Immunotherapy Shows Promise for Metastatic Solid Tumors

Early research from a small clinical trial suggests that a novel cellular immunotherapy method may be effective for treating metastatic solid tumors. Conducted by researchers from the National Institutes of Health (NIH), the study involved genetically modifying patients' lymphocytes to create receptors that identify and attack their specific cancer cells. This personalized immunotherapy showed promising results in individuals with metastatic colorectal cancer who had previously undergone multiple treatments. The therapy reduced tumor size in some patients and prevented regrowth for up to seven months. These findings were published in *Nature Medicine* on July 11, 2024.

Cellular immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy and tumor-infiltrating lymphocyte (TIL) therapy, has demonstrated effectiveness against certain blood cancers and metastatic melanoma. However, an effective cellular therapy for other types of solid tumors has been elusive. Dr. Steven A. Rosenberg, M.D., Ph.D., from the NCI’s Center for Cancer Research (CCR), and Dr. Maria Parkhurst, Ph.D., also from CCR's Surgery Branch, co-led this study.

Dr. Rosenberg emphasized the significance of these early results, stating, "The fact that we can take a growing metastatic solid cancer and get it to regress shows that the new cellular immunotherapy approach has promise.” However, he cautioned that these findings are preliminary and require further refinement and testing across more types of solid cancers.

The new approach addresses two significant challenges in cellular immunotherapy: producing large quantities of T cells that specifically recognize cancer cells and enhancing the ability of these modified T cells to proliferate once reintroduced into patients. For each patient, researchers collected lymphocytes from their tumors. Using advanced molecular techniques, they identified and isolated the receptors on these lymphocytes that recognized specific changes in the tumor. These receptors were then genetically sequenced, and a retrovirus was employed to insert the receptor genes into normal lymphocytes from the patient's blood.

The genetically modified lymphocytes were expanded into hundreds of millions in the lab before being infused back into the patients. These modified lymphocytes expressed the tumor-specific T-cell receptors and continued to multiply.

"By taking the natural T-cell receptors present in a very small number of cells and inserting them into normal lymphocytes, we can generate as many cancer-fighting cells as needed," explained Dr. Rosenberg.

In a larger phase 2 trial, seven patients with metastatic colon cancer received the experimental personalized cellular immunotherapy. Before the cell therapy, all patients received several doses of pembrolizumab (Keytruda), and following the cell therapy, they were administered IL-2. Three patients experienced significant tumor shrinkage in the liver, lungs, and lymph nodes, lasting from four to seven months, with a median progression-free time of 4.6 months.

Dr. Rosenberg noted that two of the three patients who responded positively to the treatment received T-cell receptors derived from cytotoxic T cells, which are primarily responsible for killing diseased cells. His research team is now exploring methods to incorporate these T-cell receptors into different subtypes of lymphocytes to enhance their effectiveness.

The ongoing trial includes patients with various types of solid cancers, not just colorectal cancer. Dr. Rosenberg highlighted the broader implications of this research, stating, "It's just the beginning of converting normal lymphocytes into cells capable of treating common solid cancers. This study shows it's possible, and now the focus is on improving it."