mRNA vaccine boost can help CAR T therapy treat solid cancers

NEW ORLEANS – While CAR T therapy has cured some people with blood cancer, this form of immunotherapy has so far yielded poor results for solid tumors such as lung or kidney cancer. But a new early-stage clinical trial presented 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 they get a boost from a mRNA vaccine from BioNTech.

BioNTech became a household name thanks to the Covid-19 vaccine it developed with Pfizer. Before the pandemic, the company was a relatively small biotech company that focused on developing mRNA vaccines to treat cancer. Today, it is valued at $ 42 billion based on the stock price, and the new data shows a preliminary look at how its technology can develop new cancer treatments.

CAR T cells use chimeric antigen receptors to sense and destroy cancer cells. These engineered receptors bind to a protein on the surface of a cancer cell. Once bound, CAR can trigger its T cell to kill the cancer cell. In the work presented at the AACR meeting, the 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 Dutch Cancer Institute and lead author of the study. It allows the CAR T cell to see and attack these cancer cells.

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The new treatment from BioNTech requires a two-step process. First, a patient is infused with CAR T cells that can recognize and attack the cancer. A few days later, the patient receives 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. It will trigger the engineered T cells to begin proliferating and producing cytotoxic compounds that can kill cancer cells.

In a press release from the AACR, investigators said patients received the mRNA vaccine at regular intervals throughout the study following CAR T infusion.

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The idea behind the mRNA vaccine, Haanen said in his AACR presentation, was to expand the original population of CAR T cells and remain at a high level and in an increased state of activity. It should help the engineered cells get into a tumor and continue there and kill cancer cells. Based on the early results, Haanen said it 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 had not worked before in solid tumors, so we were very excited to see how the metastases disappeared and the patients got better,” Haanen said. “These patients had a wonderful partial response, and one patient had a complete remission that is still ongoing and now lasts for almost six months.”

It’s preliminary work, but promising, said Henry Fung, director of bone marrow transplantation and cellular therapies at the 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 [blood cancers,]Said Fung in a statement sent to STAT. “Previous studies of solid tumors were disappointing. Here, a CAR T cell product targeting claudin-6 is new and has shown promising results in selected solid tumors – although the impact on the results remains unclear.”

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

But there are unanswered questions in this research, Anderson added. First, the results are too early to properly evaluate the clinical efficacy of this approach, she said. A larger number of participants must be followed for a longer period of time in a more in-depth phase 2 trial. And although the researchers did not show severe toxicity in this initial trial, it is possible that more toxic side effects could appear in larger and longer studies, especially as the patients in this phase 1 trial showed mild signs of pancreatic toxicity. In rare cases, claudin-6 has been found in healthy adult tissues, including the pancreas.

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

Cell therapy may also need additional power-ups than just an mRNA vaccine boost to completely eliminate cancer for many patients, Anderson added. “I do not know if it is sufficient to boost. It is not to remove tumors from many mouse models of 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.

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