A novel personalized cellular immunotherapy approach may be effective at treating certain patients with metastatic solid tumors, according to early findings from a recent study published by Parkhurst et al in Nature Medicine.
Background
Chimeric antigen receptor (CAR) T-cell therapy has already shown efficacy in some hematologic malignancies, and tumor-infiltrating lymphocyte (TIL) therapy has proven to be effective against metastatic melanoma. Nonetheless, there are currently no cellular therapies that are effective against any other solid tumors.
Study Methods and Results
In the recent clinical trial, the researchers collected lymphocytes present in the tumors of patients with metastatic colorectal cancer who had undergone multiple prior treatments. The researchers used molecular characterization techniques to identify and isolate T-cell receptors that recognized specific changes in each patient’s tumor.
After genetically sequencing the receptors, they then used a retrovirus to insert the genes for the receptor into normal lymphocytes collected from each patient’s circulating blood in order to produce receptors that were capable of recognizing and attacking specific cancer cells. The genetically modified lymphocytes were multiplied into the hundreds of millions in a laboratory setting and subsequently infused back into the patients—where they expressed the tumor-specific T-cell receptors and continued to multiply.
“By taking the natural T-cell receptors that are present in a very small number of cells and putting them into normal lymphocytes for which we have enormous numbers—a million in every thimbleful of blood—we can generate as many cancer-fighting cells as we want,” indicated senior study author Steven A. Rosenberg, MD, PhD, of the Center for Cancer Research at the National Cancer Institute.
As part of a larger phase II trial, seven patients with metastatic colorectal cancer were treated with the experimental personalized cellular immunotherapy. All seven of them received several doses of the immunotherapy drug pembrolizumab prior to the cellular therapy and another immunotherapy drug called IL-2 afterward.
The researchers found that three of the patients had substantial shrinkage of their metastatic tumors in the liver, lung, and lymph nodes that lasted for 4 to 7 months. The median time to disease progression was 4.6 months.
Among the three patients who responded to the treatment, two of them received T-cell receptors derived from cytotoxic T cells—which are primarily responsible for killing diseased cells.
Conclusions
The researchers noted that the novel approach may overcome two challenges in cellular immunotherapy: how to produce large numbers of T cells that can recognize specific cancer cells and how to boost the ability of modified T cells to multiply once they’ve been returned to the patient.
“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,” highlighted Dr. Rosenberg “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 [tumors],” he emphasized.
The researchers are currently exploring methods to insert the T-cell receptors into subtypes of normal lymphocytes to improve their reactivity. Colorectal cancer is just one of many solid tumors the researchers are investigating. The trial is ongoing and includes patients with different types of solid tumors.
“It's just the very beginning of converting normal lymphocytes into cells capable of treating the common solid [tumors],” Dr. Rosenberg underscored. “What this study shows is that it's possible. Once you know it’s possible, you work to improve it,” he concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
