- Recurrent, metastatic breast cancer resists treatment and is usually fatal.
- These tumors often have low numbers of immune cells in them, which renders immune therapies less effective for the disease.
- This preclinical study suggests that drugs called CDK4 and CDK6 inhibitors may make immune-cell therapies an effective option for treating recurrent ER-positive metastatic breast cancer.
COLUMBUS, Ohio - A class of drugs that inhibits breast cancer progression when used with hormonal therapy might also boost the effectiveness of immune therapy in cases of recurrent, metastatic breast cancer, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James).
Published in the journal Cell Reports, the findings of the animal study suggest that drugs called CDK4 and CDK6 (CDK4/6) inhibitors might improve the effectiveness of immune therapies for metastatic, estrogen-receptor-positive (ER+) breast cancer.
"We know that CDK4/6 inhibitors effectively slow the progression of newly diagnosed breast cancer, but they don't kill cancer cells," says principal investigator Anna Vilgelm, MD, a member of the OSUCCC - James Translational Therapeutics Program and assistant professor at the Ohio State College of Medicine. "Consequently, the disease often recurs, and then it is usually fatal because we have no effective therapies for recurrent disease.
"Our findings suggest that combining CDK4/6 inhibitors with immunotherapy might offer an effective treatment for recurrent, metastatic ER+ breast cancer," Vilgelm says.
Specifically, the study shows that CDK4/6 inhibitors can improve the efficacy of T-cell-based therapies such as adoptive T-cell transfer or T-cell-activating antibodies in animal models of breast cancer.
Immune therapies are proving to be effective treatments for a variety of cancers but not for advanced breast cancer. One problem is that breast tumors often have low numbers of cancer-killing T lymphocytes within the tumor. Such tumors tend to respond poorly to immune therapies.
"In addition, breast cancer patients with low numbers of tumor-infiltrating lymphocytes often have worse survival compared to patients with high numbers of infiltrating lymphocytes in their tumors," says Vilgelm.
The new study shows that CDK4/6 inhibitors cause breast tumors to secrete small proteins called chemokines that attract T cells. This can help to improve patients' response to cancer immunotherapies.
For this study, Vilgelm and her colleagues used the oral CDK inhibitor palbociclib, mouse models, breast cancer cell lines and analyses of The Cancer Genome Atlas (TCGA) to study the influence of CDK4/6 inhibitors and chemokine production in the tumor immune microenvironment and on patient outcomes.
Key findings include:
- Pre-treatment with a CDK4/6 inhibitor improves recruitment of T cells into tumors and improved the outcome of adoptive cell therapy in animal models;
- CDK4/6 inhibitor-treated human breast cancer cells produce T-cell-recruiting chemokines;
- TCGA analysis showed that chemokine expression is a favorable prognostic factor in breast cancer patients;
- mTOR-regulated metabolic activity is required for chemokine induction by CDK4/6 inhibition;
- T-cell-recruiting chemokines may be useful prognostic markers for stratifying patients for immunotherapy treatment.
"Overall," Vilgelm says, "our findings suggest that CDK4/6 inhibitors may offer a therapeutic strategy that can attract T cells into breast cancer tumors, which mayincrease their sensitivity to immune therapies."
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This study was supported by grants from the Breast Cancer Research Foundation, the National Institutes of Health (CA098131, CA233770-01, CA116021, CA116021-S1, CA68485, CA16672) and the Department of Veterans Affairs.
Other researchers involved in this study were Roman V. Uzhachenko, Vijaya Bharti, Zhufeng Ouyang, Chengli Shen, The Ohio State University; Ashlyn Blevins, Stacey Mont, Nabil Saleh, Hunter A. Lawrence, Sheau-Chiann Chen, Gregory D Ayers, Vanderbilt University; David G. DeNardo, Washington University, St. Louis; Carlos Arteaga, University of Texas Southwestern Medical Center; Ann Richmond, Department of Veterans Affairs, Tennessee Valley Healthcare System and Vanderbilt University.
About the OSUCCC - James
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs provided by the NCI. As the cancer program's 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. With 21 floors and more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care.
Journal
Cell Reports