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The Interplay Between T Cells, Urinary Microbiome, Immunology & Cancer

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000724656.21066.cf
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Bladder cancer:
Bladder cancer

Cancer research in the midst of a global pandemic is tough. “Most institutions have prioritized getting through COVID right now, and research has taken a little bit of a backseat,” said Shahid Ahmed, MBBS, Assistant Professor of Medicine and Genitourinary Medical Oncologist at University of Vermont Medical Center. “It's like when your kitchen is on fire, you try to find a fire extinguisher. You're not out planting your garden.”

Nevertheless, cancer research soldiers on in the hands of dedicated clinicians and scientists. Ahmed is one such human catalyst. “Bladder cancer remains a very bad disease, and despite advances in immunotherapy, there are still a lot of things that we have to learn,” he told Oncology Times. “Studying T cells responsible for immune surveillance as well as anti-tumor effect, and identifying why they work and why they may not, is vital to developing better treatment options for our patients and selecting the best treatments.”

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Shahid Ahmed, MBBS:
Shahid Ahmed, MBBS

Originally from Islamabad, Pakistan, Ahmed crossed the globe to complete clinical electives in his final year of medical school at UCLA.

“It is fair to say that there was quite a culture shock, even in terms of studying medicine,” he admitted. “For example, when I got here in 2010, the opioid epidemic was going strong in the U.S., and I was totally unaware of it. I couldn't wrap my head around that.”

Today, Ahmed has fully acculturated to life in the U.S. He is married to an infectious disease physician, and together they have two children, ages 3-1/2 years and 10 months. His non-professional hours are given over to family and a passion for music.

“I play a few instruments, but the guitar is my primary one. I don't sing; you wouldn't want to hear that,” he laughed. “But I love listening to music; I love the way it makes me feel. Music is wonderful for me when I'm not working.”

Research Projects

Of course, during the lion's share of his time, Ahmed is working in this undeniably tough field of oncology.

“I chose oncology in the third year of medical school, when a 12-year-old cousin of mine died from leukemia. That pushed me in this direction. And then there have been mentors and people who've paved the way for me. First, I give credit to my father, who has supported me in everything that I do.”

After UCLA, Ahmed found his way to Indiana University where he was mentored by Patrick Loehrer, MD, Director of the cancer center. “He's a huge person who's taken time to mentor a small person—me,” said a humble Ahmed.

While at Indiana University, he developed a randomized study under the tutelage of Shadia Jalal, MD, to test whether a diet that mimics fasting decreases the toxicity of chemotherapy while increasing efficacy in lung adenocarcinoma patients. Animal models related to the diet and chemotherapy appeared promising, and Ahmed wanted to test whether a restricted diet and chemotherapy work well in humans.

“Here's how to think about this: the cancer cells utilize energy and nutrients to grow,” he explained. “Cancer cells are preferentially using nutrients. Chemotherapy acts on cancer cells that are growing, or dividing, but a lot of normal cells that are also growing are impacted. There is recent interest in trying to figure out how we can make sure treatments only target cancer cells and not normal cells.

“One way to do that potentially could be fasting,” he continued. “When you're in a fasting state, your normal cells shut off their machinery and just go quiet, because they don't have enough to go on. They just shut down their growth. But cancer cells can't do that because they're driven by mutations, so they keep on dividing.

“I designed a study in lung cancer patients trying to figure out if giving chemotherapy to patients who had fasted would help treat the cancer, and also reduce side effects of the chemotherapy due to the fact it would not be as effective on the normal cells in a fasting state.”

That study is ongoing at Indiana University, although Ahmed has since relocated to the University of Vermont. “We don't have results yet. But recently there has been additional research and exciting things happening in the world of fasting, and how it impacts cancer treatments. I think the next step will be to figure out whether that has an impact on prevention of cancer.”

Ahmed said one of the collaborators on his study is Valter D. Longo, PhD, of University of Southern California, who has worked in this area of interest for a decade.

“His work is in animal models, testing this hypothesis which is called ‘differential stress resistance.’ It is called that because the cells are differentially resistant; they have a different threshold for stress resistance if they're cancer cells, or if they're normal cells when they're in the fasting state,” he detailed. “Dr. Longo found in mice it did make a difference. Mice [that had fasted] lived longer and did better. Furthermore, it was shown effective for multiple types of cancers in the mice model. Right now, multiple trials are being conducted in breast, prostate, and lung cancers to further investigate this.”

T Cells, Microbiome & Immunotherapy

Now at the University of Vermont, Ahmed's work has taken another fascinating direction, which begins with T cells.

“Thymoma is the cancer of the T cells of the thymus gland. Immune therapy in patients with thymoma leads to a lot of side effects. Working with Dr. Loehrer, we wondered whether we can get the benefit of the immunotherapy, but reduce the side effects by selectively killing off some of the immune cells by using rituximab. This was an idea that I took to the AACR/ASCO Educational Workshop; Methods in Clinical Cancer Research in 2018,” Ahmed detailed.

With help from oncology pioneers in attendance at the conference, Ahmed further honed and shifted his project ideas and determined he would look into T cells, “... and evaluate the T-cell repertoire. We all have immune cells in our body that are trained initially to recognize different things,” explained Ahmed.

“These T-cell receptors recognize different antigens, and based on what they see they can then respond against them or let them be. So they're the policemen of the body, doing surveillance at all times, trying to figure out where the bad guys are. Now we have the technology to sequence those T-cell receptors and find out how many different kinds of T-cell receptors are present in our body, or in a particular organ. That helps us figure out what's actually happening with the T cells in response to a disease or response to treatment. This is called ‘T-cell receptor repertoire analysis.’ And that's what I'm most interested in right now specifically in bladder cancer.”

Bladder cancer is one in which immunotherapy works, but only in a small minority of patients. “We don't understand why it doesn't work in all of the patients,” lamented Ahmed. “Immunotherapy works great for melanoma, works fairly good for lung cancer, and that's where most of the advances have happened. But not all patients with bladder cancer experience the impact of immunotherapy.

“And so my research is designed to figure out what the barriers are for those T cells to attack the cancer cells, and understand why they are not doing it in a majority of patients. One possible reason to explain that would be the interplay between the bacteria in the urine and in the bladder, and how the bacteria or the microbiome interplays with the T cells.”

Asked what role bacteria potentially might play, Ahmed answered, “Well, first of all we know that the microbiome of the gut somewhat ‘trains’ the immune system, so to speak; the more diverse the bacteria you have the more the immune system has to train on and to learn from. And so if you have more antigens, your T cells are going to be able to recognize a diverse set of things.

“There has been a lot of research in the gut microbiome, linking that with cancers and with immunotherapy. It has been shown that if you have certain bacteria you're less likely to get a particular kind of cancer, or more likely to get another particular kind of cancer. It's also shown that, if you have different kinds of bacteria, you're more (or less) likely to respond to immunotherapy. There is certainly an interplay going on between the microbiome and the T cells. We're just unraveling that. But it's a long road and, first things first, we have to find out whether there's even any correlation there at all,” he said cautiously. “But one earlier study [Sci Rep 2018;8(1):12157] did find that bladder cancer patients have over-representation of a bacteria called fusobacterium.”

That said, there really has been no research looking at the urinary microbiome, the bacteria in the urine, and how they impact the T cells in the bladder. “So that's what I'm doing,” Ahmed said. “We hope to be able to answer if the microbiome modulates the immune system to affect bladder cancer, [and] identify any interplay between the T cells and the urinary microbiome.

“If we're able to show that there is a correlation between the microbiome and the T cells, then the next step would be to do a study with people with bladder cancer who are also getting checkpoint inhibitors and other immunotherapies. We will try to determine if immunotherapy changes the T cells, and if it changes it differently for people with a particular microbiome. Eventually, we hope to use this as a biomarker to help predict cancer development, and determine who will respond to treatment and make immunotherapy more effective in people with a certain kind of microbiome.”

As all of this exploratory work goes on, Ahmed reflected on his life as a physician scientist in the midst of a pandemic.

“I am primarily a clinician, and I see patients. During COVID, a lot of cancer patients have been staying home, missing screenings or follow-ups. Some people don't even know they have cancer yet, and are not seeking care,” he explained. “They think, ‘It's better to be home, than go to the hospital.’ But cancer doesn't wait. So 3 months, 4 months down the road, everybody is sicker, everybody is more anxious. Cancers have progressed. Our clinical load is much heavier, and that takes away from the time that we spend doing research. And when cancers are missed early, patients are more advanced when we see them. And when they're more advanced, they're harder to treat. There's a huge burden on the medical community right now.”

Valerie Neff Newitt is a contributing writer.

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