Macrophages - immune cells that engulf and digest particles and pathogens - provide a first line of defense against bacteria and viruses and can also help destroy cancer cells. Macrophages play a paradoxical role, with M1 macrophages rousing the immune system to action and M2 macrophages quelling inflammation. Researchers have found that cancer cells evade destruction by macrophages in two ways - by converting cells to become docile, M2 macrophages, and by sending out an "eat me not" signal that tricks M1 macrophages into letting them be. Investigators from Brigham and Women's Hospital have developed a therapeutic that delivers a double whammy to knock out both mechanisms. In preclinical models, the new approach has yielded promising results. The team's findings are published today in Nature Biomedical Engineering.

"Clinicians are increasingly realizing that one drug or a one-size-fits-all approach is not enough when combatting cancer, and that a combination immunotherapy, such as blocking two distinct targets in the same immune cell, is the future of immuno-oncology. Our approach capitalizes on this concept," said co-corresponding author Ashish Kulkarni, PhD, a former instructor in the Division of Engineering in Medicine at BWH and assistant professor in the Department of Chemical Engineering at University of Massachusetts, Amherst.

Kulkarni and colleagues have previously reported on the design and engineering of supramolecules - therapeutics that are built from component molecules that click together like building blocks. To reinvigorate macrophages, the team designed a supramolecule that could block the "don't eat me" signal that cancer cells can produce and simultaneously inhibit signaling that converts macrophages to M2 subtype.

The researchers tested the supramolecular therapeutic in animal models of aggressive forms of breast cancer and skin cancer, comparing their drug directly with a drug currently available in the clinic. Mice that were untreated formed large tumors by Day 10. Mice treated with currently available therapies showed decreased tumor growth. But mice treated with the new supramolecular therapy had complete inhibition of tumor growth. The team also reported an increase in survival and a significant reduction in metastatic nodes.

"We can actually see macrophages eating cancer cells," said co-corresponding author Shiladitya Sengupta, PhD, BWH associate bioengineer and assistant professor of medicine at Harvard Medical School, citing confocal microscopy images published in the paper that show macrophages (red) engulfing cancer cells (green).

The researchers plan to continue testing the new therapy in preclinical models to evaluate safety, efficacy and dosage. The supramolecular therapy they have designed has been licensed and they hope to move the therapeutic into clinical trials in the years ahead should preclinical testing continue to show promise.

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Funding for this work was provided by a Department of Defense Breakthrough Award (BC132168), an American Lung Association Innovation Award (LCD-259932-N), an NCI UO1 (CA214411), a National Cancer Institute of the National Institutes of Health (P50CA168504) and Hearst Foundation/Brigham and Women's Hospital Young Investigator Award.

Paper cited: Kulkarni, Ashish et al. "A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer" Nature Biomedical Engineering DOI:10.1038/s41551-018-0254-6