Could immuno-oncology treatments get a boost from a 64-year-old antipsychotic?

Prochlorperazine (PCZ) was first approved by the FDA back in 1956 to treat psychosis, and, even though it’s been overtaken by newer antipsychotics, it’s still prescribed today to relieve nausea and vomiting. Now, Australian researchers are suggesting a new use for the drug: to improve the effectiveness of checkpoint inhibitors and other antibodies in cancer.

A team at the University of Queensland combined PCZ with EMD Sorono and Pfizer’s Bavencio, a PD-L1 inhibitor, in mouse tumors models and observed a greater shrinkage of the cancer than what occurred with either therapy alone. They also tried a combination of the antipsychotic with Eli Lilly’s EGFR inhibitor Erbitux and found it reversed treatment resistance more effectively than either drug alone. They published the findings in the journal Cell.

PCZ is a known inhibitor of endocytosis, the process by which cells ingest materials. The Queensland team hypothesized that temporarily blocking endocytosis might boost the population of receptors on tumor cell surfaces, which would improve the ability of anticancer antibodies to bind to them. To test the idea, they developed a new imaging technology that allowed them to measure endocytosis.

By studying tumor samples from patients with squamous cell carcinoma, the researchers discovered that reducing endocytosis of the EGFR protein correlated with an improved response to Erbitux.

"We found that if we stopped the drug targets getting inside the cells by inhibiting the uptake process…we got a really big immune response against the tumors in mice," said senior author Fiona Simpson, Ph.D., a cancer researcher at the University of Queensland, in a statement. Her team figured the approach could boost a range of antibodies developed to fight cancer, including checkpoint inhibitors.

The Queensland researchers completed a proof-of-concept study, administering one dose of PCZ to a small number of patients with squamous cell carcinoma of the head and neck. Tumor biopsies revealed an increase in Erbitux binding sites and EGFR clustering on the surface of the cancer cells. They are now gearing up for human trials of the approach, starting with a PCZ-Erbitux combination in triple-negative breast cancer, adenoid cystic carcinoma and head and neck cancer.

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A wide range of approaches are being examined in the quest to improve immuno-oncology treatments, including combining them with cancer-killing viruses, immune-stimulating proteins or medicines that switch off immune-suppressing pathways. Earlier this week, a team from the University of Southern California reported that the antidepressant phenelzine, first approved in 1961, is showing promise in treating men with recurrent prostate cancer. The drug, which is an MAO inhibitor, also disrupts signaling of the androgen receptor and may help prevent the growth and spread of prostate tumors, they reported.

On Friday, a team of scientists from the University of Texas (UT) Southwestern Medical Center and University of Chicago suggested yet another combination approach, this one inspired by the healthy bacteria that live in everyone’s guts.

Their study focused on CD47, a protein on the surface of cancer cells that can block the ability of the immune system to fight cancer. There are several anti-CD47 antibodies in the pipeline, but there are concerns about effectiveness stemming from mouse trials in which some animals responded but others did not.

The researchers discovered that if they used antibiotics to kill off the gut bacteria of mice that responded well to anti-CD47 treatment, the animals stopped responding. Then they took a group of mice that hadn’t responded to the CD47-blocking antibodies and supplemented them with Bifidobacteria, a healthy bacterium that normally lives in the digestive tracts of people and mice. The treatment reversed the resistance to the anti-cancer therapy. They published the study in the Journal of Experimental Medicine.

Further investigation revealed that the Bifidobacteria migrated into tumors and stimulated an immune pathway called STING. That, in turn, activated immune cells.

“Our study demonstrates that a specific member of the gut microbial population enhances the anti-tumor efficacy of anti-CD47 by colonizing the tumor,” said co-lead author Yang-Xin Fu, M.D., Ph.D., professor of pathology at UT Southwestern, in a statement. "Administration of specific bacterial species or their engineered progenies may be a novel and effective strategy to modulate various anti-tumor immunotherapies."