Data from a phase I study indicate that CD4 T cells modified to recognize MAGE-A3, a tumor-specific antigen, can be safely administered to patients with metastatic, treatment-refractory cancer. Significant tumor regression was noted in three of 14 patients with different tumor types, and two of these objective responses are ongoing.

To date, T cell–based immunotherapies for cancer have mostly involved introducing receptors (TCR) recognizing specific tumor antigens to CD8 T cells, then exploiting the natural cytotoxicity of these cells to target and eradicate tumors. More recently, researchers have started applying this strategy to the “helper” population of CD4 T cells, which are not directly cytotoxic, but trigger an immune response by releasing cytokines.

“We wanted to see if, in terms of destroying tumors, helper T cells could also sit in the driver's seat,” said Yong-Chen Lu, PhD, a research fellow at the NCI's surgery branch. At the American Association for Cancer Research Annual Meeting 2016 in New Orleans, LA, April 16–20, Lu presented preliminary data from the first phase I study investigating the therapeutic potential of genetically modified CD4 T cells against metastatic cancer.

The study enrolled 14 patients with various treatment-refractory cancers positive for MAGE-A3, a protein that's present during fetal development, lost in adult tissue, and frequently re-expressed in cancer. All study participants had the correct cell-surface protein, HLA-DPB1*0401, to present this tumor antigen for immune system surveillance and action. The researchers harvested CD4 T cells from these patients and redirected TCR specificity to recognize MAGE-A3. The cells were then amplified in the laboratory before being infused back into the patients.

The first eight patients received escalating doses of modified T cells—from 10 million to 30 billion—as the researchers waited to see if dose-limiting toxicities would develop. Because none occurred, “we were able to keep increasing the dose to the maximum of 100 billion cells,” Lu said, which the study's final six patients received. He and his team observed significant tumor regression in three patients with different metastatic tumors: cervical, esophageal, and urothelial. The objective responses for cervical and urothelial cancer are ongoing at 15 and 7 months after treatment initiation, respectively.

“I should emphasize that this immunotherapy is much safer than, say, CAR [chimeric antigen receptor] T cells targeting CD19,” Lu added. None of the patients experienced cytokine release syndrome, which is common with CAR T-cell therapy, and the main side effect—a high fever that lasted from 1 to 2 weeks—was easily controlled.

Louis Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, called this study “a promising conceptual strategy” that has yielded “exciting early responses.”

Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center in New York, NY, opined that the data so far are “intriguing, but not overwhelming.” However, he also expressed confidence that the burgeoning field of T-cell engineering will produce “many other tools to boost T-cell potency,” both individually and in concert.

Meanwhile, Lu and his group have started a phase II study of their MAGE-A3–targeting immunotherapy. He's hopeful that it will continue to demonstrate effectiveness in patients despite GlaxoSmithKline's decision in 2014 to shutter development of a vaccine against MAGE-A3, after a phase III trial in non–small cell lung cancer failed to meet two primary endpoints.

“The problem isn't MAGE-A3; it can be difficult to provoke a strong immune response with a vaccine,” Lu explained. “What we've done—infusing patients with greatly expanded numbers of T cells primed to recognize their target—is far more aggressive and effective.” —Alissa Poh

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