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May 23, 2023
An mRNA vaccine to treat pancreatic cancer
At a Glance
- A personalized mRNA vaccine against pancreatic cancer created a strong anti-tumor immune response in half the participants in a small study.
- The vaccine will soon be tested in a larger clinical trial. The approach may also have potential for treating other deadly cancer types.
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the deadliest cancer types. Despite modern therapies, only about 12% of people diagnosed with this cancer will be alive five years after treatment.
Immunotherapies—drugs that help the body’s immune system attack tumors—have revolutionized the treatment of many tumor types. But to date, they have proven ineffective in PDAC. Whether pancreatic cancer cells produce neoantigens—proteins that can be effectively targeted by the immune system—hasn’t been clear.
An NIH-funded research team led by Dr. Vinod Balachandran from Memorial Sloan Kettering Cancer Center (MSKCC) have been developing a personalized mRNA cancer-treatment vaccine approach. It is designed to help immune cells recognize specific neoantigens on patients’ pancreatic cancer cells. Results from a small clinical trial of their experimental treatment were published on May 10, 2023, in Nature.
After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech, the company that produced one of the COVID-19 mRNA vaccines. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens.
Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks.
All patients received a drug called atezolizumab before vaccination. This drug, called an immune checkpoint inhibitor, prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.
Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.
By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine. In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year. In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.
“It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer—which urgently needs better treatments,” Balachandran says. “It’s also motivating as we may be able to use such personalized vaccines to treat other deadly cancers.”
More work is needed to understand why half the people did not have a strong immune response to their personalized vaccines. The researchers are currently planning to launch a larger clinical trial of the vaccine.
—by Sharon Reynolds
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References: Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D'Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD, Jarnagin WR, Drebin J, O'Reilly EM, Balachandran VP. Nature. 2023 May 10:1-7. doi: 10.1038/s41586-023-06063-y. Online ahead of print. PMID: 37165196.
Funding: NIH’s National Cancer Institute (NCI); Stand Up to Cancer; Lustgarten Foundation; Damon Runyon Cancer Research Foundation; Ben and Rose Cole Charitable PRIA Foundation; Mark Foundation; Pershing Square Sohn Cancer Research Alliance; Pew Charitable Trusts; Cycle for Survival; Marie-Josée and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; imCORE Network; Genentech; BioNTech.