Robert H. Vonderheide, M.D., D. Phil. Medline search
Assistant Professor of Medicine

Abramson Family Cancer Research Institute
(Click to go to my Abramson page)
551 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104

(215) 573-4265 telephone
(215) 573-8590 fax

RESEARCH INTERESTS
My research has been aimed at identifying and testing universal tumor antigens, starting with the novel characterization of the catalytic subunit of telomerase (hTERT). 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. A screening system necessary to identify multiple CTL epitopes restricted to multiple HLA alleles has been established. hTERT-specific T cells generated in this system selectively kill hTERT+ tumors from a wide range of histologies, but not telomerase-positive hematopoietic progenitor cells. The first epitope reported, hTERT I540, was used to generate HLA-A2-restricted CTL from normal donors and cancer patients that lysed hTERT+ cell lines and primary tumors from multiple histologies (carcinoma, melanoma, sarcoma, hematologic malignancies).

Several additional epitopes have now been described, including an epitope that triggers HLA-A3-restricted CTL from normal donors and cancer patients which also kill a broad range of tumors in an antigen-specific, MHC-restricted fashion. Based on these findings, we have initiated a phase I study of telomerase vaccination in cancer patients. This trial, which has FDA approval of an investigator-sponsored IND, uses autologous dendritic cells (DC) as a powerful source of antigen presenting cells. DC are generated from peripheral blood, incubated with hTERT and control peptides along with keyhole limpet hemocyanin, and subsequently administered. Exhaustive clinical and immunological assessments are used in the laboratory to address the primary aim of this trial: to determine whether hTERT immunity can be induced and whether toxicity is acceptable.

CURRENT AND FUTURE RESEARCH PLANS
1 . To characterize the immunogenic profile of the telomerase catalytic subunit

2. To determine the clinical and immunological impact of vaccinating cancer patients against the telomerase catalytic subunit

3. 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

REFERENCES
1. 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.

2. Trojan A, Schultze JL, Witzens M, Vonderheide RH, Ladetto M, Donovan JW, Gribben JG. Immunoglobulin framework-derived peptides function as cytotoxic T cell epitopes commonly expressed in B cell malignancies. Nature Medicine. 2000; 6:667-672.

3. 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) (AVRENDTM) in cancer patients. J. Clin. Onc. 2001. 19:3280-87.

4. Schultze JL & Vonderheide RH. From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens. Trends Immunol. 2001. 22:516-523.

5. 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. 2001. Clin Can Res, in press.

6. 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. 2001. Cancer Res, in press.