mRNA’s next trick? Reprogramming off-the-shelf cell therapies for cancer and autoimmune diseases

mRNA’s next trick? Reprogramming off-the-shelf cell therapies for cancer and autoimmune diseasesRyan CrossSenior Science CorrespondentLei Lei WuNews ReporterA handful of biotechs, including Moderna, are betting that simple infusions with mRNA could supercharge immune cells to fight cancer and other diseases in what would be a fresh take on CAR-T cell therapies.Instead of collecting a patient’s immune cells, engineering them in the lab, and reinfusing them — an intensive process that requires chemotherapy and comes with an array of side effects — these companies hope they can use mRNA to simplify the process while delivering the same benefits of current cell therapies.“This has the potential to be the most streamlined approach to engineering cells directly within the body rather than outside of the body,” Michael Klichinsky, co-founder and chief scientific officer of Carisma Therapeutics, told Endpoints News. “This is a therapy that can sit on the shelf, like a Covid vaccine, and can be administered readily while still engineering a patient’s own cells. At the Society for Immunotherapy of Cancer’s annual meeting last weekend in San Diego, Carisma presented the first data from its collaboration with Moderna using mRNA to engineer cancer-eating immune cells called macrophages. Capstan Therapeutics and Orna Therapeutics also presented data using different kinds of mRNA to engineer T cells to attack cancer.These therapies all supply genetic instructions for the cancer-targeting chimeric antigen receptor, or CAR, to immune cells. The approach would bypass the complex manufacturing process needed for current cell therapies, but the drawback is that multiple doses will likely be required since mRNA is short-lived.The approach, which hasn’t yet been tested in humans, could have wide-ranging applications in treating cancer and autoimmune diseases. Orna is planning its first clinical trial to begin in 2024.Moderna’s Trojan horseSo far, most CAR-T programs have focused on destroying blood cancers. One challenge in getting the therapies to attack solid tumors is that these cancers often raise defenses to keep T cells away. But macrophages and other myeloid cells of the immune system are often welcome in tumor microenvironments, so Carisma believes these cells will be key to infiltrating those tumors.Once inside, the engineered macrophages, dubbed CAR-M, can wreak havoc on the tumor and recruit other immune cells to pile on. “It’s a Trojan horse approach,” Klichinsky said.In January 2022, the company partnered with Moderna to deliver the CAR genes encoded in mRNA via an infusion of lipid nanoparticles. In a presentation at SITC, Carisma showed that an infusion of nanoparticles into mice primarily targeted myeloid cells — including macrophages, monocytes and dendritic cells.Carisma tested the approach in a mouse model of metastatic pancreatic cancer. A bioluminescent marker caused cancer cells to light up on body scans of the animals. After five weeks, the cancer spread across the entire bodies of mice given a control infusion — nanoparticles containing a random sequence of mRNA. For the rodents given an infusion of the CAR-M therapy, the cancer plummeted after a week and stayed low during the five-week study.Importantly, the therapy helped control metastasis in the livers and lungs of treated mice, Klichinsky said. “Either the macrophages that are being engineered are finding their way around the body,” he said, “or the lipid nanoparticles themselves are finding their way to macrophages around the body.”Carisma could earn up to about $250 million in milestone payments each for up to a dozen targets in the Moderna partnership. Neither company has said when the first human studies will take place.Expanding access beyond blood cancersCAR-T cell therapies for leukemia and lymphoma are one of the great triumphs of cancer research in the past decade, but the bespoke treatments can be very expensive and are a logistical nightmare, making the potentially curative cancer treatment inaccessible for some patients.Haig Aghajanian“One of the big issues with CAR-T cells is access,” Capstan’s head of research and co-founder Haig Aghajanian said. That also complicates expanding CAR-T treatments into diseases beyond blood cancers, such as autoimmune conditions.“These larger populations can’t be addressed by ex vivo autologous CAR-T cells,” he said.Many companies have tried to recreate those therapies with generic stem cells that could be made in large numbers and given to many patients. So far, those allogeneic therapies have largely floundered as several have struggled to keep cancer at bay for more than six months. Some small biotechs have shelved their off-the-shelf CAR-T programs, and Big Pharma companies have cut ties with partners developing the treatments.At SITC on Friday, Capstan shared early progress via a poster that suggested its treatment could stop tumor growth in mice. The company spawned from research published in 2022 in a Science paper that was co-authored by several prominent University of Pennsylvania scientists, including CAR-T pioneers Carl June and Bruce Levine, and Drew Weissman, who recently won the Nobel Prize for his work on mRNA.While that paper studied an mRNA CAR-T to restore heart function, Capstan is developing treatments for cancer and autoimmune diseases, with a focus on the latter. The company incorporates antibodies in its lipid nanoparticles to guide them to T cells in the spleen. “It’s more than just getting to the right place — you really need to get to the right cells,” Aghajanian said.Capstan declined to say when it hopes clinical trials will begin.Going full circleOrna Therapeutics is developing a twist on mRNA called circular RNA, which it believes will lead to longer expression of the CAR protein than traditional linear mRNA. In a poster at SITC, the company showed that an infusion of its therapy every two weeks in a mouse model kept the leukemia practically undetectable over an eight-week study.Robert Mabry“We think of our modality more like a recombinant protein in the sense that it’s transient,” Orna chief scientific officer Robert Mabry told Endpoints. He thinks the approach will make it easier to prevent cytokine release syndrome, a dangerous immune reaction that can result from a large single dose of traditional CAR-T therapy.The final rodent and monkey studies are now underway, Mabry said, and Orna’s first clinical trial, focused on blood cancers, is slated for 2024. “We believe we can dose every two or three weeks,” he added.There are in vivo CAR-T approaches that use viruses instead of LNPs as well. Companies such as Umoja Biopharma are using viral vectors to deliver CARs to immune cells. Umoja plans to submit an IND to test the approach in blood cancers in the first half of next year and gynecologic tumors in the second half of 2024.

AUTHORS Ryan CrossSenior Science [email protected] Lei WuNews [email protected]@leilei_wuu