Expanding Targets for Cell Therapy

Chimeric antigen receptor T-cell therapy, or CAR T, involves collecting a patient’s T cells and reengineering them in a lab to recognize and bind to specific proteins, or antigens, on the surface of cancer cells. When infused back into the body, the CAR T cells continue to multiply and, thanks to guidance from their receptors, seek out and destroy cancer cells that have the target antigen on their surface.

At right, colored scanning electron micrograph of a breast cancer cell (pink) being attacked by a chimeric antigen receptor T cell (yellow). Courtesy of Eye of Science.

Since 2017, six CAR T-cell therapies have been approved by the U.S. Food and Drug Administration for blood cancers, including lymphoma, leukemia and multiple myeloma. However, when it comes to solid tumors, CAR T has been largely unsuccessful. It is difficult to identify antigens on the surface of solid tumors that aren’t also on healthy cells, and solid tumors of the same cancer type can be very different from patient to patient. Other obstacles include physical barriers that prevent the CAR T cells from reaching a tumor and immune-suppressing molecules produced by a tumor that can cause CAR T cells to malfunction.

At Moffitt, work is underway to address these challenges and identify new targets for solid tumors:

• Researchers have developed a chimeric antigen receptor that introduces follicle-stimulating hormone (FSH) into T cells. The new genetically modified CAR T cells seek out and destroy cancer cells expressing an FSH receptor protein that is found on a large number of ovarian cancer cells. A phase 1 trial, led by gynecologic oncologist Robert Wenham, MD, is now open to test the safety and efficacy of CAR T for ovarian cancer.

• Moffitt is also participating in a unique CAR T trial for multiple solid tumor types. The trial will start investigating the treatment in colon and pancreatic cancers and expand into lung and head and neck cancers in the future. The therapy uses a dual-signaling receptor to help overcome the major challenge of discriminating between healthy and cancer cells.

Dr. Kedar Kirtane, medical oncologist, Head and Neck Oncology Program

“One is a blocker, the other is an activator,” said medical oncologist Kedar Kirtane, MD, who is heading up the trial at Moffitt. “The blocker recognizes normal cells, so if you engage the blocker, you don’t kill it. If the activator is engaged, you kill the cell. It’s a unique way to avoid the pitfalls of killing normal tissue.”

• Researchers have identified a target protein called OR2H1, which is expressed in a variety of solid tumors, including lung and gastrointestinal cancers. Initial studies showed CAR T cells specific to the OR2H1 protein killed cancer cells that expressed the protein but had no effect on healthy cells. The goal is to open a phase 1 trial for patients with intrahepatic cholangiocarcinoma, which occurs in parts of the bile ducts within the liver, because OR2H1 is expressed in about 80% of those tumors.
  
  

  Dr. Daniel Abate-Daga, immunologist

• While traditional CAR T uses alpha beta T cells, research led by Daniel Abate-Daga, PhD, is investigating the use of gamma delta T cells in CAR T for solid tumors, particularly prostate cancer that has spread to the bone. Bone metastasis is a frequent complication in advanced prostate cancer and remains incurable. In preclinical studies, gamma delta T cells were engineered to target prostate stem cell antigen, or PSCA, which is overexpressed on prostate cancers but rarely on healthy cells. Combining CAR T with bisphosphonates helped localize the treatment to the bone, which prevented unwanted toxicity, and ultimately resulted in tumor regression and extended survival.

“Gamma delta T cells are a less abundant type of T cell found in blood that have very different biological properties in terms of how they recognize a target cell and how they kill it,” Abate-Daga said. “We have been looking to leverage those specific biological properties in order to maximize the efficacy of the treatment for certain diseases.”

• Moffitt is also one of only a handful of sites across the country participating in the first phase 1 CAR T trial for advanced kidney cancer. While the data is still being collected, early results look promising and next steps could include a phase 2 trial combining CAR T with another therapy or using it earlier in treatment.
  
  
• Other trials that are open or planned to open investigate the use of CAR T in gastrointestinal tumors such as gastric, pancreatic, biliary and colorectal cancers, as well as triple-negative breast cancer.

This article originally appeared in Moffitt’s Momentum magazine.