John Yannelli, Ph.D.

Dendritic cell vaccines in lung cancer: Non-small cell lung cancer (NSCLC) is a leading killer of men and women around the world. While conventional therapies exist including surgery, chemotherapy and radiation therapy; they are not successful a high % of the time. Immunotherapy, the development of immunologic reagents to combat disease, is considered by some to be the 4th modality of cancer treatment. Immunotherapy has seen considerable success in melanoma and a number of patients have responded with significant biologic responses to this therapy. Dr. Yannelli has been involved in immunotherapy research since 1985 and has contributed significantly to the development of these treatments for melanoma. While at the University of Kentucky, Dr. Yannelli has developed an immunotherapy for NSCLC which utilizes dendritic cells (DCs) pulsed with apoptotic bodies derived from an allogeneic NSCLC line.

To date, Dr. Yannelli’s lab has prepared this dendritic cell vaccine for 22 patients with results for 16 of the patients recently published in the Journal of Clinical Oncology and Lung Cancer. Results from the study have shown that patients with various stages of NSCLC are responsive to the DC vaccine. Eleven of the 16 patients immunized developed vaccine-specific T cells in response to the immunization. In 6 of the patients, the response appeared to be tumor-specific. Along with his clinical colleague Dr. Ed Hirschowitz, they are continuing the studies in an effort to cure patients of this deadly disease.

Cytotoxic T cell (CTL) response to NSCLC: Immunotherapy has the potential to become an important mode of therapy for patients with non-small cell lung cancer (NSCLC). Our lab is seeking ways to apply principles of immunotherapy to the treatment of this disease. In the early 90s, a retrospective analysis of laboratory data obtained from clinical trials of immunotherapy in melanoma showed that clinical responses were correlated with the delivery of reagents that had anti-tumor reactivity. Specific T cells, capable of lysing or secreting cytokines in response to melanoma were critical. We are extending these observations to NSCLC. In a clinical trial of an NSCLC vaccine using dendritic cells (DCs), we have shown the ability to immunize patients against NSCLC tumors.

Key to the further development of the vaccine, however, is a better understanding of the T-cell-defined antigenic nature of the disease. In earlier published studies from our lab, we have shown that specific CTL and cytokine-producing CD4 helper cells exist in the disease. In addition, using an allogeneic system of antigen presentation and a cDNA cloning strategy, we were able to identify three antigens recognized by T cells from NSCLC patients. Unfortunately, due to the allogeneic nature of the system, we identified HLA-C3 and two minor histocompatibility antigens (GNAS and IMPA) as targets for CTL. In the present system, we have developed an autologous system for antigen identification consisting of 4-NSCLC tumor cell lines, autologous fibroblasts, autologous EBV cell lines and tumor tissue as a source of CD8 T cells. The TC lines have been passaged and are currently cryopreserved for long terms analysis. Our study has 4 specific aims. In the first specific aim, we are defining the known antigenic nature of the TC lines and introduce the costimulatory molecule CD80 by transfection. This will allow the TC lines to serve as antigen-presenting cells. In specific aim 2, we are evaluating the immunogenicity of each of the lines by analyzing the ability to generate NSCLC-specific CTL. In the third Specific aim, we will clone CTL-defined antigens using cDNA cloning strategy. The 4th specific aim will examine the relevancy of the CTL-defined antigens, evaluate their ability to be presented by multiple HLA types, and examine their expression by other tumors and normal tissue. The clinical relevance of this project is that we will improve our current approach to DC vaccination using novel CTL-defined antigens in NSCLC. This will allow more defined in vivo manipulations and allow us to assess more accurately, the immune response to vaccination.