Preliminary data presented at the American Association of Cancer Research Annual Meeting has provided promising signs for a new cancer treatment that combines immunotherapy with an mRNA vaccine. The first reports from the Phase 1 human trial indicate the experimental treatment is safe and potentially effective against solid tumors.
The research focuses on an emerging type of cancer immunotherapy known as CAR-T cell therapy. This involves harvesting a patient’s immune T-cells, reprogramming them to target proteins on cancer cells, and then reintroducing those T-cells back into the patient.
CAR-T cell immunotherapy has proved to be a groundbreaking new treatment for blood cancers but researchers have struggled to get it to work safely and effectively in cancers featuring solid tumors. John Haanen, an oncologist from the Netherlands Cancer Institute working on the new mRNA research, said it has been challenging to find ways to get the modified T-cells to target solid tumor cells.
“One of the main limitations is that most of the proteins present on solid tumors that could be used as targets are also found at low levels on normal cells, making it difficult to specifically direct the CAR T cells against tumor cells and spare healthy ones,” said Haanen. “Other challenges include the limited persistence of CAR T cells observed in solid tumors and their difficulty reaching the tumors and penetrating the center of the mass.”
The new treatment works in two steps. First a patient is administered a traditional CAR-T cell therapy, with the immune cells engineered to target an antigen called claudin 6 (CLDN6). Prior studies have pointed to CLDN6 as a good antigen target for solid tumors as it can be found on the surface of many types of cancer cell but not other healthy cells.
Then, a few days after the CAR-T cell infusion, the patient is given a shot of a mRNA vaccine designed to prompt cells to produce claudin 6. The extra boost of these antigens cause the engineered T-cells to proliferate. More cancer-targeting T cells in the blood means a better chance of those cells hunting down and destroying tumors.
This first human trial of the experimental treatment involved 16 patients, most presenting with either testicular or ovarian cancers. Around 40 percent of those in the trial developed an adverse inflammatory side effect known as cytokine release syndrome. This excessive immune response is a common side effect of CAR-T cell therapy, but in this small trial Haanan said it was manageable and not severe in any patient.
Only 14 of the patients treated in the trial were evaluated for efficacy. Speaking to STATnews, Haanen said six of those 14 patients showed significant decreases in tumor sizes.
“I was quite skeptical at first because CAR T-therapy hadn’t worked before in solid tumors, so we were very excited to see how the metastases disappeared and the patients improved,” Haanen explained to STATnews. “These patients had a wonderful partial response, and one patient had a complete remission that is still ongoing, lasting now for almost six months.”
Of course it is crucial to stress these are very early Phase 1 results and plenty of work is still needed to understand the best way to deploy this novel treatment. Several different mRNA dose strategies are being explored. Patients in this initial study were given a variety of dose schedules, from an mRNA shot every two weeks for 100 days to one shot every six weeks.
“The infusion of CLDN6 CAR T, alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers,” Haanen said. “CLDN6 was never targeted before with cellular therapy, but in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumors.”
A number of other research teams around the world are also looking for ways to better target CAR-T therapy at solid tumors. Last year scientists from the University of California San Diego demonstrated a unique way to use targeted ultrasound as a way of helping the engineered T-cells home in on tumors. Researchers at MIT are also working on a vaccine to boost CAR-T cell efficacy, however, that method does not leverage mRNA technology.
These new mRNA trials are sponsored by BioNTech, the company recently responsible for the technology behind Pfizer’s well-known mRNA COVID-19 vaccine. This new CAR-T mRNA combo therapy is just one of several mRNA cancer vaccine pathways currently being investigated by BioNTech.
