Marcela Maus, MD, PhD: Breaking barriers in pancreatic cancer.

Over the last two decades, cell and gene therapy has revolutionized the cancer treatment landscape. But while CAR T-cell therapies have been successfully used to treat blood cancers, the unique immunosuppressive environment of solid tumors has proven a barrier to these next-generation treatments.

Marcela Maus, MD, PhD (Massachusetts General Hospital), has consistently worked at the cutting edge of cell and gene therapy research throughout her career. Now, she’s turned her attention to pancreatic cancer, heading a bold new study to leverage genetic engineering technology to break down these barriers to immunotherapy treatment.

Dr. Marcela Maus’s background in cell and gene therapy research.

Dr. Maus is the Paula J. O’Keeffe Endowed Chair and Director of the Cellular Immunotherapy Program at Mass General Brigham Cancer Institute, and the Associate Head and Head of Cell Therapies at the Mass General Brigham Gene & Cell Therapy Institute. She is also a Professor of Hematology and Oncology at Massachusetts General Hospital and Harvard Medical School.

A mentee of cell and gene therapy pioneers Carl H. June, MD (University of Pennsylvania) and Michel Sadelain, MD, PhD (Columbia University), Dr. Maus has dedicated her career to furthering research into the efficacy of CAR T cell therapy, establishing her own laboratory in 2015 at Mass General to design and evaluate next-generation T cells.

The Maus Lab at Mass General has been a nexus of innovation in cell and gene therapy since its establishment. There, Dr. Maus has focused on engineering new CAR T cells to maximize their effectiveness against cancer, understand how they function in patients, and how they can best be deployed.

That process has included extensive research on how the gene-editing platform CRISPR can be used to optimize T cell production and effectiveness. Years of insights have now led Dr. Maus to tackle pancreatic cancer.

Turning T cells against pancreatic cancer.

It’s been quite clear to many researchers that developing cell and gene therapies to treat solid tumors, which constitute the majority of cancer types, is extremely challenging. Pancreatic cancer is one of the most deadly and aggressive forms of cancer in existence.

The challenge is not just to physically insert T cells into the tumor microenvironment, but to get the patient’s immune system to recognize them and allow them to do their work. In Dr. Maus’ study, she aims to use CRISPR screens to identify key changes to engineered T cells that will allow them to thrive in a pancreatic cancer environment. CRISPR screens are large-scale experiments that use the CRISPR gene-editing system to systematically disable or modify every gene in a cell to identify which are involved in a specific biological process. Turning multiple genes or sets of genes on and off will enable Dr. Maus to understand which combinations make CAR T-cells more powerful against cancer.

“We think that human T cells are the most potent anti-tumor killer,” Dr. Maus said. “The trick has been in trying to get them not only to recognize pancreatic cancer, for which we have a couple of ideas that I think are suitable, but that once they get there, they’re uninhibited. I think right now there are a lot of barriers to their sustained function and ability to eliminate tumors. We think we might need to tweak the T-cell a little bit to enhance its power when it enters that suppressive, hostile environment that is a pancreatic cancer tumor.”

Dr. Maus has good reason to believe this process will be effective in pancreatic cancer, as she is building off similar research in multiple myeloma that produced highly promising results.

“What we’ve done recently in separate work in multiple myeloma is we’ve knocked out 101 of 135 different genes each in a different cell, and raced them against each other in a model,” Dr. Maus said. “Using that strategy, which in broad strokes is called a screen, we identified some new genes that really seem to help CAR T-cells. And so, we’ve been working preliminarily on using a similar strategy in pancreatic cancer.”

Not a one-size-fits-all process.

Dr. Maus hopes that her previous work in multiple myeloma can provide a template for her research into pancreatic cancer, funded with a $500,000 grant from ACGT. But each type of cancer is different, and applying a similar process to pancreatic cancer will still require starting essentially from scratch.

“Overall, the big picture steps, I would say, are quite similar, but you can’t necessarily translate the best strategy for a brain tumor and assume that that’s going to be the same in pancreatic cancer,” Dr. Maus said. “You have to just kind of do it again in that disease, even if your overall process is similar and can be mapped from one tumor to another. How we engineer T cells, we can take those learnings and leverage them across settings. But the ideal way to do it is not necessarily the same one across all cancers.”

However, if Dr. Maus and her lab make a breakthrough in pancreatic cancer, it’s easy to envision a future in which her use of CRISPR screening to create more effective CAR T cells can be a game-changer across many other types of cancer.

“I hope that this makes a significant clinical impact for patients, that by identifying ways to really enhance T-cell therapies and CAR-T therapies in particular, that we’ll be able to have disease responses that really leverage the power of the T-cell,” Dr. Maus said. “Ideally, something durable in the future that prevents cancer from coming back after an initial surgery.”

Continuing ACGT’s legacy.

Dr. Maus’s support from ACGT comes at a time when funding for medical research in the United States is increasingly uncertain – but also at a unique time when cell and gene therapy research is poised to make significant breakthroughs in treating and potentially curing cancer.

Dr. Maus’s mentors, Drs. June and Sadelain, are not only two of the leading figures in the development of cell and gene therapy for cancer, but they were also two of the earliest recipients of ACGT grants. As such, Dr. Maus is keenly aware of the organization’s impact on the field and its importance moving forward.

“I stand on the shoulders of giants in terms of identifying T-cells as an incredibly potent therapy,” Dr. Maus said. “I’ve been interested in this for a long time, over 30 years. I feel like we’re just on the cusp of making a real impact in diseases like pancreatic cancer. We’ve made such incredible headway in leukemia and lymphoma, in part thanks to the historical legacy of ACGT-funded projects and investigators. So, really building on that legacy and taking it to other tumors, including cancers like pancreatic cancer, I think, will only increase the impact of the foundation.”