Pittsburgh Researchers Launch Novel Cell Therapy Trial Using Immune Cells From Fluid That Would Otherwise Be Discarded

Key Takeaways

• AHN Cancer Center is actively enrolling patients in a first-in-human Phase 1 clinical trial testing a personalized immunotherapy for malignant pleural effusion, a serious complication of advanced cancer that causes fluid buildup around the lungs.
• The RIOT-4 trial repurposes pleural fluid routinely drained from a patient's chest as a source of tumor-fighting immune cells that would otherwise be discarded.
• Unlike conventional tumor-infiltrating lymphocyte (TIL) therapies that can require surgery to obtain tumor tissue and several weeks of laboratory processing, RIOT-4 can generate a personalized cell therapy product in eight to 12 days.
• The study's primary goal is to evaluate safety and feasibility while helping researchers better understand how the immune system responds to cancer in the pleural cavity and whether the treatment shows early signs of clinical benefit.

PITTSBURGH - Allegheny Health Network (AHN) Cancer Center is actively enrolling patients in a first-in-human clinical trial testing an innovative cell therapy for advanced cancers that have spread to the lining around the lungs, a condition known as malignant pleural effusion.

Pleural effusion describes fluid buildup in the pleural cavity, the space around the lungs. Malignant pleural effusion is the abnormal buildup of fluid and cancer cells in that space and is most often associated with advanced lung and breast cancers, though it can occur with other cancers.

The fluid can cause shortness of breath, chest discomfort and a significant decline in quality of life. Current treatments mainly focus on easing symptoms and controlling fluid buildup, rather than treating cancer directly in the pleural space.

The Phase 1 clinical trial, known as RIOT-4, or Regional Immuno-Oncology Trial 4, repurposes fluid drained from the chest cavity of cancer patients as a source of tumor-fighting immune cells, offering a faster and less invasive path to cellular immunotherapy.

The lead clinical investigator for the trial is Patrick L. Wagner, MD, MPH, vice chair of surgery and chief of surgical oncology at AHN Cancer Center. Researchers in the cellular therapy lab at AHN, directed by Albert D. Donnenberg, PhD, vice chair of clinical research, rapidly grow and activate the cells before returning them directly to the patient's pleural cavity, where the cancer is located.

"This trial is designed to harness the body's own immune system and deliver it directly to the site where cancer is causing harm," said Wagner. "By using immune cells already present in the fluid around the lungs, we can create a personalized treatment in days instead of the weeks typically required for many cellular therapies."

The investigative team also includes David L. Bartlett, MD, professor and chair of AHN Cancer Center, and president of the AHN Research Institute; Vera Donnenberg, PhD, professor of cardiothoracic surgery at the University of Pittsburgh School of Medicine; and Neda Dadgar, PhD, assistant professor in translational science. Together, the team developed the treatment approach and clinical trial protocol using tumor-infiltrating lymphocytes (TIL) therapies specialized immune cells that have naturally recognized cancer within the body.

Unlike traditional TIL therapies, which typically require surgery to remove tumor tissue followed by several weeks of laboratory processing, RIOT-4 uses immune cells collected from pleural fluid that would otherwise be discarded after drainage. Researchers expand these cells over approximately eight to 12 days before re-infusing them directly into the pleural cavity. The resulting products are known as FastTILs.

By sourcing cells from fluid that is already being removed as part of routine patient care, the RIOT-4 approach eliminates the need for an additional surgical procedure and substantially shortens the manufacturing timeline compared with conventional TIL therapy, potentially expanding access to cellular immunotherapy for patients with limited time or treatment options.

The trial also includes a low dose of interleukin-2, or IL-2, an immune-stimulating medication intended to help the cells survive and multiply after treatment.

The study's primary goal is to assess safety and feasibility while also evaluating immune response and any early signs of clinical benefit. Researchers believe delivering the therapy directly into the pleural space may offer advantages over standard intravenous cell therapies. Because the treatment is given where cancer is present, the immune cells can interact with tumor cells immediately and may reduce the loss of therapeutic cells that can occur when treatments are delivered through the bloodstream.

"Patients who are eligible for this study have often exhausted available treatment options and face a very challenging diagnosis," said Dr. Donnenberg. "We hope this strategy opens the door to a new form of personalized immunotherapy for patients with cancers affecting the pleural cavity, while helping us better understand how the immune system responds to cancer in this environment."

The trial is expected to enroll patients with biopsy-confirmed malignant pleural effusions caused by metastatic cancer who have received standard treatments and have no remaining therapies expected to provide clinical benefit. The study will begin with a small group of participants to evaluate safety before expanding enrollment.

Patients who qualify will undergo drainage of pleural fluid, followed by preparation of the personalized cell therapy product in AHN's cellular therapy facility.

The trial is supported by funding from the Department of Defense Congressionally Directed Medical Research Programs, or CDMRP, which has continuously funded the team's broader research program in adoptive cellular therapy for metastatic breast cancer and other malignancies, as well as by local foundations including A Glimmer of Hope Foundation and The Pittsburgh Foundation.

The study is approved by the AHN Institutional Review Board and registered on ClinicalTrials.gov under NCT07192900.