Chimeric antigen receptor (CAR) T-cell therapy is a form of cellular immunotherapy that has demonstrated effectiveness against certain blood cancers while tumor-infiltrating lymphocyte (TIL) therapy is another form that has shown promise in treating metastatic melanoma. However, finding a cellular therapy that works against other solid cancers has been more challenging. Now, early findings from a small clinical trial suggest that a new cellular immunotherapy approach might be effective for treating metastatic solid tumors.

In the trial, researchers from the National Institutes of Health (NIH, Bethesda, MD, USA) genetically engineered normal white blood cells, or lymphocytes, from patients to produce receptors that target and destroy their specific cancer cells. Their preliminary findings, published on July 11, 2024, in Nature Medicine, are from patients with metastatic colorectal cancer who had undergone multiple prior treatments. This personalized immunotherapy led to tumor shrinkage in several patients and prevented tumor regrowth for up to seven months. The innovation addresses two major hurdles in cellular immunotherapy: producing large quantities of T cells that specifically target cancer cells and boosting the proliferation of these modified T cells after reintroduction into the patient.

For each participant in the study, the team harvested lymphocytes from their tumors. They employed advanced molecular characterization techniques to identify and isolate receptors on those lymphocytes, called T-cell receptors, which recognized specific changes in each patient’s tumor. After genetically sequencing these receptors, the researchers used a retrovirus to insert the receptor genes into normal lymphocytes taken from each patient's blood. These genetically modified lymphocytes were then multiplied into hundreds of millions in the lab and infused back to the patients, where they expressed the tumor-specific T-cell receptors and multiplied further.

In a subsequent phase 2 trial, seven patients with metastatic colon cancer received this experimental personalized cellular immunotherapy. Before and after the cell therapy, patients were treated with the immunotherapy drugs pembrolizumab and IL-2, respectively. Three of these patients experienced significant reductions in metastatic tumors in the liver, lung, and lymph nodes, with the effects lasting between four to seven months. The median time before disease progression was recorded at 4.6 months. Notably, two of the three responsive patients had T-cell receptors derived from cytotoxic T cells, which are crucial for eliminating diseased cells. The research team is now investigating how to integrate T cell receptors into different subtypes of normal lymphocytes to boost their effectiveness. The ongoing trial is expanding to include patients with various types of solid tumors, exploring broader applications of this therapeutic approach.

“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,” said Steven A. Rosenberg, M.D., Ph.D., of NCI’s Center for Cancer Research (CCR), who co-led the study. “However, it’s important to understand that these findings are preliminary and that the approach needs to be further refined and tested in more types of solid cancers.” 

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