A novel approach for pancreatic cancer.

Pancreatic cancer is the third leading cause of cancer death in the United States and is trending to move into second place within the next several years. Despite that, the options available to treat pancreatic cancer have not significantly changed in recent years.

Ben Stanger, MD, is working to change that. Partnering with cell and gene therapy leader Carl H. June, MD, Dr. Stanger is embarking on a bold new study that has the potential to reshape the treatment of pancreatic cancer as we know it.

Dr. Ben Stanger’s background in cell and gene therapy research.

Dr. Stanger is the Hanna Wise Professor in Cancer Research and Director of the Penn Pancreatic Cancer Research Center at the University of Pennsylvania. He became an Alliance for Cancer Gene Therapy (ACGT) Research Fellow in 2025 through the Edward Netter Memorial Investigator Award in Cell and Gene Therapy Research for Pancreatic Cancer. 

Dr. Stanger’s lab has focused specifically on pancreatic cancer biology, tumor immunology and therapy resistance, looking to break down barriers to treatment for what is often one of the most aggressive and difficult-to-treat cancers. He’s made searching for breakthroughs in pancreatic cancer the focus of his career and sees cell and gene therapy as the way to make those breakthroughs happen.

That focus has led him to a collaboration with his University of Pennsylvania colleague and ACGT Scientific Advisory Council member, Dr. Carl June – one of the preeminent trailblazers in the development of cell and gene therapy for cancer, and one of ACGT’s earliest Research Fellows.

Drs. Stanger and June are serving as co-principal investigators. Dr. June’s earliest research into cell and gene therapy directly led to the 2017 FDA approval of the first-ever CAR T-cell therapies for cancer, work he began over two decades ago. He provides a wealth of experience inaddressing the central issue of using CAR T cells effectively against solid tumors.

“Dr. June has, of course, been a leader in CAR T therapy for hematologic malignancies. And he’s had a longstanding interest in pancreatic cancer for a variety of professional and personal reasons. We’ve been talking over the years and the main challenge that he has faced has been how to get the CAR T cells into the solid tumor,” Dr. Stanger said. “How to get them to navigate through the barriers that solid tumors put up, how to get them to stay there, how to get them to be active enough to kill cancer cells. And so, when a couple of developments have happened elsewhere in the field that create that opportunity, we discussed a collaboration. It seemed very natural to be able to work together by combining two different types of therapies that open the door to CAR T cells.”

Changing the tumor microenvironment in pancreatic cancer.

Drs. Stanger and June focused specifically on pancreatic cancer because of one major recent development in the treatment of solid tumors, specifically pancreatic, colon and lung cancers: the rise of the KRAS inhibitor.

“Those cancers have a high rate of mutations in a gene called KRAS,” Dr. Stanger said. “Those mutations are present in about 95% of pancreatic cancer patients, so it’s a very high-frequency mutation. It’s been an obvious target for therapy and drug development for 40 years since the oncogene was first identified. And all the efforts, millions, if not billions of dollars spent to try to develop small molecule inhibitors have failed until about five years ago, when innovations allowed small molecule inhibitors to actually show benefit in preclinical models.”

Dr. Stanger sees this as a game-changer. The use of KRAS inhibitors displays major potential to reshape the tumor microenvironment in pancreatic cancer – not only to attack cancer cells themselves, but to more easily allow T cells to enter solid tumors. 

“If you inhibit the KRAS signal, the cancer cells melt away. But what we’ve found is that in addition to its effect on the cancer cells, directly inhibiting KRAS causes a change in that impenetrable barrier that the tumor puts up,” Dr. Stanger said. “And that’s because the KRAS signal not only causes the cancer cell to divide, but it also establishes the microenvironment that is very inhospitable to T cells. So, we get a two-for-one benefit. We attack the cancer cell when we treat it with the KRAS inhibitor, but we also open up the opportunity for T cells to get into the tumor and do what we want them to do.” 

A two-pronged approach towards pancreatic cancer treatment.

To take full advantage of this opportunity, the other arm of Drs. Stanger and June’s study uses CAR T cells aimed at a tumor barrier’s fibroblast activation protein (FAP), which could allow T cells to force their way into a tumor and allow for greater anti-cancer activity.

“What we’re hoping to do is, by combining a KRAS inhibitor with immunotherapy, or in this particular case, CAR T-cell therapy, is to get the anti-tumor benefit but make it durable and ideally cure people before the tumor can develop resistance mechanisms,” Dr. Stanger said. 

The research project builds upon existing work on KRAS inhibitors and FAP-CAR T cells in animal models to understand how these interventions alter the tumor microenvironment. The research team will also investigate whether combining the two therapies can have additive effects, potentially leading to cures.  

The next stage focuses on patients, building on an ongoing clinical trial in pancreatic cancer with CAR T cells against mesothelin. The goal is to determine whether pretreatment with a KRAS inhibitor before CAR T infusion results in a greater number of CAR T cells infiltrating the tumor.  

Finally, the project will focus on a clinical trial of FAP-CAR T cells to assess whether these CAR T cells penetrate patient tumors and reshape the tumor microenvironment in a favorable manner. A crucial facet of this study is the observation in animal models that this treatment promotes greater activity of the body’s naturally occurring T cells, driving recovery even further.

“We have some preliminary data that this is going to be true of the CAR T cells as well,” Dr. Stanger said. “When we treat with either of these agents, we do see better penetration and better activity of CAR T cells of the anti-tumor CAR T cells in animal models. And our proposal wants to take that further, show that that is indeed the case, and then move on eventually to clinical trials where we can test that hypothesis in people.”

Crucial funding for bold research.

If successful, Dr. Stanger envisions the formulation of something lasting and curative that could change the face of pancreatic cancer treatment. Dr. Stanger calls the development of KRAS inhibitors a “giant step forward” in cancer therapy, but it needs something else to provide a durable anti-tumor benefit before the cancer can develop anti-drug resistance. It is here, Drs. Stanger and June hope, that CAR T cell therapy comes in.

And it’s here that ACGT comes in. Dr. Stanger acknowledges that his research, while extremely promising and with great potential, is bold and difficult. The support of ACGT is vital for ensuring its continued progress.

“This is a high-risk, high-reward type of research that would unlikely be funded through traditional funding mechanisms like the NIH,” Dr. Stanger said. “The preclinical studies are hard to do. They require expertise and collaboration between different scientists. So that’s something that ACGT has in its DNA, if you will. And that has been a huge help.”