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| Engineered T cells kill tumors but spare normal tissue in an animal model Posted: 06 Apr 2013 09:00 PM PDT The need to distinguish between normal cells and tumor cells is a feature that has been long sought for most types of cancer drugs. Tumor antigens, unique proteins on the surface of a tumor, are potential targets for a normal immune response against cancer. Identifying which antigens a patient’s tumor cells express is the cornerstone of designing cancer therapy for that individual. But some of these tumor antigens are also expressed on normal cells, inching personalized therapy back to the original problem.
T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell’s function. Importantly, CARs allow patients’ T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients’ own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen. To address this issue, Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, and director of the Cellular Therapy Tissue Facility, developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity — mesothelin and a-folate receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer. Powell likens this dual CAR approach to having two different gas pedals, one for starting the immune system and a second for revving it up. Dual CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue. Dual CAR T cells showed weak cytokine production against target cells expressing only one tumor-associated antigen in lab assays, similar to first-generation CAR T cells bearing the CD3 activation domain only, but demonstrated enhanced cytokine production upon encountering natural or engineered tumor cells expressing both antigens, equivalent to second-generation CAR T cells with dual, but unseparated signaling. In a mouse model of human ovarian cancer, T cells with the dual-signaling CARs persisted at high numbers in the blood, accumulated in tumors, and showed potent anti-cancer activity against human tumors. Dual CAR T cells were equivalent to second-generation CAR T cells in activity against tumors bearing two antigens. However, the dual-signaling CAR T cells did not react vigorously with normal tissue expressing one antigen while second- generation CAR T cells did. “This new dual-specificity CAR approach can enhance the therapeutic efficacy of CAR T cells against cancer while minimizing reactivity against normal tissues,” says Powell. Their findings have been published in the inaugural issue of Cancer Immunology Research, the newest journal from the American Association for Cancer Research. ### This work was supported by grants from the W.W. Smith Charitable Trust, the Sandy Rollman Ovarian Cancer Foundation, the Ovarian Cancer Research Fund (PPD-Penn-01.12), the National Cancer Institute (RO1-CA168900) and the Joint Fox Chase Cancer Center and University of Pennsylvania Ovarian Cancer SPORE (P50 CA083638). Co-authors include Evripidis Lanitis, Mathilde Poussin, Alex W. Klattenhoff, Degang Song, and Carl H. June, all from Penn. 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 $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 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 $398 million awarded in the 2012 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; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community. Contact: Karen Kreeger |
| 2-step ovarian cancer immunotherapy made from patients’ own tumor shows promise Posted: 05 Apr 2013 09:00 PM PDT As many as three quarters of advanced ovarian cancer patients appeared to respond to a new two-step immunotherapy approach — including one patient who achieved complete remission — according research from the Perelman School of Medicine at the University of Pennsylvania that will be presented today in a press conference at the AACR Annual Meeting 2013 (Presentation #LB-335).
The immunotherapy has two steps ? a personalized dendritic cell vaccination and adoptive T-cell therapy. The team reports that in the study of 31 patients, vaccination therapy alone showed about a 61 percent clinical benefit, and the combination of both therapies showed about a 75 percent benefit. The findings offer new hope for the large number of ovarian cancer patients who relapse following treatment. The first step of the immunotherapy approach is to preserve the patient’s tumor cells alive, using sterile techniques at the time of surgery so they can be used to manufacture a personalized vaccine that teaches the patient’s own immune system to attack the tumor. Then, the Penn Medicine team isolates immune cells called dendritic cells from patients’ blood through a process called apheresis, which is similar to the process used for blood donation. Researchers then prepare each patient’s personalized vaccine by exposing her dendritic cells to the tumor tissue that was collected during surgery. Because ovarian cancer symptoms can be stealth and easily mistaken for other issues ? constipation, weight gain, bloating, or more frequent urination ? more than 60 percent of patients are diagnosed only after the disease has spread to their lymph nodes or other distant sites in the body, when treatment is much less likely to produce a cure compared to when the disease is detected early. As the fifth leading cause of cancer-related deaths among women in the United States, it takes the lives of more than 14,000 women each year. “Given these grim outcomes, there is definitely a vast unmet need for the development of novel, alternate therapies,” said lead author Lana Kandalaft, PharmD, PhD, MTR, a research assistant professor of Obstetrics and Gynecology and director of clinical development and operations in Penn Medicine’s Ovarian Cancer Research Center. “This is the first time such a combination immunotherapy approach has been used for patients with ovarian cancer, and we believe the results are leading us toward a completely new way to treat this disease.” Both treatments are given in conjunction with bevacizumab, a drug that controls the blood vessel growth that feeds tumors. Combining bevacizumab with immunotherapy makes a powerful duo, Kandalaft says. The vaccine trial is still open to accrual to test new combinatorial strategies. ### The other Penn authors are Janos Tanyi, Cheryl Chiang, Daniel Powell, and George Coukos. This study was funded by a National Cancer Institute Ovarian Specialized Program of Research Excellence grant, the National Institutes of Health and the Ovarian Cancer Immunotherapy Initiative. Dr. Kandalaft will present the findings of the trial on Saturday, April 6, 2013 in the Late Breaking Clinical Trials press conference at 1:00 p.m. ET in room 153 of the Walter E. Washington Convention Center, 801 Mt Vernon Pl. NW, Washington, DC. She will also present during the Late-Breaking Research: Immunology poster session in Hall A-C (Poster Section 46) on Wednesday, April 10, from 8 a.m. to noon ET. RELATED NEWS RELEASES: http://www.uphs.upenn.edu/news/News_Releases/2013/01/kandalaft/ http://www.uphs.upenn.edu/news/News_Releases/2011/12/personalized-ovarian/ 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 $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 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 $398 million awarded in the 2012 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; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community. Contact: Holly Auer |
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