Researchers include first author David L. Bajor, MD, instructor of Medicine in the division of Hematology/Oncology, and senior author Robert H. Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research.
“We’ve had wonderful success with immunotherapies, but we are barely scratching the surface,” Bajor said. “Checkpoint inhibitors are just the beginning. When they are thoughtfully combined with immune-stimulating compounds like CD40 or drugs targeting other facets of the immune system we hope to be able to increase the response rate to previously approved therapies.”
Known as a checkpoint inhibitor, tremelimumab is an investigational monoclonal antibody that “cuts the brakes” of the immune system by targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a protein that can switch off a patient's immune response. Anti-CD40 drugs (in this trial, CP- 870,893) antagonize the CD40 receptor, and effectively “push the gas” on the immune system to make it work harder.
Today, new immunotherapy drugs have shown great promise in melanoma, but many patients fail to respond, underscoring the need to further improve the drugs’ abilities. There have been trials investigating the CTLA4 and CD40 pathways separately, but none have targeted melanoma with both of these agents simultaneously.
For the new study, researchers enrolled 24 patients with metastatic melanoma who had never been treated with either drug nor any CTLA-4 or PD-1/PD-L1 inhibitor. Patients received doses of tremelimumab every 12 weeks and doses of anti-CD40 every three weeks. They were followed for side effects continuously, and response was evaluated every three months.
After a median follow-up of 22 months, the team found that the drugs were safe and shrank tumors in a subset of patients, with an overall response rate of 27 percent, which included complete responses in two patients and partial responses in four patients. The median progression-free survival was 2.5 months and the median overall survival was 26.1 months.
“There was clear, clinical evidence of response to this combination, even in some patients with highly morbid, visceral disease,” Bajor said. There was concern that stimulating the immune system while “cutting the brakes” with checkpoint inhibition could lead to increased incidence or severity of side effects, but that was not the case.
The researchers also analyzed specific immune cells called cytotoxic T cells isolated from the patients’ blood and found increases in biomarkers indicative of immune activation.
However, there was still a dampening of the immune response in many cases, according to the researchers. Part of the body’s natural response to activation of the immune system is to produce a compensatory immunosuppressive signal. Tumors use this to their advantage by expressing molecules such as PD-L1, which cause T cells to become less active or “exhausted”. The researchers saw evidence of this phenomenon, which may suggest future combinations with PD-1/PD-L1 inhibitors.
The next step at Penn is to combine anti-CD40 with chemotherapy in operable pancreatic cancer and to test new anti-CD40 compounds.
Co-authors include Rosemarie Mick, Matthew J. Riese, Lee P. Richman, Xiaowei Xu, Drew A. Torigan, Erietta Stelekati, Martha Sweeney, Brendan Sullivan, Lynn M. Schuchter, Ravi Amaravadi and E. John Wherry.
This study was funded by a Penn-Pfizer alliance grant and the National Cancer Institute.###Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.
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