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New combination of chemotherapy and immunotherapy combats breast cancer cell recurrence

Masoud Manjili, D.V.M., Ph.D.

In pre-clinical experiments, researchers at VCU Massey Cancer Center have reported promising results toward the eradication of breast cancer recurrence through a combination of chemotherapy and immunotherapy. Breast cancer is the most frequently diagnosed non-skin cancer in women and ranks second among cancer deaths in women after lung cancer. An estimated 246,660 new cases of invasive breast cancer will be diagnosed in women in the U.S. in 2016, and approximately 2,600 new cases in men, according to Breastcancer.org.

Massey scientist Masoud Manjili, D.V.M, Ph.D., along with a team of Massey researchers, developed a chemo-immunotherapeutic protocol that overcame tumor-induced suppression, heightened tumor cells’ vulnerability to immunotherapy and extended survival in animal models of metastatic breast cancer.

Manjili’s study, published in the Journal of Leukocyte Biology, tested a combination of Adriamycin (generic name doxorubicin), a standard chemotherapeutic agent, with a form of immunotherapy on mouse models of breast cancer and found that the majority of cancerous cells died as a result.

The researchers determined that chemotherapy or radiation therapy alone killed the majority of tumor cells but also produced a residual population of two types of dormant cancer cells: indolent and quiescent. The remaining dormant cells were resistant to additional doses of these therapies.

Although dormant cancer cells experience arrested growth and division, they pose a dangerous risk because they can go medically undetected for years and then suddenly multiply uncontrollably, initiating cancer recurrence.

Indolent cancer cells grow at a slow rate, while quiescent cells no longer express cell division.

Manjili said that when the drug-induced dormant cells were treated with a product of the immune system called interferon gamma, only indolent cells were able to escape, suggesting that this immunotherapy could be highly effective against quiescent cells.

Interferon gamma is a cell signaling protein that is secreted by cells of the immune system and plays a significant role in adaptive immune response and the inhibition of viral replication. In fact, tumor-reactive immune cells that are adoptively transferred into cancer patients can secrete interferon gamma, thereby killing tumor cells and facilitating tumor escape simultaneously.

Immunotherapy is a form of treatment that stimulates a person’s immune system to fight back internally against cancerous cells; however, there are still questions as to the exact administration of this treatment for various types of cancer. Due to many encouraging results demonstrating the successful destruction of tumor cells, immunotherapy has recently been placed at the forefront of many global cancer research initiatives, including the Obama administration’s $1 billion Cancer Moonshot initiative designed to accelerate breakthroughs in cancer research and care.

“Immunotherapy is all about timing. I’m hopeful that we can eventually cure cancer if we use immunotherapy at the right time during tumor dormancy,” Manjili said.

Manjili, member of the Cancer Cell Signaling research program at Massey and associate professor of Microbiology and Immunology at the VCU School of Medicine, said the findings suggest that the administration of immunotherapy following the completion of chemotherapy, and during tumor dormancy, could help prevent deaths due to the recurrence of metastatic cancer.

Although some dormant tumor cells from the indolent population were able to adapt and escape immunotherapy treatment, Manjili said they were able to identify how this occurred and how they might prevent it.

Looking forward, Manjili plans to continue this research in hopes of achieving more effective treatments for metastatic breast cancer. He said that he is testing low dose metronomic chemotherapies with cyclin dependent kinase (CDK) inhibitors as a conditioning regimen for an effective immunotherapy against breast cancer. If this treatment is successful in animal models of breast cancer, it will be translated into a clinical trial.

Manjili collaborated on this study with Kyle Payne, a Ph.D. student in Manjili’s lab and currently postdoctoral fellow at the Wistar Institute, Philadelphia; Harry Bear, M.D., Ph.D., the Dr. Walter Lawrence, Jr. Chair in Surgical Oncology, professor in the Department of Microbiology and Immunology at the VCU School of Medicine, director of the Breast Health Program and member of the Developmental Therapeutics research program at Massey; Laura Graham, research and lab manager for the VCU Health Department of Surgery; Michael Idowu, M.P.H., M.B.B.S, associate professor of pathology at the VCU School of Medicine, Massey research member and co-director of Massey’s Tissue and Data Acquisition and Analysis Core; Amir Toor, M.D., professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine and a member of the Developmental Therapeutics research program at Massey; Wen Wan, M.D., Ph.D., assistant professor in the VCU Department of Biostatistics; Shawn Wang, Ph.D., professor of human and molecular genetics at the VCU School of Medicine and member of the Cancer Molecular Genetics research program at Massey; Rebecca Keim, M.S., student in the Department of Microbiology and Immunology at the VCU School of Medicine.

This research was supported by the American Association of Immunologists (AAI) Careers in Immunology Fellowship Award, a Massey Cancer Center Pilot Program grant (2013-JunPP-04) and the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program and, in part, by VCU Massey Cancer Center’s National Cancer Institute Cancer Center Support Grant P30 CA016059. Services and products in support of the research project were generated by Massey’s Flow Cytometry Shared Resource Core.

Written by: Blake Belden

Posted on: December 8, 2016