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