Robin Parihar, MD, PhD, is 8 years older than his brother. He fondly recalls helping to raise his younger sibling-even changing diapers-and later showing him the ropes of life as only a big brother can. "That experience made me want to work with children," revealed Parihar, who has taken that formative desire to extraordinary lengths.
Today, Parihar is an Assistant Professor of Pediatrics at Baylor College of Medicine and an oncologist at Texas Children's Hospital, Houston. He maintains his own translational research lab focused on cancer immunotherapy for children. His efforts are already providing insights into the importance of understanding the tumor microenvironment and yielding new approaches for enabling the immune system to work at a more efficient level as it battles cancer.
Parihar began his higher education by earning a degree in chemistry at Wake Forest University. "However, over time, I discovered that I hated chemistry. Although a great discipline, a chemistry career just wasn't for me. I wanted to find something different, so I looked in the want ads and moved home to Cincinnati to take a job in an immunology lab. I had never even thought of immunology before, couldn't even spell immunology at that point," he joked. "Honestly, I had no idea what it was." Nor what it was to become over the next two and a half years-his passion.
The Call of Immunology
"I discovered that I loved immunology, so I went to graduate school at Ohio State University and got a PhD in cancer immunology. While there I worked with a surgical oncologist, William E. Carson, MD, at the university's Comprehensive Cancer Center. He was an amazing mentor who worked really well moving between the research lab and the clinical world. With him I did a lot of work in the lab, of course, but also a lot of work in clinical trials. He would take me along to meet the patients who were on our clinical trials and it was always the highlight of my week. I fell in love-again-this time with the idea of combining these two worlds of research and patient care, and being able to go back and forth to answer important questions that were directly translatable to patients."
Of course this new revelation meant more education was necessary, so Parihar went to medical school at Wright State University, followed by a residency at Cleveland Clinic Children's Hospital and a fellowship in pediatric oncology at Texas Children's Hospital.
While he said he most closely identifies as a clinician, his reality includes 80 percent of his time in the research lab. "I have always loved seeing patients and want to continue, but working in the lab and getting that work to clinical trials takes a great deal of time. We are in the process of translating some of our work from lab into trials. Doing predevelopment phases of the clinical trials, getting funding in place, getting regulatory approvals from the FDA, going through internal review board-things like nitty-gritty paperwork takes a year or two to accomplish."
Parihar's lab objectives derive from what he saw in the clinic during training. "My interest clinically is in pediatric solid tumors of the bone, muscle, and other organs. We find a small handful of these patients have what we call low-risk disease-readily curable with conventional chemotherapy, surgery, or radiation therapy. But we have a hard time curing those patients who have high-risk disease," he explained. "We may get them to a certain place where they live a long while, but eventually they are either refractory to the therapy or their tumor comes back, even though we thought we had gotten rid of it."
Not only does this present a clinical problem, "...it is also a lifelong emotional problem for these kids and their families," said a very empathetic Parihar. "We end up failing and losing some of these kids. It's not something I can turn away from."
The Suppressive Role of MDSCs
Parihar's lab at Texas Children's Hospital, part of the Center for Cell and Gene Therapy, is focused on trying to make the immune system work better in the face of cancer.
"The tumor in a patient with high-risk disease has an ability to suppress the immune system from working correctly," explained Parihar. "There is something about the tumor that makes it immunosuppressive. We are exploring aspects of the tumor that make this immune system go haywire; we call this the suppressive tumor microenvironment. We want to know what that is, exactly, and how we can reverse or fight it."
He and his team have shown that a particular cell called an MDSC is a highly suppressive cell of the immune system, particularly in patients with cancer. "We find them in the body all the time, but it is typically in such a small frequency that it doesn't cause any problems. In fact, it probably helps us usually, because it prevents the immune system from going haywire and attacking everything," Parihar told Oncology Times. "However, tumors have found a way to force our body to make more of these cells and recruit them to the site where the tumor is trying to grow. It recruits them so they can turn the immune system off."
Parihar and colleagues published a paper on their findings (Cancer Immunol Res 2019; doi: 10.1158/2326-6066.CIR-18-0572), which explained that many pediatric solid tumors have a high presence of MDSCs. It further described the lab's development of a cell therapy that can somewhat eliminate the MDSCs in the tumor and make the tumor more susceptible to immune attack by anti-tumor T cells.
Parihar explained, "The first thing we did was engineer natural killer (NK) cells, part of the innate immune system. NK cells normally cannot find the MDSCs. So we re-engineered them in the lab and expressed a certain molecule on their cell surface that is able to interact with the MDSCs. It binds to a protein on the MDSCs that they always express when inside solid tumors. We can take advantage of that interaction because the NK cells have a receptor that allows it to interact with that protein, and find and kill the MDSCs. And instead of just interacting, the receptor actually acts to tell the NK cells to start killing. It is a killing receptor."
Next, the investigators took MDSCs from children with cancer, put them in a test tube, and introduced the engineered NK cells to see if they could kill the MDSCs. "In fact, they did," said Parihar. "It was much to our surprise actually. No one had ever thought about this interaction before, so we didn't know what to expect. But indeed they killed. We thought maybe that was just a test tube phenomenon, and it wouldn't work in a body."
To find out, Parihar's next step was to develop a mouse model in which tumors containing human MDSCs grow as solid tumors. The investigators found the MDSCs helped the tumors grow "...really fast and really large," said Parihar. "When we treated the mouse with this tumor with our engineered NK cells, the tumor started to shrink a little bit, but it didn't go away completely. Yet, when we looked inside the tumor, all of the MDSCs were gone. The NK cells were able to go inside the tumor in this animal model and get rid of all the MDSCs."
Hopeful Implications
The implication of this finding is that the eradication of MDSCs may allow other therapies to work better. "That is what we propose in trials we are trying to start," said Parihar. "When we added another type of immunotherapy-CAR T cells-to this mix, all of the tumors disappeared."
Parihar noted CAR T cells by themselves typically do not work well with solid tumors. "We believe one of the reasons is because of this suppressive tumor microenvironment. But when we introduced these NK cells, got rid of the MDSCs, all of a sudden the CAR T cells that before did nothing suddenly had a lot of activity and got rid of the tumors." He is hoping to open a clinical trial that will involve a combination of engineered NK cells with CAR T cells to fight solid tumors.
The Long View
Ultimately, Parihar hopes to cure patients with cancers that currently are not curable with immune therapies. "CAR T cells, for example, have been revolutionary in leukemia. There are patients with refractory or relapsed leukemia who, 10 years ago, would not have survived. But now they are being cured with immunotherapy which, relative to chemotherapy and radiation, is much less toxic. But in the solid tumor world, patients are not responding to CAR T-cell therapy, so we have to find a different way to make it work.
"The main thing we've learned over last 4 years in our project is that one immune cell is not going to solve the problem in solid tumors. The human body coordinates an amazing immune response to infection or cancer with many immune cells and proteins all working together to get rid of all these problems. We cannot expect one protein or one cell to do the work of the entire immune system. As we go forward, we must look for combinations of things-different kinds of immune cells and different kinds of immune proteins that act together-to fight these cancers."
Asked how he balances the thrill of discovery against the possible disappointment of a failed hypothesis, Parihar said, "Disappointment comes with this job. But what keeps me excited every day is the fact that we learn every time we do something, whether we succeed or fail. Learning from our work in lab, and learning from our patients who volunteer their time, their effort, their lives, and their emotions in our trials-that's what keeps us going. The more we learn, the sooner we can find that magic bullet."
Married and father to a son, 5, and a daughter, 3, Parihar said his devotion to his children has helped to inform his professional sensitivity and push him toward specific goals. "It drives me in a very specific way. I understand how valuable children are to their parents. When I tell parents in the hospital for the very first time that their child has cancer, we go through a long conversation about what this means, what we are going to do, and what we can offer. I can't help but think about what must be going through their minds when they hear these words. I understand their desperation," said Parihar.
"It makes me want to work hard in the lab to find things we can offer to parents when we have those hard conversations," he reflected. "I think about how this project in the lab right now may allow me have a better conversation with a parent in the next 5-10 years. Instead of saying, 'This is a high-risk disease and the likelihood of cure is low,' I want to be able to say, 'We have this great new therapy that we've developed and we think we've got a great shot at curing your child.' It would be a very different kind if conversation for a parent to hear. That's the goal I have in mind. We have to keep asking, 'What better option can we offer?'"
Valerie Neff Newitt is a contributing writer.
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