Investigators have developed a novel personalized T-cell therapy approach that may identify specific targets unique to a patient’s cancer cells more effectively than current treatments, according to findings published in Nature.
T-cells are essential to the body’s immune response in fighting off infection and cancer. T-cells express receptors that specifically recognize antigens including those presented on cancer cells, and signal the T-cells to respond and attack them. T-cells’ high level of precision also enables them to detect single mutations expressed from the genomes of cancer cells, which opens the door for therapies to exclusively target cancer cells.
In the current study, investigators built off this unique ability of T-cell receptors and developed a new personalized therapy approach that isolates receptors that recognize specific neoepitopes, or novel peptides from proteins that are generated from mutations in cancer cells.
First, the investigators sequined the entire genome of the cancer, creating synthetic DNA standards that can be inserted into DNA samples, and then isolated neoepitopes from the cancer cells. These neoepitopes were then platted in a way to capture T-cells circulating in the blood of cancer patients that recognize the neoepitope.
Next, the investigators isolated and sequenced the receptors of these T-cells and transferred the receptors through CRISPR/Cas9 editing. Next, they knocked out two native T-cell receptor genes — TRAC and TRBC — and introduced the new receptors directly into the knocked out sequence. These specific T-cells were from 16 patients diagnosed with refractory solids tumors, which were then infused into each patient.
“In this way, we can knock out the normal receptor and knock in the receptor for the neoantigen,” said Sosman, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “T-cells that are identified are not only specific for the neoantigen, but they’re specific and they pre-exist circulating in the blood.”
In a phase I clinical trial, all 16 patients received up to three different genetically engineered neoantigen-specific T-cell receptor products in the normal T-cells, each expressing a patient-specific and neoantigen-specific T-cell receptor.
Follow-up analysis of tumor biopsies after treatment demonstrated higher levels of neoantigen-specific T-cell receptor-transgenic T-cells compared to levels of native T-cell receptors before treatment.
The study demonstrates the feasibility and safety of the gene-edited, neoantigen-specific T-cell products, and the ability of the new transgenic T-cells to traffic into the patients’ tumors, according to the authors.
Moving forward, Sosman said the approach needs improvement, specifically the speed and effectiveness of the genetic sequencing and selecting the correct T-cell receptors, with the hope that the treatment can be more widely used across cancer types.
“While the treatment is likely to be more successful in cancers that express many neoantigens such as melanoma, the long-term goal is for the treatment to be effective in all types of cancers,” Sosman said.
Antoni Ribas, MD, PhD, professor of Medicine, Surgery, and Molecular and Medical Pharmacology at the University of California Los Angeles, and Stefanie Mandl, PhD, chief scientific officer at PACT Pharma, were co-senior authors of the study.
The work was funded by PACT Pharma.