Turning the corner in pancreatic cancer.

While considerable effort has been expended in researching effective treatments, a pancreatic cancer diagnosis is still greatly challenging for both patients and their physicians with 5-year survival rates at approximately 13%, according to the American Cancer Society.

That’s why Philip Greenberg, MD – one of the preeminent experts in cell and gene therapy development – has turned his attention towards pancreatic cancer. After losing his father to the disease and seeing little progression in survival rates, he’s bringing his lifetime of expertise to advance effective cell and gene therapies for pancreatic cancer.

Dr. Philip Greenberg’s background in cell and gene therapy research.

Dr. Greenberg is the head of the immunology program at Fred Hutchinson Cancer Center, a member of the Fred Hutchinson Cancer Center Immunotherapy Integrated Research Center and Pathogen-Associated Malignancies Integrated Research Center, and the Rona Jaffe Foundation Endowed Chair and Professor of Medicine (Hematology Oncology) and Immunology at the University of Washington.

Dr. Greenberg became an Alliance for Cancer Gene Therapy (ACGT) Research Fellow in 2025 through the ACGT – Mark Foundation Award in Cell and Gene Therapy for Pancreatic Cancer Research, which was awarded in conjunction with The Mark Foundation for Cancer Research.

Over the course of a near-50-year career at Fred Hutchinson Cancer Center, Dr. Greenberg has been recognized worldwide as a trailblazer in cell and gene therapy. In the 1990s, he led the first group to demonstrate that antigen-specific T cells can eradicate disseminated cancer cells, and his work has been at the cutting edge of T-cell research for cancer treatment ever since.  

It was a personal tragedy that helped lead Dr. Greenberg to focus specifically on pancreatic cancer in his latest study, which aims to develop new methods to target the deadly and aggressive disease.

“Along the way, my dad developed pancreatic cancer and died,” Greenberg said. “And I think like many of us, I have friends and family members who have died of pancreatic cancer. It became an increasing problem and reality in terms of diseases that affect people. 

“And the sad part is that, as an oncologist, there were virtually no therapies that had any significant impact on the survival of people with pancreatic cancer. I know my dad died two months after his diagnosis. That’s a little sooner than the average, but six months would be more typical. So, it was the kind of disease that really needed an intervention.”

Finding an immunologic target in pancreatic cancer.

To develop an effective treatment for pancreatic cancer, Dr. Greenberg first needed to figure out where to look. That led him to a study previously performed by Elizabeth Jaffee, MD (Johns Hopkins University), which identified the protein mesothelin as being overexpressed in pancreatic cancer, and a vaccine study that showed an immune response.

An old hand at designing T-cells for specific purposes, Dr. Greenberg’s thought was to use this promising data on mesothelin to guide his research.

“Our lab is one that has gotten into engineering T-cells to essentially see the tumor better than a natural response would,” Greenberg said. “And we said, ‘Maybe we can make a T-cell that recognizes mesothelin and use that to treat the disease.’ We started out studying that in the mouse model. And if that would work, we would advance that to clinical trials in people. We were incredibly surprised by the activity we saw in the mouse model.”

In animal studies, Dr. Greenberg saw that these CD8 T cells engineered with a tumor-specific T cell receptor (TCR) targeting the tumor antigen mesothelin could infiltrate pancreatic tumors resulting in an immune response to the cancer. This research then led to a clinical trial in which patients with metastatic pancreatic cancer were treated with their own CD8 T cells that were engineered with a human mesotheIin-specific TCR. 

To better sustain the T cell responses, Dr. Greenberg is now introducing the TCR plus CD8 genes, which improve the TCR binding to its mesothelin target, into both CD4 and CD8 T cells to create a coordinated T cell response in which both types of T-cells can recognize and respond to the same and adjacent tumor cells. By sustaining the immune response and preventing the therapeutic T-cells from becoming exhausted, Dr. Greenberg hopes this approach can be the next major step toward further understanding and manipulating the tumor micro-environment and then infiltrating and eliminating the tumor.

“What we’ve been trying to focus on is how we can build responses that will eliminate the tumor, not just shrink it,” Greenberg said. “And we’re getting closer and closer in that regard. One of the things we can do in these mouse models is we can study every gene in the cell and understand which ones help the cell work better, which ones are interfering, and we can modify those.”

Moving towards the future of pancreatic cancer treatment.

Although Dr. Greenberg has seen some interesting early results, progress hasn’t been a straight line. Dr. Greenberg has repeatedly seen these T-cells hit “obstacles” in the TME and lose function. 

Funding from ACGT will be used to help Dr. Greenberg further analyze these findings, determine what these obstacles are and how to overcome them, and in doing so generate new ideas for how to approach and understand pancreatic cancer.

“We are already looking at generating next generation strategies,” Greenberg said. “And that is a critical aim in our proposal. We won’t just be conducting a trial and evaluating it, but we will be learning from that trial and using our findings to build the next generation of therapies.”

None of this would be possible without the generosity of the patients involved in the trial, all of whom have volunteered for numerous biopsies to allow for the in-depth study of their tumors.

“We’ve been able to do that in the mouse model in the past, but we’ve never been able to do that in patients before,” Greenberg said. “This is all voluntary. They have every right to say, ‘No, I don’t want to be biopsied.’ There’s nothing pleasant about getting biopsied. But it’s the incredible generosity of patients that is really helping move this field forward.”

Important funding in an uncertain time.

In an environment in which it has proven difficult for scientific research to acquire and maintain funding, support from organizations like ACGT is more necessary than ever.

Dr. Greenberg has commended ACGT for its support, underlining that this grant has allowed his research to keep moving forward.

“The funding from ACGT is a godsend,” Greenberg said. “The reality is this has become an extraordinarily difficult time in funding for biomedical research.

“Getting awards like this from ACGT has really changed what we can do and what we are doing, and it’s allowed us to sustain momentum that otherwise would be lost. So, I can’t say enough how much, and in enough ways, the gratitude I have to ACGT for providing us with these resources.”