A Bacterial-Based Immunotherapy for PDAC

Taking advantage of childhood tetanus vaccinations and the bacterium Listeria monocytogenes, researchers at Albert Einstein College of Medicine in Bronx, NY, have figured out a potential immunotherapy for pancreatic ductal adenocarcinoma (PDAC). They hope their strategy's preclinical promise eventually extends to patients, given PDAC's immunologically “cold” phenotype and poor responsiveness to checkpoint inhibitors (Sci Transl Med 2022;14:eabc1600).

Studying two well-established mouse models, the team, led by Claudia Gravekamp, PhD, first gave tetanus shots to young mice prior to PDAC development. Cancer cells that appeared were then infected with tetanus toxoid (TT), delivered by Listeria. Serving as a tumor neoantigen, TT's presence provoked robust reactivation of preexisting memory T cells that homed in on and destroyed the “tetanized” tumors.

“We chose Listeria because it selectively gets TT to tumor, not normal, cells,” Gravekamp says. Typically, the immune system would deploy mature myeloid-derived suppressor cells (MDSC) to snuff out such bacteria, but this doesn't happen within the tumor microenvironment (TME). There, MDSCs not only remain immature, but are themselves readily infected by Listeria. “Ironically, the primary tumor also releases cytokines that attract these same MDSCs,” she explains, which is how Listeria and its TT cargo then reach tumor cells. “It's the Trojan horse effect.”

Although the researchers used attenuated Listeria for safety, they retained a key protein, ActA, which enables motility. “We thought it was important for the bacteria to be able to spread from one tumor cell to the next, secreting TT along the way” and, in effect, colonizing the TME, turning PDAC immunologically “hot,” Gravekamp says.

The team discovered that combining Listeria–TT with low-dose gemcitabine further alleviated immunosuppression in the TME, increasing therapeutic efficacy. Mice with early-stage PDAC had near-complete disease elimination. Meanwhile, in mice with advanced PDAC, primary tumors shrank by 80% and metastases by 87%; survival improved by 40% compared with an untreated control group.

To Peter Ujhazy, MD, PhD, of the NCI, “triggering intrinsic immune responses toward pancreatic cancer by taking advantage of the TT-specific memory T cells all of us have is an elegant approach, and it does seem to work in a preclinical setting.” He is particularly intrigued by the finding that “CD4⁺, not CD8⁺, T cells were responsible for tumor reduction.”

Gravekamp agrees. “We initially expected activity from classical, cytotoxic CD8⁺ T cells, which were, in fact, highly stimulated by Listeria–TT,” she says. “But when we looked within the tumors, they weren't there—it looks like they can't efficiently infiltrate, whereas CD4⁺ T cells seem much better at doing so.”

In the clinic, one hurdle may be the need for intraperitoneal rather than intravenous administration of Listeria–TT: The bacteria would otherwise be rapidly eliminated in the bloodstream, with little if any reaching tumor cells, Gravekamp explains. As such, “more clinicians will need to be educated” about peritoneal port placement—implanting a small chamber under patients’ skin for treatment delivery.

“I hope this immunotherapy makes it to early-phase trials,” Ujhazy says, to shed light on not only safety and efficacy, but also “tolerability among individuals weakened by a devastating cancer.” Successfully treating PDAC remains a major challenge, he notes, “so any attempt to use out-of-the-box solutions deserves attention, especially if it's accompanied by strong preliminary data.”

Discussions with the FDA are underway about initiating a phase I study through Loki Therapeutics, Gravekamp's start-up. In time, she's cautiously optimistic about expanding beyond TT to Listeria-mediated delivery of other childhood antigens, such as those for measles and poliovirus.

“I think our strategy could apply to other cancers that have an immunosuppressive environment or are poorly immunogenic,” Gravekamp observes, “because it addresses both these problems.” –Alissa Poh