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An mRNA vax boost may help CAR T-therapy treat solid cancers

While CAR T-therapy has cured some people with blood cancers, this form of immunotherapy has so far produced lackluster results for solid tumors like lung or kidney cancer. But a new early-phase clinical trial presented on Sunday at the American Association of Cancer Research (AACR) conference suggests that CAR T-cells may be able to shrink some solid tumors — as long as it gets a boost from an mRNA vaccine from BioNTech.

BioNTech became a household name thanks to the Covid-19 vaccine it developed with Pfizer. Before the pandemic emerged, the company was a relatively small biotech firm focused on developing mRNA vaccines for treating cancer. Today it’s valued at $42 billion, based on its stock price, and the new data show a preliminary look at how its technology might develop new cancer treatments.

CAR T-cells use chimeric antigen receptors to sense and destroy cancer cells. These engineered receptors attach to a protein on a cancer cell’s surface. Once bound, the CAR can trigger its T-cell to kill the cancer cell. In the work presented at the AACR meeting, researchers used a target called claudin-6, which is commonly found on testicular, ovarian, and endometrial cancer cells, explained John Haanen, a cancer immunotherapy researcher at the Netherlands Cancer Institute and lead author on the study. That enables the CAR T-cell to see and attack these cancer cells.

The new treatment from BioNTech requires a two-stage process. First, a patient is infused with CAR T-cells that can recognize and attack the cancer. A few days later the patient is given the mRNA vaccine, which carries the genetic code for claudin-6. The idea is that immune cells known as antigen-presenting cells will take up the vaccine, produce claudin-6, and then present the protein to the CAR T-cells circulating in the body. That will trigger the engineered T-cells to begin proliferating and producing cytotoxic compounds that can kill cancer cells.

In a press release from AACR, the investigators said that patients received the mRNA vaccine periodically throughout the study after CAR T infusion.

The idea behind the mRNA vaccine, Haanen said in his AACR presentation, was to expand the initial population of CAR T-cells and remain at a high level and in a heightened state of activity. That should help the engineered cells get into a tumor and persist there, killing cancer cells. Based on the early results, Haanen said that appears to have happened. Among 16 patients treated in the study, 14 were evaluated for efficacy and, of those, six saw their tumors shrink or disappear, Haanen said.

“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 said. “These patients had a wonderful partial response, and one patient had a complete remission that is still ongoing, lasting now for almost six months.”

It’s preliminary work but promising, said Henry Fung, the chair of bone marrow transplant and cellular therapies at Fox Chase Cancer Center in Philadelphia, who was not involved in the trial. “CAR T-cell therapy has become the standard of care for selected patients with [blood cancers,]” Fung said in a statement emailed to STAT. “Prior studies for solid tumors were disappointing. Here, a CAR T-cell product targeting claudin-6 is novel and demonstrated promising results in selected solid tumors — though the impact on outcomes remains unclear.”

Using an mRNA vaccine to augment a patient’s CAR T-cell population is an idea that might well carry into future work in cell therapy, Kristin Anderson, a cell therapy researcher at the Fred Hutchinson Cancer Research Institute who did not work on the trial, told STAT. “Part of the problem with cell therapy in solid tumors is you do all this work to engineer T cells and then they might not get in and infiltrate tumors. But then, if they do, they won’t last long,” she said. “So it’s exciting to see that they have an opportunity to boost their engineered cells in vivo.”

But there are unanswered questions in this research, Anderson added. For one, the results are too early to be able to properly evaluate the clinical efficacy of this approach, she said. A larger number of participants will need to be followed for longer in a more in-depth Phase 2 trial. And while the researchers didn’t see severe toxicity in this initial trial, it’s possible that more toxic side effects could emerge in larger and longer studies, particularly since the patients in this Phase 1 trial showed mild signs of pancreatic toxicity. In rare cases, claudin-6 has been found on healthy adult tissues, including the pancreas.

When the question of off-tumor toxicity was posed to Haanen at AACR, he agreed that the possibility exists. “We don’t know what would happen if we treat patients with a higher dose,” he said. “That is something we still have to learn.”

Cell therapy may also need additional power-ups other than just an mRNA vaccine boost to fully clear cancer for many patients, Anderson added. “I don’t know if just boosting will be sufficient. It’s not to clear tumors from many mouse models in late disease,” she said, raising the possibility that solid tumors may need to be hit harder by combining cell therapy with other immunotherapy drugs to generate deeper responses for many patients. Stat

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