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Robert H. Vonderheide, MD, DPhil

Robert H. Vonderheide, MD, DPhil

faculty photo
Hanna Wise Associate Professor in Cancer Research
Department: Medicine
Graduate Group Affiliations

Contact information
8-121 Smilow Center for Translational Research
3400 Civic Center Blvd
Philadelphia, PA 19104
Office: 215-573-4265
Fax: 215-573-2652
Lab: 215-746-8901
Education:
BSc (Chemical Engineering)
University of Notre Dame, 1985.
DPhil (Immunology)
Oxford University, 1989.
MD
Harvard Medical School, 1993.
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Description of Research Expertise

RESEARCH INTERESTS
My laboratory combines efforts in both basic research and clinical investigation to advance the understanding of tumor immunology and to develop novel immunotherapies for cancer. Our chief hypothesis is that successful approaches in tumor immunotherapy will need to (a) optimize target antigens with regard to clinical applicability and risk of antigen loss, (b) repair host immuno-incompetence in antigen presentation and T cell function, and (c) circumvent immuno-suppressive factors of the tumor and tumor microenvironment.

RESEARCH DETAILS
Four specific areas of research focus are:

Tumor antigen discovery.
My laboratory works on the discovery, characterization, and translation of universal tumor antigens for cancer immunotherapy. In particular, we focus on the in vitro and in vivo characterization of the human telomerase reverse transcriptase (hTERT) as tumor antigen. Telomerase is expressed by >85% of all human cancers but absent in most normal cells. Telomerase function has been directly linked to oncogenesis and its inhibition in telomerase-positive human tumors leads to growth arrest.

Telomerase vaccination.
We are also exploring the clinical and immunological effects of vaccinating cancer patients against telomerase. Our approach uses investigator-sponsored clinical trials and bedside-to-bench laboratory assessments. In a recently completed trial, we induced hTERT-specific T cells in vivo via peptide vaccination in patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) specific for telomerase were evident after, but not before vaccination. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-gamma production, and tumor lysis. Median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not, suggesting that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer. Current clinical trials are testing telomerase peptide vaccination in combination with daclizumab to target regulatory T cells as well as an immuno-gene therapy approach for patients in remission after initial standard therapies for a variety of solid tumor malignancies.

CD40 activation of antigen presenting cells.
My laboratory works on the role of CD40 in activating the host immune system. In particular, we have explored the immunobiology of CD40 activation on human B cells and dendritic cells. In multiple clinical trials, we have tested this hypothesis in patients using an agonist CD40 monoclonal antibody and found evidence for immune activation associated with tumor regression. Current clinical trials combine this antibody with chemotherapy. We have also developed novel technology for RNA-transfection of CD40-activated human B lymphocytes and have used this technology as a novel cancer vaccine in privately owned dogs with large cell lymphoma.

Immuno-surveillance of cancer.
The resurgent theory of cancer immunosurveillance holds that the immune system plays an important role in the suppression of tumors, particularly in the elimination of early neoplastic lesions. Tumors with reduced immunogenicity or those that have acquired mechanisms to suppress immune effector functions, however, can emerge from this selection pressure and grow progressively. This is an especially important issue in pancreatic cancer, which although inflammatory in vivo is nevertheless highly aggressive and nearly always lethal. Using genetically defined mouse models of pancreatic adenocarcinoma, we have found that the immune system may be complicit in the inception and progression of pancreatic cancer. Host immune cells with suppressive properties infiltrate the pancreas early during tumorigenesis, even at the earliest stages of neoplasia, preceding and effectively undermining any lymphocytes with potential antitumor function. Thus, in pancreatic adenocarcinoma, the failure of immunosurveillance is likely an early event during tumorigenesis, a concept that carries important implications for our current work to design novel immunotherapeutics in this disease and other cancers.

LABORATORY PERSONNEL

Bayne, Lauren
PhD Student, CAMB GTV

Beatty, Gregory, MD, PhD
Hematology-Oncology Fellow

Colligon, Theresa
Research Manager

Leight, Jennifer
Administrative Assistant
215-573-3269
Leightj@exchange.upenn.edu

Rech, Andrew
Research Specialist

Recio, Adri, RN
Oncology Research Nurse

Reshef, Ran, MD
Hematology-Oncology Fellow

Rueter, Jens, MD
Hematology-Oncology Fellow

Trosko, Jenna
Research Specialist

Vonderheide, Robert
Associate Professor of Medicine
(215) 573-4265
551 BRB II/III
rhv@exchange.upenn.edu

Description of Clinical Expertise

Medical Oncology and Experimental Therapeutics, in particular Immunotherapy

Selected Publications

Markosyan N, Chen EP, Evans RA, Ndong V, Vonderheide RH, Smyth EM: Mammary carcinoma cell derived cyclooxygenase 2 suppresses tumor immune surveillance by enhancing intratumoral immune checkpoint activity. Breast Cancer Research 15(5): R75 [Epub ahead of print] Sep 3 2013.

Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O'Dwyer P: A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clinical Cancer Research Page: [Epub ahead of print] Sep 4 2013.

Bayne LJ, Vonderheide RH: A myeloid-derived suppressor cell-mediated T-cell suppression assay for functional evaluation of immune cells in tumor-bearing mice. Cold Spring Harb Protoc. 2013(9), Sep 1 2013.

Vonderheide RH,Burg JM, Mick R, Trosko JA, Li D, Shaik MN, Tolcher AW, Hamid O : Phase I study of CD40 antibody CP-870,893 in combination with carboplatin and paclitaxel in patients with advanced solid tumors OncoImmunology 2: e23033, 2013.

Tchou J, Wang LC, Selven B, Zhang H, Conejo-Garcia J, Borghaei H, Kalos M, Vonderheide RH, Albelda SM, June CH, Zhang PJ. : Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Can Res Treat 133: 799-804, 2012.

Doi H, Iyer TK, Carpenter E, Li H, Chang KM, Vonderheide RH, Kaplan DE: Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-Positive B-cell population. Hepatology 55: 709-719, 2012.

Meisel JL, Domchek SM, Vonderheide RH, Giobbie-Hurder A, Lin NU, Winer EP, Partridge AH: Quality of life in long-term survivors of metastatic breast cancer. Clin Breast Cancer 12: 119-126, 2012.

Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr, Colligon TA, Trosko JA, Leinbach LI, Pletcher CH, Tweed CK, DeMichele A, Fox KR, Domchek SM, Riley JL, Vonderheid RH: CD25 blockade depletes and selectively reprograms regulatory T-cells in concert with immunotherapy in cancer patients Science Translational Medicine 4: 134ra62, 2012.

Rhim AD, Mirek ET, Aiello N, Maitra A, Beatty GL, Bailey JM, Reichert M, Vonderheide RH, Leach SD, Stanger BZ : EMT and dissemination precede pancreatic tumor formation. Cell 148: 349-361, 2012.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH : Tumor-derived granulocyte-macrophage colony stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21: 822-835, 2012.

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Last updated: 10/17/2013
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