New form of immunotherapy being studied for cancer that is resistant to conventional T-cell therapies

Medical researchers hypothesize that a combination of two treatments that activate myeloid cells could effectively treat a recalcitrant form of pancreatic cancer that thwarts conventional immunotherapy.

Mobilizing the immune system to destroy cancers has been one of the revolutionary treatments of the last decade, spurring the defeat of cancers via immunotherapies that marshal T cells to wage war against malignancies. The problem facing oncologists and their patients is that T-cell immunotherapy works well for some cancers, but not for all forms of the disease.

Activated T cells are extraordinary killers in immunotherapies, and although these lymphoid cells are effective when mobilized against certain cancers, new strategies apparently have a role to play, scientists now say.

A team of cancer biologists studying an approach that activates myeloid cells against tumors says they have seen positive results in treating a resistant form of pancreatic cancer.

New research at the University of Pennsylvania is investigating the potential for a different type of immunotherapy in an experimental approach that relies on two immunotherapies targeting myeloid cells.

Research into this strategy is underway through studies on animal models and the first clinical trials in humans. The basic concept guiding both the animal model and human research relies on a deceptively simple concept: combining two treatments that activate myeloid cells may prove effective against tumors where more conventional immunotherapies based on T cells failed.

Write in Scientific immunologycancer biologists at UPenn’s Perelman School of Medicine have discovered that combined targeting of the myeloid cell activating receptors CD40 and dectin-1 can trigger potent anti-tumor immunity.

“By co-targeting myeloid activating molecules, we exploited the myeloid compartment as a therapeutic vulnerability,” wrote Dr. Max M. Wattenberg, lead author of the recently published research in a mouse model.

“Myeloid cells in solid tumors expressed activating receptors, including the pattern recognition receptor dectin-1 and the TNF receptor superfamily member CD40. In mouse models of dot inhibitor-resistant pancreatic cancer control, co-activation of dectin-1, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors,” added Wattenberg, who conducts research in the division of Hematology and Oncology from the Perelman School of Medicine.

Launching a two-pronged approach highlights the potential of myeloid cells as powerful cancer fighters, particularly against a particularly resistant tumor type that has failed to respond to the single therapeutic approach.

In the analyses, Wattenberg and a team of collaborators used systemic β-glucan in tandem with CD40 agonist antibody therapy and found that this combination successfully activated anti-tumor T cell responses, where conventional immunotherapy targeted to the T cells had not done so.

Myeloid cells are immune cells that mature in the bone marrow and play an important role in antitumor immune activity. There are three myeloid cell lineages: granulocytic, erythroid and megakaryocytic. These cell lines include a long list of familiar names, such as erythrocytes; platelets; the granulocyte family: basophils, eosinophils and neutrophils; monocytes and myeloid dendritic cells.

Perhaps more than their lymphoid counterparts, myeloid cells can be reprogrammed to be immunosuppressive when they enter the tumor microenvironment, Wattenberg and colleagues report.

In their laboratory research involving animal models of human pancreatic ductal adenocarcinoma, the team found that established pancreatic tumors that were resistant to T-cell-targeted immunotherapy could be eradicated with their new strategy. Targeting myeloid cell activating receptors – CD40 and dectin-1 – created a potent myeloid response against tumors, overcoming naturally immunosuppressive signals from the tumor microenvironment.

“Antitumor activity was dependent on T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules,” Wattenberg wrote. “In contrast, targeting CD40 resulted in T cell-mediated interferon-gamma signaling, which converged with dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses.”

To be clear, the antitumor activity of dectin-1/CD40 activation required T cells, but it was completely independent of T cell cytotoxicity and immune checkpoint pathways, the results demonstrate.

Wattenberg and colleagues point out that antitumor activity also required interferon gamma and intratumoral macrophages. The results demonstrate that targeting myeloid cell activation pathways can generate strong anti-tumor immune responses against tumors resistant to conventional immunotherapy.

“These results define a previously undescribed immunotherapy paradigm via co-activation of complementary myeloid signaling pathways,” Wattenberg concluded, noting that a clinical trial studying a combination immunotherapy treatment for patients with Pancreatic ductal adenocarcinoma is ongoing.

© 2023 Science X Network