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Member Information
Robert H. Vonderheide, MD, PhD
Assistant Professor of Medicine
Department of Medicine, Hematology-Oncology Division
Office Phone:
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Website(s): http://www.uphs.upenn.edu/abramson/vonderheide.html; http://www.med.upenn.edu/camb/faculty/cgc/vonderheide.html
Education:
Keywords: Immunology, tumor immunity, viral immunity, cancer therapy, telomerase
Research and/or Clinical Interest(s):
Identification and clinical evaluation of T lymphocyte epitopes for vaccination and adoptive therapy
Summary:
My research is aimed at identifying and testing universal tumor antigens for cancer immunotherapy, with a particular focus on the characterization of the human telomerase reverse transcriptase as tumor antigen. Unlike other tumor antigens previously described, telomerase is expressed by >85% of all human cancers but absent in most normal cells. Telomerase maintains the telomeric ends of linear chromosomes. Its function has been directly linked to oncogenesis and its inhibition in telomerase-positive human tumors leads to growth arrest. We are evaluating telomerase and control viral antigens, including HIV antigens, with an extensive discovery component in the laboratory as well as a clinical translational effort at the Abramson Cancer Center . Moreover, we are working to discovery additional such antigens, reporting two this year, both linked to carcinogenesis or oncogenesis. Finally, we are exploring the use of a novel vaccine modality based on RNA-transfection of activated human B lymphocytes, which has particular relevance to pediatric diseases. The specific aims of my lab are:
To characterize the immunogenic profile of the telomerase reverse transcriptase;
To identify multiple T cell epitopes restricted to multiple HLA alleles, including MHC class II, that trigger patient T cell responses against hTERT-positive tumors but not normal cells;
To determine the clinical and immunological impact of vaccinating cancer patients against hTERT;
To implement phase I safety and feasibility trials that assess the immunologic response of vaccinated patients, including direct tracking and functional assessment of hTERT- and control-specific T cells;
To develop methods of expanding hTERT-specific T cells ex vivo for the clinical evaluation of hTERT-specific adoptive T cell therapies;
To identify, scrutinize, and translate new universal tumor antigens to the clinic and to pool antigens with acceptable safety for the evaluation of combination antigen-specific T cell immunotherapy;
To characterize in vitro the ability of CD40-B cells transfected with RNA to induce anti-tumor specific CTL.
Representative Publications:
Vonderheide RH, Hahn WC, Schultze JL, Nadler LM. The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity. 1999; 10:673-679.
Vonderheide RH, Dutcher JP, Anderson JE, Eckhardt SG, Stephans KF, Razvillas B, Garl S, Butine M, Perry VP, Armitage RJ, Ghalie R, Caron DA, Gribben JG. Phase I study of recombinant human CD40 ligand (rhuCD40L) (AVREND TM ) in cancer patients . J. Clin. Onc. 2001. 19:3280-87.
Schultze JL & Vonderheide RH. From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens. Trends Immunol. 2001. 22:516-523.
Vonderheide RH, Anderson KS , Hahn WC, Butler MO , Schultze JL, Nadler LM. Characterization of HLA-A3-restricted T cells reactive against the universal tumor antigen telomerase for widely applicable anti-cancer immunotherapy. Clin Can Res, 2001. 7, 3343-3348
Vonderheide RH, Schultze JL, Anderson KS, Maecker B, Butler MO, Kuroda MJ, von Bergwelt-Baildon MS, Bedor MM, Hoar KM, Schnipper DR, Brooks MW, Letvin NL, Wucherpfenning KW, Stephans KF, Hahn WC, Nadler LM. Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals. Cancer Res, 2001. 61, 8366-8370.
Vonderheide, RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene, 2002. 21:674-679.
von Bergwelt-Baildon MS, Vonderheide RH, Maecker B, Hirano H, Anderson KS, Butler MO, Xia Z, Zeng WY, Wucherpfennig KW, Nadler LM, Schultze JL. Human primary and memory cytotoxic T lymphocyte responses are efficiently induced using CD40-activated B cells as antigen presenting cells: Potential for clinical application. Blood, 2002. 99:3319-3325
Gordan JD, Vonderheide RH. Universal tumor antigens as targets for immunotherapy. Cytotherapy, 2002, 4:317-327.
Schmollinger JC, Vonderheide RH, Hoar KM, Maecker B, Schultze JL, Hodi FS, Soiffer RJ, Jung K, Kuroda MJ, Letvin NL, Greenfield EA, Mihm M, Kutok JL, Dranoff G. The inhibitor of apoptosis protein ML-IAP is a target for immune mediated tumor destruction. Proc Natl Acad Sci USA , 2003, 100:3398-3403.
Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, Bunin N, Strobl FJ, Cotte J, Zheng Z, Gregson B, Rivers P, Vonderheide RH, Liebowitz DN, Porter DL, June CH. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin's lymphoma following CD34-selected hematopoietic cell transplantation. Blood, Epub May 22, 2003.
Maecker B, Anderson KS, von Bergwelt-Baildon MS, Weller E, Vonderheide RH, Richardson PG, Schlossman RL, Menezes IA, Xia Z, Munshi NC, Anderson KC, Nadler LM, Schultze JL. Viral antigen-specific CD8+ T-cell responses are impaired in multiple myeloma . Br. J. Hematology, 2003, 121:842-848.
Maecker B, Sherr DH, Vonderheide RH, von Bergwelt-Baildon MS, Hirano N, Anderson KS, Xia Z, Butler MO, Wucherpfennig KW, O'Hara C, Cole G, Kwak SS, Ramstedt U, Tomlinson AJ, Chicz RM, Nadler LM, Schultze JL. The shared tumor associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood, Epub July 17, 2003.
