from birth, infant mortality and maternal fetal care all the way through the challenges of life including a lot of mental health issues around, the lessons, the diseases that come as you grow older - cancer, hypertensions and others all the way to palliative care and dignity around death. We are seeing the entire spectrum across the globe. So in every country there are somewhat different manifestations.
If you are in a particular country in the African continent, maybe your crisis is Ebola, if you are in Seattle may be you are facing down breast cancer, but the spectrum of disease is vast and is turning out to be quite universal. One interesting statistic which you may not know, and has not been talked about is that in countries where we think most of the deaths are from infectious diseases are slowly turning around. For countries like Tanzania are seeing trends in which the number of deaths from infectious diseases is fewer than the number of deaths from hypertensions or from diabetes or from kidney diseases. So the entire world is experiencing spectra of diseases that range from things that we thought would be sort of flames in one corner but in fact are across the entire world.
Do you see more venture backed funding, especially when we talk about new therapies, new research?
Biotech has been in the United States now one of the most attractive arenas recently. We looked enviously at the tech industry, at the software tech industry and at social media and I have to say personally I barely use social media, and I have to say social media might have created more ills than it solved. Now it has left biotech to solve those ills or medicines to solve those ills.
I think there has been resurgence of interest in ventures in the biotech world. The risks are very unlike, we are dealing with human bodies, we are dealing with regulations that bio ways should have been also imposed on social media as we know now, we are dealing with regulations that are historic. Medicine has been historically regulated, we have very strong ethical boundaries that we have to abide by and for good reasons because we in the past have violated those ethical boundaries and I think that similar ethical boundaries should have been drawn for all technologies including social media. We are doing those in retrospect but I will leave those comments.
Why are you not on social media at all?
I am on Twitter, it is the only social media that I use and I use it quite sparingly. I don’t find using anything less particularly inspiring. I like to talk to people directly. If you very carefully curate as a scientist or a writer, if you very carefully curate who you follow on Twitter it can be very useful because you can get news, but I like traditional news, I like the long form news and I have never found that joy that some people find in connecting through social media. But I am the dinosaur, clearly there are other people - I like reading newspaper.
Is there another book in the works?
There are two books in the works, very broadly speaking one of them will address the history of medicine and very broadly speaking the other will address questions of immortality, our search for immortality digital, social and other.
Has the writing process for you changed? I know that you had rules about how to structure your chapters and so on and so forth? Has it changed over the years?
It has been very much the same. My writing process begins with a lot of research and reading, it begins in a very close space. I need silence, I need a lot of time to think and then it comes out as a work.
How much time do you spend writing every day?
I try to spend at least a couple of hours writing every day, but the writing can be diverse, and they interlock with each other.
You are working on both the books at the same time?
No, but for instance it might involve writing a long letter to a regulator about a clinical study that I am excited about and then switch to the book. Now you could say those are two completely different parts of your brain but they are not. You see if even every experience that I have becomes fuel for the writing, this interview might find its way into a book I can never tell because this interview might generate an idea, I can never tell that. The clinical study that we are doing in leukemia, this previously incurable leukemia and mortality death rates of a 100 percent, 98 percent sometimes in young children, it will almost certainly become a book. What is interesting is that even if it fails it will become a book, it will become a book about failure. So nothing is off the record in some ways to me in my brain.
That is the best thing for a journalist to hear by the way.
So it becomes part of the process, it is always part of the process. That comment might find itself in a book and it is all open. People say are you doctor or a writer or are you both or are you scientist or a writer. I make no distinctions. I think to write, sometimes a writing generates a new idea that idea might go into the laboratory, it might come back from the laboratory and become part of the book. The windows are open on all sides.
What is the one thing that gives you the most hope as we look ahead and what is the one thing that worries you the most?
I think the most hopeful thing is the community of thinkers that exists around the world and by thinkers as I said, I think of myself as a doctor and a writer. I think a vibrant community of thinkers has arisen in India asking vibrant questions.
The more we resist the temptation of groupthink, scientists especially, writers especially, journalists of course, the more likely we contribute to the world of ideas – that is inspiring for me. What is worrisome is just the opposite. What is worrisome is that the dissent into groupthink.
Recent political developments around the world have not given much hope. People are retiring backwards, towards a kind of a nostalgic isms driven by fear typically, those are typically times or circumstances where innovation and invention stop happening, they put a stop cap on innovation and invention and we have seen that around the world.So that is what worries me the most that in 2019 we are living at the end of a cycle of innovation and invention which has been unprecedented in history and if we were to take all these isms and make them, put them on national stages, these isms will inevitably stop the cycle of innovation that we are inheriting and we will not pass it on to our children, we will deny them a generation of invention and innovation and that is a very sad thing. We should be very careful about it.