Pioneering Immuno-Oncology Through a Love of Science
How a love of science and frustration with a lack of curative treatments for cancer led one researcher to the leading edge of cancer immunotherapy.
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Sangeeta Goswami is one of a relatively rare breed – a physician-scientist, a medically qualified researcher who balances her role as a physician treating patients with a research career in the laboratory. Physician-scientists are uniquely placed to identify and then address some of the most pressing priorities in biomedical research, but it’s a journey that requires sacrifices and resilience to make it for the long haul.
Goswami’s own journey began in Assam, India. Her initial fascination with science was inspired by her grandfather who was a biochemist working in academia. This ingrained a love for science at a very early age and, coupled with an inherent curiosity about the world, made studying medicine a natural choice. “India is a very densely populated country and, training in a tertiary medical center, I saw a large volume of patients,” she explains. “It was a privilege taking care of them, and something I knew I wanted to do for the rest of my life. But increasingly, I was struck by the lack of definitive curative medicines for most of the diseases we treat, and that’s where my interest in research began, when I first thought about doing a PhD.”
Becoming a clinician-scientist
Goswami was the only one in a class of 160 students who decided to pursue a PhD. As there was no integrated MD-PhD program in India, she began by working on a year-long collaborative project between a Council of Scientific & Industrial Research (CSIR) laboratory and the All India Institute of Medical Sciences in Delhi. The experience confirmed her gut feeling – she wanted to delve into research in the next stage of her career. Goswami applied for PhD studentships in the United States and was accepted at Baylor College of Medicine in the Department of Immunology.
Combining medical training with research is not an easy decision. “It’s a long road and it takes a lot from your life,” Goswami says.
Not only is the medical training itself lengthy, but you are also adding on a separate degree or separate training to hone your research skills. As a junior investigator, it's a significant time commitment. “Sometimes, you feel you're in no man's land between two different communities – with your physician and basic science researcher counterparts having particular expectations of you,” Goswami describes. The clinical training comes first, she emphasizes. Patient care is paramount, so there can never be any compromise on your clinical skillset.
At Baylor College of Medicine, she was mentored by physician-scientists Dr. Farrah Kheradmand and Dr. David B. Corry, which not only opened her eyes into the field of clinical medicine and discovery science, but also marked the beginning of a passion for immunology.
“The immune system is always fascinating. It’s such a finely tuned system, it’s like the porridge in Goldilocks – it can be neither too hot nor too cold. If it gets too hot, you get autoimmune disease. It's too cold, you get infections and cancer,” says Goswami. “The nuances of the immune system and how it balances all that different pathophysiology has always been fascinating to me.”
Modulating the immune system has been an important goal in many complex diseases for decades, but the development of immune checkpoint inhibitors (drugs that take the brakes off the immune system) and advances in single-cell RNA sequencing has led to an explosion in our understanding of the interplay between tumor-associated immune cells and cancer treatment and progression. T cells have been seen as key players because of the varied roles of cytotoxic T cells, T helper (TH) cells, and regulatory T cells (Tregs) in the immune responses within the tumor environment, but focus is now expanding to other cell types – from B cells involved in immune memory, to additional cell-killing power offered by natural killer cells, and the diverse roles myeloid cells play in the tumor-microenvironment.
At the early stage of her career, Goswami could not yet know that her appreciation of the beauty of the immune system, and fundamental training in T cell biology, would lead her to work in a field that has transformed the cancer treatment landscape.
The importance of timing
Goswami completed her PhD before beginning her internal medicine residency at University of Pittsburgh Medical Center. “This is where my love for oncology began because I was undertaking training rotations through oncology wards and I felt a connection with patients going through such a difficult journey,” she recalls.
The timing was such that, while she was in her residency, the first-in-class checkpoint inhibitor, ipilimumab, was approved for metastatic melanoma. “Suddenly, tumor immunology, which had been somewhat in the periphery of cancer research for decades, actually came to the forefront,” says Goswami. “I saw it as a sign: my love for immunology and my love for oncology coming together as tumor immunology. I knew this is what I wanted to do.”
Goswami applied for a medical oncology fellowship and secured a position at The University of Texas MD Anderson Cancer Center, where she had the “pleasure and privilege” to work under the mentorship of Dr. Padmanee (Pam) Sharma.
Sharma had been instrumental in the clinical research behind many of today’s immune checkpoint agents. “It was like a dream come true for me to learn from the best,” recalls Goswami. “From the start, Dr. Sharma gave me full scientific independence to pursue my research interests, while always being there as a mentor to guide me through and help me understand the big picture.”
The opportunity also arose to work closely with Dr. James P. Allison, whose fundamental immunology research into checkpoint inhibition won the 2018 Nobel Prize in Physiology or Medicine (together with Dr. Tasuku Honjo).
Autonomy to address key questions
Since 2018, Goswami has been a faculty member at MD Anderson in the Department of Genitourinary Medical Oncology, where she sees patients with kidney and bladder cancer and leads a lab conducting research. “We are trying to understand pathways of response and resistance to immune-based therapies across different tumor types,” she explained.
Resistance to immunotherapy can be categorized as primary (tumor does not respond to immunotherapy), adaptive (where the tumor is recognized by the immune system, but it adapts to evade destruction) and acquired (where a tumor initially responded to immunotherapy but stopped). There are multiple, complex mechanisms behind these types of resistance – from low tumor mutational burden causing the tumor to be immunologically “cold” in the first place, to changes in the functions of the T cells that were once effective.
Goswami was intrigued by how immune cells within tumors changed their state as cancer progresses. “We know that it’s not genetics that’s changing, so I wondered: are cues from the environment regulating genes that are in turn controlling the immune cells’ state?” she explains. “I had two questions: how does this change when we first give immune checkpoint therapy, and how does the altered immune cell state eventually dictate the response or resistance to immunotherapy?”
To address these questions, Goswami had to study the epigenetic regulation of the immune cells – that is, how the gene activity within T cells was being altered by environmental cues around them. There are four main epigenetic mechanisms that control gene activity: the structure of chromatin, non-coding regions of the genome and chemical modification of DNA and histones (the proteins that provide structural support to DNA.)
As an immunologist, not an epigeneticist, this was a foray into a new field, and it taught her perseverance. “I definitely had my share of heartaches,” she recalls. “There were tears in the initial years when I was wondering, ‘am I asking the right question or not?’ ‘Is it worthwhile?’, when everyone was publishing and I was at the stage where my first experiment was not working.”
But Goswami did persevere, and it paid off. She discovered that patients receiving immune checkpoint therapy, especially anti-CTLA4, had increased levels of an epigenetic enzyme called EZH2 in T cells. When Goswami’s lab explored this further, they found EZH2 maintains a suppressive chromatin structure in regulatory T cells – suppressing the immune response. Moreover, adding an EZH2 inhibitor alongside checkpoint inhibitors in preclinical models, improved tumor response and survival.
“This is where mentorship from Dr. Sharma became so critical. Not only did she give me full independence to pursue what I wanted to do in science, but when I got to this stage, she helped me to bring the preclinical concept to the clinic,” Goswami says. “She connected me to the right people.”
In collaboration with another faculty member at MD Anderson – Dr. Ana Aparicio – Goswami initiated a clinical trial combining anti-CTLA4 with an EZH1/EZH2 inhibitor in patients who are either primary-resistant or have developed acquired resistance to Immune checkpoint therapy. That trial is ongoing, and Goswami is applying a similar reverse translational approach to other questions she identified as a junior investigator.
This includes trying to find biomarkers to enrich patient selection for immunotherapy – an area where researchers are already heavily investing time and resources but might not be looking in the right place.
“To date, studies have looked either at tumor-specific factors like tumor mutation or burden, or were only looking from the immune perspective, such as PD-L1 expression or interferon gamma signature,” she says. “We found we need to integrate these perspectives because the immune microenvironment doesn't work in silos. And when we did, we started to find markers.”
One such project is combining two biomarkers – mutational status of a chromatin modifying complex and levels of the chemokine CXCL13 – to identify patients who are likely to respond to immune checkpoint treatment. These markers are currently being validated in patients taking part in immunotherapy trials, with a view to using them to stratify patients for treatment in future studies. Goswami’s lab is also expanding their work to the most intractable cancers, making progress in immune profiling glioblastoma brain tumors to find novel immune targets and demonstrating that through blocking an epigenetic regulator in myeloid immune cells it becomes possible to sensitize “immunologically cold” glioblastoma cells to checkpoint inhibitors.
The next chapter
What does Goswami want to achieve in the next chapter of her career? First, to feel she has made a difference in a patient's life through her clinical expertise and scientific research – to improve their survival or help their cancer shift from palliative to curative. “I want to learn from every patient. I really hope we soon get to the stage where we can do biomarker analysis upfront to initiate treatment and then have longitudinal sampling, so it’s no longer a guessing game for the clinician to know which treatment will work best at different stages.”
Her second aspiration is to train the next generation of physician-scientists in oncology, especially providing female and immigrant scientists the opportunities and mentorship she feels have benefited her own career.
“In every generation, you will find a handful of people who feel driven to take this career path, and we need to identify them early so you can nurture them and protect them,” she says. Protected time away from clinical duties to allow her to carry out her research was critical, she says, and something she wishes was rolled out to more countries. “It’s simply not productive for someone to spend the first 20 years seeing patients and suddenly switch 100% to become a researcher. We need better integration of MD-PhD programs into mainstream medical education worldwide, if we want to propel clinical research or even fundamental research forwards.”
Goswami wants people – especially students aspiring to be physician-scientists – to understand that it’s a long journey involving sacrifices, commitment, and perseverance. “Especially as a female, immigrant scientist. It is not an easy decision to leave your parents behind to come to a different country for the love of science,” she says. “That’s why I'm very much motivated to train the physician-scientists of the future, especially women scientists. I have a lab of seven women at this point of time, because I feel my career has been so heavily driven and influenced by women, from my mom to my mentors, who have been instrumental in shaping my career. I feel that now the onus is on me to train the next generation, to train those seven brilliant women and more.”
About the interviewee:
Dr. Goswami is one of the inaugural members of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center where she plans to carry on her research projects to improve outcomes with immune checkpoint therapy.
