1st ARPA-H Grant: mRNA-Based Anti-Cancer and Anti-Microbial Vaccine Development

Cancer vaccines utilizing mRNA vaccine technology have such potential that ARPA-H, a newly established White House-originated program, has made it the focus of its first ever grant, announced today. The total grant is $25 million over three years, to be split among teams at Emory University, Yale School of Medicine, and the University of Georgia. Research teams at the three institutions are working together to strive to harness the natural immune system for development of personalized therapeutic vaccines against cancer and emerging infections, along the lines of how the mRNA vaccine targets SARS-CoV-2.

As an outgrowth of President Biden’s Cancer Moonshot program against cancer, the administration recently launched a $2 billion research funding agency known as the Advanced Research Projects Agency for Health [ARPA-H]. The mission of this new federal agency is to catalyze field-shaping health science investigation and invention by accelerating exceptionally promising research programs.

A team led by principal investigator Philip Santangelo, PhD, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, and prominently including as a co-principal investigator Richard Edelson, MD, Anthony N. Brady Professor of Dermatology at Yale School of Medicine, is the first to receive one of the agency’s three-year $25 million grants, with the Yale group receiving a $6.5 million portion. Combining Santangelo’s expertise in mRNA and Edelson’s in dendritic cells—the most prominent initiators of selective immune reactions—the multi-institutional team will be studying how to advance technology from the burgeoning mRNA vaccine field to program dendritic cells to produce therapeutic immune reactions, with personalized cancer vaccines as the ultimate goal.

The teams are working together to use mRNA—the essential element of vaccines that were developed to prevent COVID-19 infection—to program the dendritic cells to process antigenic proteins, thereby triggering selective immunological responses. “The mRNA teaches these dendritic cells how to ignite the desired systemic immune reaction,” says Edelson, former chair of Yale Dermatology and a past director of Yale Cancer Center. “Without understating the challenges ahead, the possibilities are immense.”

“The ARPA-H grant is a vote of confidence that our collective mission may be achievable,” he says, and its support will help the group accelerate progress. Together, this collaborative effort is aimed at development of new therapeutic vaccines for a range of immunogenic cancers as well as emerging infectious diseases. “The vast majority of therapies, including immunologic therapies, are medically manmade,” says Edelson. “The cancer vaccine we’re striving to create is not manmade. We’re trying to harness and direct a powerful, nature-invented force, the natural immune system, and we think that we have a genuine fighting chance of accomplishing that goal.”

“Our work will hopefully forge closer collaboration between physicians and the natural immune system itself,” says Edelson. While Ralph Steinman of Rockefeller University received the 2011 Nobel Prize in Physiology for his discovery of dendritic cells, efforts to translate that breakthrough into treatments for cancer and serious infections have been stymied by two key scientific roadblocks: need to understand how the body naturally produces dendritic cells that function well in patients, and learning how to efficiently program these pivotal cells to produce desirable therapeutic responses. Now that those two roadblocks have been scientifically overcome, exciting opportunities to develop potent dendritic cell vaccines may be on the near-term horizon. "

The human immune system stops many cancers in their tracks in their earliest stages. “Many cancers are naturally eliminated before we can clinically see them,” says Edelson. “But by contrast, individuals receiving long-term immunosuppression, to prevent rejection of transplanted organs, commonly develop very large numbers of dangerous skin cancers that normally would have been naturally destroyed in their infancy by an intact immune system.” This well-recognized phenomenon is a clear demonstration of the anti-cancer potency of natural potent immunity.

Cancers that become clinically evident have already evaded the immune system and, with that foothold, they essentially have become stealth bombers, effectively avoiding detection and destruction by natural immunologic radar. “It is as though the immune system has been tricked into acting as if the cancer belongs there, just as one’s normal organs are not immunologically rejected,” says Edelson. In his lab, his team has been striving to figure out how to turn the immune system back on so that it will reject the cancer just as it would a transplanted organ. “It’s potentially the ultimate cancer therapy,” he says.

Dendritic cells are key players in the immune system’s capacity to destroy cancer, serving as the ignition of the immune system. These cells commonly emerge from monocytes, a type of readily accessible white blood cell, a precursor of dendritic cells which process and present antigens such as those distinctive to cancer cells or viruses. Under optimal circumstances, T cell responses can then target and destroy the invaders.

For decades, dendritic cells have been considered the tantalizing holy grail for initiating preventative and therapeutic immune reactions. Investigators envisioned that by loading an individual’s dendritic cells with antigens in the lab, they could develop into cellular personalized vaccines for those patients. But, until scientists could understand how the body produces dendritic cells—where and when they are needed—artificial methods were required to produce them outside the body, in order to then arm them with the antigens that could serve as the GPS directing them to the enemy, unchecked cancer cells and dangerous microbes.

The clue that Edelson and colleagues pursued arose from a remarkable, now widely recognized and applied clinical success. Forty years ago, Edelson, while a young investigator pursuing novel anti-cancer immunotherapies, serendipitously stumbled upon the solution when he developed a therapeutic vaccination for cutaneous T cell lymphoma. That therapy is now regularly administered at major medical centers worldwide. But how that advantageous immunotherapy actually works remained a mystery. “We had somehow landed on the answer to how dendritic cells were naturally produced and engaged in the body, but needed new scientific tools to decipher the steps involved,” he says. “And so, together with numerous colleagues worldwide, we have spent a rather long time trying to figure out how that happened.”

These years of effort paid off—his team has now successfully uncovered how the body naturally produces dendritic cells from monocytes. Rather than by bathing precursor monocytes in massive amounts of growth factors unattainable in patients, this is accomplished by specific elaborate signaling by platelets, the abundant pieces of cells that are best known for their roles in blood clotting and wound healing. “By uncovering how dendritic cells, the principal master switches of selective immunity, are naturally made in the body, we learned how to produce and procure them for therapeutic immunizations. Then, in tight collaboration with the Santangelo team, we learned how to program them to produce immunity against the protein targets of choice and need. Essentially, we now can educate dendritic cells to perform the tricks we want,” says Edelson. That permits the team to set its sights on applying their newfound knowledge to patient-specific immunogenic cancers and novel dangerous infections.

Edelson’s research group includes Aaron Vassall, MD, Kazuki Tatsuno, MD, Douglas Hanlon, PhD, Najla Arshad, PhD, Olga Sobolev, PhD, Eve Robinson, BS, and Mary Pitruzzello, BS. They have received critical expert advice from two senior Yale colleagues, Peter Cresswell, PhD, Eugene Higgins Professor of Immunobiology and professor of cell biology, and Marcus Bosenberg, MD, PhD, Anthony N. Brady Professor of Dermatology, Pathology, and Immunobiology and director of the Yale Center for Immuno-Oncology, The management team of the Yale startup Transimmune has provided key support, as has the Bill and Melinda Gates Foundation. “This scientific project would not be possible without the synergistic combination of skill sets of our and Santangelo’s teams” says Edelson.