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Investigating Mechanisms to Better Understand Immune Response

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000535062.74147.75
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Randy Sweis, MD

Randy Sweis, MD

Randy Sweis, MD, spends hours upon hours in his lab at the University of Chicago trying to unravel mechanisms of resistance to cancer immunotherapies and develop strategies to modulate the tumor microenvironment, with a goal of improving anti-tumor immune responses.

But that is only half of the professional load he has undertaken. Sweis is also a caring, patient-facing clinician who has created an impressive symbiotic relationship between the lab and his clinical practice. He translates his laboratory findings to patient care by asserting his expertise in drug development and early-phase clinical trials.

The University of Chicago physician-scientist reports weekly to his clinical practice where he treats patients with genitourinary malignancies including bladder, kidney, prostate, and testicular cancers. “I see patients dying from cancer. They are a constant reminder of why I must do what I do,” said Sweis. “Lab work is tedious and challenging and often we don't get the results we want; it would be easy to slow down or back off. But the clinic reminds me I have to keep at it. I am lucky to have that advantage.”

The southwestern Chicago native has been loyal to his home turf, having done undergraduate science studies at the University of Chicago. He worked as a medicinal chemist for Merck right after college, then decided to go to Pritzker School of Medicine at University of Chicago because he wanted “... to be at the front lines of patient care.”

In medical school, Sweis observed several ongoing positive developments in cancer therapy and decided oncology was an area where he could apply his interest in science and background in drug development to improve therapies and prevention, and treat patients in serious need.

While doing a subsequent internal medicine residency at the University of Michigan, Sweis saw emerging immunotherapies and the benefits they provided to responsive patients. “That led me to cancer immunology as the field I wanted to focus on,” he recalled.

Sweis returned to the University of Chicago for a dual fellowship in hematology/oncology and clinical pharmacology, and stayed on as instructor of medicine. Mentored in the lab of cancer immunologist Thomas Gajewski, MD, PhD, Sweis is now building his own lab from that sturdy foundation. Like his mentor, he has embraced the life of a physician-scientist.

“Clinical work and research are distinct. They activate different parts of the brain, so there are benefits to doing both. The two pursuits feed off each other because I keep both arenas very closely linked,” he told Oncology Times. “For example, I am investigating mechanisms of immunotherapy resistance that were discovered from work I did on patient sample material that revealed specific molecular patterns. That led me back to the lab to develop causality between phenotypes of tumors and determine if this is something that actually drives immune response. In parallel, I am now developing a phase I immunotherapy clinical trial combining two agents, so it is really a circular loop—patient to lab, and lab to patient. I am building a practice in that way, and it is working out.”

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Inroads in Immunology

Immunotherapy is arguably one of the biggest revolutions in cancer therapy. “In bladder cancer, there were five immunotherapy drugs approved within the 1-year period of 2016-2017,” said Sweis, adding that during the prior 30 years there had only been one drug approval in bladder cancer.

“Immunotherapy is getting a lot of hype in the media, and appropriately so because we now have patients with metastatic disease who are going on 3-plus years survival with complete resolution of their cancer,” Sweis explained. “Before immunotherapy, these same patients with advanced metastatic disease would have had almost no chance of living beyond 3 years. Second-line chemotherapy didn't work very well. But now we see patients having remarkable outcomes.”

Yet there remains a persistent problem. “Only a small percentage of patients are responding in that way. Right now in bladder cancer it is only about 20 percent who respond. That is the frustration. If we can inch it up, maybe to 40 percent as a start, that would be wonderful,” he said.

Toward that end, Sweis has reported some early successes. “Earlier we published a study identifying genetic alterations associated with immune response in bladder tumors of patients,” he recounted (Cancer Immunol Res 2016;4(7):563-568). Sweis and team had explored bladder tumor samples obtained through their participation in the national collaborative The Cancer Genome Atlas, a large initiative to conduct genetic sequencing of tumors from 10,000 patients with different cancer types.

“My initial project was interrogating those tumors likely to be unresponsive to immunotherapy. I found specific molecular pathways that might be aberrant in those tumors,” Sweis explained. “Now we have drugs available through collaborations with pharmaceutical companies which we are using in an attempt to increase the sensitivity of cancers to immunotherapies. When we find these pathways activated in tumors, we want to block them with drugs and also give immunotherapies in the hope that those resistant patients will be able to respond to immunotherapy.”

Out of the bladder cohort of 400 patients came a massive compendium of data that is now available online to any researcher anywhere in the world. The tumors were completely sequenced and all the genetic information has already led to innumerable papers reporting new scientific findings.

“There is something about the tumor environment that makes the therapy work or not. We are only beginning to dissect the reasons,” Sweis explained. “There are environmental factors. For example, the composition of the gut microbiome matters—there are actually specific bacteria that are present in patients who are responding to immunotherapy. And there are host genetic influences—some people may have a higher propensity to have an immune response against cancer than others.

“Additionally, there are influential tumor genetic alterations that can subsequently block or dampen a body's immune response to cancer, which is my focus right now. In my view, there is no single magic bullet. The approach I am pursuing is just one small incremental advance of many that are coming.”

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In the Lab

Asked to describe what the work of discovering relevant pathways actually looks like in the lab, Sweis said it looks a lot like mice. Specifically, mouse models are developed that most closely recapitulate the human tumors that he saw and analyzed in the first place.

“We can induce bladder tumors in mice and modulate certain genes—the same aberrant ones we saw in the human samples—to turn them on or off. We employ molecular biology, immunology, and we also study response by different interventions. We give anti PD-L1 antibodies—the same target pathway for which all of the immunotherapies in humans are approved—to the mice so we can mimic the treatments and see if they work better or worse depending on whether our genes of interest are impacting them,” he detailed.

Sweis said his work is progressing with a still unpublished hypothesis about an additional pathway, and yet another in his sights. “My hope is to develop drugs to turn pathways on or off, then move them into clinical as quickly as possible in parallel with publishing preclinical data from the lab.”

However, Sweis was quick to stress that devising new paradigms of how cells interact or how immune response acts requires many years of underlying fundamental research to set things in motion. “It is the fundamental research that is hard to accelerate. Even in the explosion in immunotherapies, the PD-1 target (for which the aforementioned five drugs were approved recently) was discovered through fundamental research in 1992. It took all that time to develop it. There are not a lot of shortcuts. Basic research will lead to the next explosions 10-15 years from now.

“We need to keep the pipeline moving from the beginning to the end. So yes, I am often at the interface where targets have been discovered that I can validate in mouse models and bring rapidly to clinic. But there is extremely valuable work at an earlier stage that needs to be continually encouraged through funding.”

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High-Intensity Recreation

It's not “all work-and-no fun” for Sweis, who is married and has an infant son. “My son is already throwing a mini-ball around and he's isn't even a year old, so I expect we'll be on the court playing one-on-one soon. I've always been a basketball fan, having grown up in Chicago with the Bulls in '90s,” he revealed.

Throughout medical school, residency, and now his career with clinical and lab work, he has managed to remain active on the basketball court. “I play pickup no matter where I am,” Sweis said. “The fitness aspect is a bonus because I enjoy it so much that I don't realize I am getting a high-intensity workout. And there are mental benefits, too. At work I am constantly thinking about research, care plans, patients, questions around treatments...my mind is always active. But with basketball I'm active in a different way. I ‘zone out’ because I am so tuned into the task at hand. It shuts off all the ‘noise’ from work. I think it is critical to diffusing tensions and maintaining health.”

Looking ahead, Sweis said one of his main objectives is to grow his lab into a stable, robust, independent entity. But the bigger goal for him is to push therapies into clinic as quickly as possible, “...likely involving immunotherapy that would lead to long-term durable response—if not cure. My hope would be that I can see a patient with newly diagnosed cancer have molecular sequencing data from their tumor, then guide them to one of perhaps 10 combination therapeutic approaches personalized to fit their tumor and their circumstance that will have a high chance of controlling the tumor. We are just in the infancy of this.”

He added, “Even though I have seen the hype around immunology, I can say honestly that it is remarkable. When patients do have responses, they can go from metastatic bladder cancer, which was universally considered fatal 3 or 4 years ago, to having their disease completely resolved. Immunotherapy is one therapy that, when it works, delivers phenomenal responses. It is super exciting. The positive responses motivate me and make me want to get that response for everybody by going back to the lab. It is the future and it is also happening now. We need to improve upon it.”

Furthermore, Sweis tipped his hat to the patients in clinical trials who allow this important work to continue. “I always remind them that patients in trials, even those who might be getting a placebo in an adjuvant study, are creating the cutting edge. They are the cutting edge. They are ushering in the next wave of advances in their cancer and they are the ones who will improve the lives of the next generation of patients.”

Valerie Neff Newitt is a contributing writer.

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