Siddhartha Mukherjee and the song of the T-cell
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Interview | Siddhartha Mukherjee and the song of the T-cell

The Pulitzer Prize-winning oncologist talks about his latest book and the promise of a new, accessible pathway to treat cancer in patients for whom chemotherapy has stopped working

January 19, 2023 02:21 pm | Updated January 23, 2023 11:40 am IST

A doctor, researcher of translational medicine and author, Siddhartha Mukherjee, 52, is astonishingly eclectic. The Indian-American biologist, an associate professor of medicine at Columbia University, best known for his Pulitzer Prize-winning book The Emperor of All Maladies: A Biography of Cancer, has been on an enduring quest to discover new treatments that could give cancer patients a fresh lease of life.

ALSO READ | Providing affordable cancer treatment in India paramount: Physician 

In his latest book, The Song of the Cell: An Exploration of Medicine and the New Human, which has been named The New York Times ‘Notable Book of 2022’, Mukherjee characteristically uses metaphors: an antibody, for instance, becomes a ‘gunslinging sheriff’.

Siddhartha Mukherjee speaks in New York City.

Siddhartha Mukherjee speaks in New York City. | Photo Credit: Getty Images

On his visit to India, he is juggling between speaking at the Kolkata and Jaipur lit fests and monitoring his team’s clinical work in India. He may look sleep deprived, but the excitement in his voice is palpable. On January 21, Mukherjee and his colleagues will introduce to the world some of India’s first cancer patients to be treated with T-cell therapy. T-cells, which develop from stem cells in the bone marrow, are an essential part of the immune system and normally kill virus particles and infected cells. However, when genetically modified, emerging science shows they may be used to treat advanced cancer. If successful, it will be India’s ‘Emily Whitehead moment’.

The Song of the Cell

The Song of the Cell | Photo Credit: Special Arrangement

Whitehead, now 17, suffered a near-fatal recurrence of cancer when she was six; she became the first child in the world to receive T-cell therapy and is now considered cured 11 years later. Mukherjee describes meeting her in 2019 in The Song of the Cell:

‘I wondered how she felt, knowing that there were three versions of her in the hospital: the one here today, on a break from school; the one in the pictures, who had lived and almost died in the ICU; and the one frozen in the Krusty the Clown freezer next door.

“Do you remember coming into the hospital?” I asked.

“No”, she said, looking out into the rain. “I only remember leaving.”’

 17-year-old Emily Whitehead from the U.S., who received T-cell therapy when she was six, is now considered cured.

 17-year-old Emily Whitehead from the U.S., who received T-cell therapy when she was six, is now considered cured. | Photo Credit: Emily Whitehead Foundation/Twitter

“The first Indian recipients of T-cells have not been publicly documented, but they are very much alive,” Mukherjee says in an interview to the Magazine. It is indeed early days for patients in India, having received the lifesaving therapy barely a year ago, says Gaurav Narula, professor, medical oncology at Tata Memorial Centre, Mumbai. “Emily Whitehead has been free of cancer for 11 years now. We need to monitor patients, in all the Indian trials, who have received T-cell therapy for longer to observe results,” he says. Tata Memorial and the Indian Institute of Technology Bombay, are also doing path breaking research on T-cell therapy in the country.

T-cell therapy involves extracting cells from a patient’s body, growing them in the laboratory, weaponising them via gene therapy, and infusing them back into the patient’s body so the modified cells are better equipped to destroy large metastasizing tumours.

Tata Memorial has finished phase I trials to test for the safety of the therapy. Mukherjee’s trials have progressed to the phase II (b) stage, where both safety and efficacy of the therapy are studied.

 A 3D rendering of cancer cell

 A 3D rendering of cancer cell | Photo Credit: Getty Images

T-cell therapy is expensive; it costs between ₹3-₹4 crore in private health facilities in the U.S. Mukherjee’s Bengaluru-based biotech start-up, Immuneel Therapeutics — with Biocon’s Kiran Mazumdar-Shaw and Kush Parmar — aims to make cancer treatment more affordable for patients, for whom chemotherapy has stopped working. The company has raised $15 million as part of a series-A funding round. But conceiving and running the cancer unit has not been easy: “It is like sending a rocket to the moon,” says Mukherjee.

Edited excerpts from the interview:

Tell us more about the T-cell therapy clinical trials you and your team are running in India.

We have enrolled 10 children and adults living with what’s called a relapsed cancer, which no longer responds to chemotherapy, in the trial.

These patients would have otherwise died. In the phase II (b) clinical trial that we are running in Bengaluru, the [patient’s] T-cells are genetically engineered [almost weaponised to express a gene that would recognise and kill the cancer] and infused into the patient’s bone marrow. In some ways now, T-cells are being entirely produced in India for Indians. It is one of the first-of-its-kind efforts in India that has now expanded into a multi-centre study.

The Bengaluru unit was initially conceived in 2019 and built through the pandemic. It is an extremely sterile environment and has storage capacity in-house. The astonishing thing about building a unit like this is that it’s like sending a rocket to the moon. It is not like making a pill and throwing it at someone. It is technologically very intensive and requires a deep knowledge of biology.

Siddhartha’s library
I read so widely it seems like there is no real theme. I was re-reading Amitav Ghosh’s The Shadow Lines recently. I have been an enormous fan of Salman Rushdie’s books; my daughter is reading Midnight’s Children. We are also reading Arundhati Roy’s introduction to B.R Ambedkar’s book [The Doctor and the Saint] together. I am looking forward to Rana Dasgupta’s book on globalism, which is coming out next September. In science, I am about to start reading Andrea Wulf’s The Invention of Nature.

You mention the advances in treatment of leukemias and a cure for the condition. My aunt suffers from multiple myeloma and underwent a bone marrow transplant. The risk of relapse always looms large. How far has science progressed on tackling myelomas?

So, the next cell treatment that is now going through the regulatory process is for multiple myeloma. It will be ready in around March or April. Clinical trials have been designed and submitted to regulatory authorities. It is against a particular antigen called BCMA and the treatment will be the first of its kind in India.

For acute lymphoblastic leukemias, when T-cell therapy works — which is 70% to 80% of the time — patients are cured. On the other hand, multiple myeloma patients are looking at an extension of life with a possibility of a relapse and we are potentially moving towards a cure.

There is an unmet need for treatment in India for all patients in whom cancer has relapsed: whether they be lymphomas, leukemias or myelomas. To meet that need there should be a liaison, some kind of coming together of the Indian government and patients to make therapy affordable and accessible.

In The Song of the Cell, you mention German scientist Rudolf Virchow’s work on busting myths about race, and then Hitler comes in: the founder of myth-building who sort of dismantles the work Virchow has built upon. It resonates with the current political scenario in India. Don’t you think scientists and doctors who speak rationally, engage in research methodology, should be given more importance than political myth-building?

This book is a scientific book but every chapter has a political resonance. It is not a polemic book, yet it is a book about polemics. I am very conscious about the fact that these ripples are very universal and, in fact, very contemporary.

The idea behind putting it there is for people like you to say: “Hey! Wait a second, but isn’t it true today?” For IVF-related genetic modification that happens in China, the instance is put there not to just remind us about the particular history of that event, but to send a clink and shiver down your spine, and ask a question: if this happens in China then is it not happening in India, Mexico, Argentina, Thailand, Indonesia or Japan? My job is to show you that there are historical resonances.

The IMAGINE study
IMAGINE is India’s first phase II multicentre CAR-T cell therapy study, led by Mukherjee. Ten patients, out of an initially planned 24 patients, were enrolled for the study. These include adults and children with acute leukaemia and lymphoma on whom standard lines of treatment had failed. The therapy is working on six out of nine evaluable patients. The tenth patient succumbed to the disease. These patients demonstrated complete response to the therapy for over 112 days since it was administered to them.

You have been extremely candid about your mental health in your new book. Two instances: 2017, after your father passed away, and then the pandemic that collectively dampened our mental health, have been particularly tough. Where do we draw a line between the universal feelings of sadness and happiness and clinical depression?

Well, I am not a psychiatrist, so I can speak from personal experience. Obviously, there is grief that everyone experiences, but there is a certain tipping point when that grief becomes dysfunctional, and it takes over your life. That grief, although you know its antecedents — why it happened, where it happened — that grief continues, and starts creating a cycle, a cycle of its own. This is where we draw the line between situational grief and clinical depression. It is a very gray line, that line is very hard to draw.

There is a lot of talk about this in the U.S. and elsewhere, that depression is over-diagnosed and that too many pills are being supplied. Right now, our pharmacopoeia of antidepressant drugs is quite limited, basically limited to selective serotonin reuptake inhibitors [SSRIs] and some other drugs related to neuro-transmitter changes, but I hope we have a better pharmacopoeia that talk about some of the new ways — deep brain stimulation and potentially the use of psychedelics in a monitored setting to heal and help depression.

Perhaps the most important thing is that there is a strong cognitive and behavioural component to depression, and the treatment to that is not just pushing Prozac and Paxil on patients, but undertaking talk therapy. Modifying the situational component to it. In trial after trial, it has been shown that talk therapy in conjunction with drugs is extraordinarily important.

The road to trials
The regulation of this research is undertaken by the Drug Controller General of India (DCGI) as this therapy, even though it involves infusing a patient’s T-cells back into their body, are genetically re-engineered before infusion. So, they are referred to as drugs. Approvals need to be sought from DCGI before beginning phases of trials, be they pre-clinical and animal safety studies, or phase I, II or III of the clinical trials.

Patients with cancer who are tackling depression will have it even harder...

Yes, there is a huge and justifiable fear of opioids and pain medicine in India. Open use of opioids created an epidemic of its own causing hundreds of deaths every week in the U.S. In India, the situation is quite the opposite. The fear has turned into its own monstrosity, such that people who need opioids and other medicines to take their pain away, can’t get them. Because of the fear that it will unleash the demons of addiction. Obviously, there is a middle line. I have seen a great deal of progress in palliative care in dealing with patients in India and elsewhere, but I don’t think we are fully there yet.

What are your observations on life post-pandemic?

Many patients with chronic diseases could not go to their doctors during the pandemic. Although tele-health has now reached a much greater audience, medicine cannot be entirely practised on a tele-health basis. You need to have a physician visit, a doctor needs to do interventional procedures, and it is quite clear that there was disruption in the normal practice of medicine, extending far beyond cancer care. There is a backlog of patients who did not receive the care they needed, and several studies are slowly coming out that this has had an effect on morbidity and mortality of patients.

How to enrol
Patients (adults and children) in whom cancer (lymphoma or leukaemia) has relapsed and are keen on participating in the CAR-T clinical trials, can write to imagine@immuneel.com to find out their eligibility to get enrolled in the trials.

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