Storming the fortress in ovarian cancer

No fortress is impenetrable. In ovarian cancer, the walls have held for decades, but ACGT Research Fellow Joseph A. Fraietta, PhD, hopes he may have a way to breach them.

Ovarian cancer is the deadliest of the gynecologic cancers, and its lethality is often due to its stealthy nature. Tumors grow quietly, often without symptoms, so most women are diagnosed only after the disease has spread throughout the abdominal cavity. Surgery and chemotherapy can help initially, but 70 to 80 percent of patients ultimately experience relapse. And when the cancer returns, it typically returns aggressively and resists prior treatments 

In immunological terms, ovarian tumors are “cold.” The immune system rarely detects them because they carry few detectable mutations and surround themselves with a dense, fibrous stroma that acts as both a castle wall and an invisibility cloak.

Should any immune cells breach that wall, they confront a profoundly hostile environment, full of cells and signals that seek to exhaust the immune cells and shut them down. For years now, that barrier has repelled even the most powerful weapons in the immunotherapy arsenal.

Dr. Fraietta, an Associate Professor of Microbiology at the University of Pennsylvania (UPenn), has spent his career studying why those immune-based treatments fail against solid tumors like ovarian cancer and how to make them successful. Supported by an Alliance for Cancer Gene Therapy (ACGT) Investigator Award in Cell and Gene Therapy for Gynecological Cancer Research, Dr. Fraietta is now focused on launching a coordinated, multi-wave assault.

Breaching the Walls: An Oncolytic Virus Siege

The siege begins with a saboteur sent behind enemy lines.

That saboteur is an oncolytic virus, engineered to selectively replicate inside cancer cells while sparing healthy tissue. It kills tumor cells, but its real power lies in what it does to the fortress’s integrity. The engineered VCN-01 virus that Fraietta is using is equipped with an enzyme, hyaluronidase, that digests the dense stromal matrix, weakening the shield so that immune cells can infiltrate. Meanwhile, tumor cells killed by the virus spill their tumor antigens—the proteins and molecular fragments that the immune system can use to identify the cancer cells—and release a flood of danger signals that act like a built-in alarm, summoning important immune sentinels and rallying them to action. 

This oncolytic virus priming step is designed to do something else, too, that would matter enormously to patients. This consideration comes into play during the second phase of Fraietta’s therapeutic strategy: the delivery of chimeric antigen receptor (CAR) T cells.

The Second Wave: CAR T Cells

CAR T cells are created by taking a patient’s own T cells and re-engineering them to target cancer. Conventional CAR T-cell therapy requires lymphodepletion, a harsh regimen that clears out a patient’s existing T cells before the engineered ones are re-infused. If the oncolytic virus can create the same inflammatory conditions that result from lymphodepletion, Fraietta hopes to spare patients by skipping lymphodepletion entirely. 

This is an especially meaningful consideration for women whose fertility and long-term health are at stake. The goal is a gentler therapy that could one day be delivered on an outpatient basis, leaving the patient’s immune system and reproductive health intact.

Fraietta’s CAR T cells are programmed to recognize the folate receptor-alpha (FRα) protein, which is overexpressed in roughly 80 to 90 percent of high-grade serous ovarian cancers but whose expression is tightly restricted in healthy tissue. That combination of high tumor expression, low normal expression, and the target already being clinically validated by an approved therapy makes FRα an ideal target.

In addition to their target, the delivery route of the CAR T cells matters, too. Rather than infusing the CAR T cells into the bloodstream and asking them to find their way to the tumor, Fraietta’s team delivers them directly into the peritoneal cavity, which, as he said, “puts the CAR T cells directly where the disease lives and thrives.”

Beyond getting the cells into tumors efficiently, they need to remain there and stay lethal long enough to finish the job.

Part of the solution, Fraietta reckons, lies in what kind of T cell arrives. In particular, tissue-resident memory T cells are a specialized subset of long-lived cells that can take up permanent residence inside tissues rather than circulating through the body, standing at the ready to strike the moment they see their cancer target. In ovarian cancer, the density of these T cells within a tumor is one of the strongest predictors of long-term survival.

Three mechanisms converge to encourage that specific tissue resident memory state. Intraperitoneal delivery is the first, placing the cells directly in the tissue they are meant to occupy. The oncolytic virus, having already primed that tissue, leaves behind cytokine signals that push the arriving T cells toward residency. Fraietta’s team is also engineering the cells with features that favor a tissue-resident program rather than the exhausted state that has hindered previous efforts. Together, these are meant to establish a standing garrison inside the tumor rather than a raiding party passing through.

But even a garrison can only fight the enemy it recognizes. And an ovarian tumor is not one enemy, it is many.

The Third Prong: Bispecific Antibodies and Immune Recruitment

The third force Fraietta is bringing to bear on ovarian cancer is one that his team has taught the CAR T cells to manufacture themselves within the tumor. Here, the CAR T cells secrete a bispecific antibody, a small molecule with two grabbing arms: one that latches onto any passing T cell, and one that latches onto mesothelin, another protein blanketing many ovarian tumor cells. Once both arms are engaged, the T cell can lock on to the cancer cell and destroy it.

These bispecific antibodies not only engage the engineered CAR T cells, but they also conscript the patient’s existing T-cell repertoire into the fight. This matters because tumors are not uniform, a challenge known as antigen heterogeneity. Some tumor cells express FRα, some express mesothelin, some express neither. And under pressure to survive, cells can shift their expression of various proteins to escape the immune system’s grasp.

By striking two antigens at once and recruiting the broader immune army, Fraietta’s design seeks to put more of the tumor in the immune system’s crosshairs. And as tumor cells die, they release still more antigens, allowing the recruited T cells to mount fresh attacks against new targets. The assault becomes self-amplifying, beginning with two targets and building toward an immune response that encompasses the tumor in all its diversity.

A Blueprint Beyond Ovarian Cancer

Few research institutions could attempt an approach this complex. Fortunately, UPenn is one of the birthplaces of CAR T cell therapy, and that legacy is also reflected in the infrastructure at Fraietta’s disposal. The Center for Cellular Immunotherapies, led by fellow ACGT Research Fellow and Scientific Advisory Council member Carl H. June, MD, spans basic immunology, GMP manufacturing, and clinical translation under one roof—a pipeline few institutions in the world can match. Nearly everything else this three-pronged program requires is on site as well, from in-house oncolytic virus engineering to an ovarian cancer program whose surgeons and oncologists run trials in this patient population.

What Fraietta’s own lab adds is the ability to tell what is actually working.

“We don’t just engineer the cells and infuse them. We follow them to track how long the CAR T cells persist and how they change over time, so we can feed that biology back into the next iteration of the design,” he said.

“This feedback loop is essential when you’re combining three modalities,” Fraietta added, “because you need to know which therapeutic arm is doing what.”

This kind of ambition is also difficult to fund.

“ACGT’s willingness to back an integrated design before any one aim has been individually de-risked is crucial to our work. This award enables the foundational preclinical work, manufacturing development, and the design of a first-in-human trial. Without this support, we’d be running these three arms sequentially over many years. But with it, we can run these arms in parallel and accelerate the pace of discovery and clinical translation,” Fraietta emphasized.

This strategy also has the potential to affect more than a single disease. The obstacles Fraietta is confronting in ovarian cancer—antigen escape, a hostile tumor microenvironment, poor CAR T-cell persistence, the toxicity of lymphodepletion—are the same ones that have hindered cell therapy in conquering other solid tumors. Solve them here, and the same playbook could be deployed in pancreatic cancer, mesothelioma, and beyond.

For now, the fortresses protecting these deadly cancers still stand. But now, at least, there is a blueprint for how we might take them down.