Cancer Discovery Could Revive Failed Treatments for Solid Tumors

Jogender Tushir-Singh, PhD, of the UVA School of Medicine

New research from the University of Virginia (UVA) Cancer Center could rescue once-promising immunotherapies for treating solid cancer tumors, such as ovarian, colon, and triple-negative breast cancer, that ultimately failed in human clinical trials.

The research led by UVA’s Jogender Tushir-Singh, PhD, explains why the antibody approaches effectively killed cancer tumors in lab tests but proved ineffective in people. He found that the approaches had an unintended effect on the human immune system that potentially disabled the immune response they sought to enhance.

The new findings allowed Tushir-Singh, of the UVA School of Medicine’s Department of Biochemistry and Molecular Genetics, to increase the approaches’ effectiveness significantly in lab models, reducing tumor size and improving overall survival. The promising results suggest the renewed potential for the strategies in human patients, he and his team report. The findings also have significant potential to improve further the clinical efficacy of PD-L1 targeting antibodies already approved by the U.S. Food and Drug Administration for use in solid tumors, particularly the ones approved for deadly triple-negative breast cancer.

Immunotherapy aims to harness the body’s immune system to recognize and destroy cancer cells. Lab-engineered antibodies remain the core facilitator of immunotherapies and CAR T-cell therapies, which have generated tremendous excitement in the last decade. However, these therapies have proved less effective against solid tumors than against melanoma (skin cancer) and leukemia (blood cancers). One major obstacle: It is difficult for immune cells to make their way efficiently into the core of solid tumors.

To overcome that problem, scientists have developed an approach that selectively uses antibodies to target a receptor on the cancer cells’ surface called death receptor-5 (DR5). This approach essentially tells the cancer cells to die and enhances the permeation of the body’s immune cells into a solid tumor without the toxicity associated with chemotherapy. However, when tested in Phase II human clinical trials, these antibodies consistently failed to improve survival in patients.

Tushir-Singh, an antibody engineer, and his collaborators found that the anti-DR5 antibody approaches unintentionally triggered biological processes that suppress the body’s immune response. This allowed the cancer tumors to evade the immune system and continue to grow.

Tushir-Singh and his team found it was possible to restore the potency of the DR5-based antibody approach in human cancer cells and immune-sufficient mouse models by co-targeting the negative biological processes with improved, immune-activating therapy. The new combination therapy “markedly” increased the effectiveness of cancer killer immune cells known as T cells, shrinking tumors and improving survival in lab mice, they reported in the scientific journal EMBO Molecular Medicine.

“We would like to see these strategies in clinical trials, which we strongly believe have huge potential in solid tumors,” Tushir-Singh said.

Meanwhile, researchers elsewhere reported in Nature Communications that they had found another possible explanation for why many cancer drugs that kill tumor cells in mouse models won’t work in human trials.

In a study at The University of Texas Health Science Center at Houston School of Biomedical Informatics and McGovern Medical School, investigators found the extensive presence of mouse viruses in patient-derived xenografts (PDX). PDX models are developed by implanting human tumor tissues in immune-deficient mice, and are commonly used to help test and develop cancer drugs.

“What we found is that when you put a human tumor in a mouse, that tumor is not the same as the tumor that was in the cancer patient,” said W. Jim Zheng, PhD, professor at the School of Biomedical Informatics and senior author on the study. “The majority of tumors we tested were compromised by mouse viruses. …It makes the results of a cancer drug look promising when you think the medication kills the tumor—but in reality, it will not work” in human trials the way it does in mice.

Edited by Gary Cramer