THE VONDERHEIDE LABORATORYResearch Interests
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. Two other universal tumor antigens, survivin and CYP1B1, are also being actively explored in the lab.
Telomerase vaccination. We are also exploring the clinical and immunological effects of vaccinating cancer patients with telomerase peptide. Our approach uses investigator-sponsored clinical trials and bedside-to-bench laboratory assessments. We have recently completed the dose escalation part of a phase I trial of telomerase peptide in adjuvant with GM-CSF for HLA-A2+ patients with metastatic breast cancer. We have recently initiated a trial combining this vaccine and chemotherapy. Our immune assessment data suggest that telomerase peptide vaccination is biologically active and leads to in vivo immune recognition of carcinoma by effector lymphocytes, associated with tumor necrosis. There is a correlation of vaccine-induced immune response and survival.
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. We have recently described novel technology for RNA-transfection of CD40-activated human B lymphocytes with potential for clinical translation. This technology has driven our efforts to characterize survivin as a tumor-associated antigen in neuroblastoma, leukemia, and other cancers. We have recently opened a large-animal study evaluating tumor RNA-loaded CD40-activated B cells as a cancer vaccine in privately owned dogs with large cell lymphoma. A human phase I clinical trial targeting CD40 is also underway.
Immuno-surveillance of cancer. While it is clear that the immune system can influence tumorigenesis, its earliest interactions with nascent neoplastic lesions remain poorly understood, in part because of the limited tissue available for these studies in humans and the non-physiological systems used to simulate cancer in many mouse models. In a collaboration with the Tuveson laboratory, we are evaluating the kinetics and components of immunosurveillance as a function of tumor progression in a recently described mouse model of pancreatic ductal adenocarcinoma (PDA). We have found that pancreatic specimens from K-ras G12D mice have multi-lineage leukocytic infiltrates even in early stages of disease, and by end-stage disease, CD45 + leukocytes comprise on average half of all cells in the pancreatic tumors. The dominant leukocyte subset is Gr-1 + CD11b + immature myeloid cells, which infiltrate both the stroma and tumor. We are exploring that hypothesis that suppressive cellular elements of the host immune system appear early during tumorigenesis, preceding and outweighing anti-tumor cellular immunity, and likely contributing to disease progression.