Researchers have designed a new method for developing immunotherapy drugs using engineered peptides to elicit a natural immune response inside the body. More specifically, they showed, in antigen presenting cells, that “the hydrophobicity, electrostatic charge, and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress.”

In preclinical models of locally advanced and metastatic breast cancer, this method improved tumor control and prolonged survival, both as a monotherapy and in combination with immune checkpoint inhibitors.

This work is published in Nature Biomedical Engineering in the paper, “Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

“Amino acids are the building blocks of life and, when a few of them are linked together, they create a peptide. All the biological functions performed by our body are done by proteins and peptides, so our goal was to find a way to redesign these small molecules to possess the unique ability to activate our immune system,” said Betty Kim, MD, PhD, professor of neurosurgery at the University of Texas MD Anderson Cancer Center.

Cancer cells often exploit weaknesses in the immune system to avoid detection. Current immune checkpoint inhibitors are antibodies designed to block specific immune signaling pathways.

These findings suggest that an engineered peptide improves the immune system’s ability to detect and destroy cancer cells. Rather than using an external compound to initiate a response, or harvesting and modifying immune cells for cell therapies, the peptide serves as a messenger to activate specific signaling pathways in immune cells to boost their performance.

More specifically, one of the three engineered polypeptides activated “two major intracellular DNA-sensing pathways (cGAS–STING (for cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells.”

The authors noted that, in mouse models of locally advanced and metastatic breast cancers, the polypeptides led to “potent DNA-sensor-mediated antitumor responses when intravenously given as monotherapy or with immune checkpoint inhibitors.”

They added that activating multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumor immune responses.

“These findings open a whole new avenue for developing immunotherapy drugs. By using designed polypeptides, we can potently activate immune signaling pathways to enhance antitumor responses. Additionally, since these are naturally derived agents, we anticipate the toxicity profile would be significantly better than with synthetic compounds,” said Wen Jiang, MD, PhD, associate professor of radiation oncology.

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