Seminar by Dolores Schendel June 17th New immunotherapies. Third generation DC-based vaccines and TCR gene therapy

Abstract:

New Immunotherapies: Third generation DC-based vaccines and TCR gene therapy
Dolores J. Schendel
Institute of Molecular Immunology
Helmholtz Zentrum München
German Research Center for Environmental Health
Munich, Germany

Dendritic cells (DC) provide an important basis for development of anti-tumor vaccines. While DC vaccines have been proven to be safe, their limited clinical efficacy to date spurs further development. Several factors may have contributed to the failure to achieve the desired clinical results with many DC vaccine trials which now can be altered based on a continually evolving understanding of DC biology. It is now apparent that DC should display three important signals for induction of optimal anti-tumor immunity. MHC-peptide complexes (Signal 1) expressed by DC determine the specificity of T cell responses. The use of ivt-RNA provides an elegant means to provide reliable sources of tumor-associated antigens to DC, guaranteeing efficient antigen-loading for better quality DC. The use of mature DC that deliver optimal costimulatory signals (Signal 2) to lymphocytes is particularly important to avoid induction of anergic effector cells and negative regulatory T cells. We have found that DC produced within 3 days display properties that nicely fulfil this requirement, while reducing the costs and complexity in GMP production of vaccines. Finally, DC that produce cytokines (Signal 3) that polarize immune responses for effective anti-tumor immunity are important. We have developed new maturation cocktails that provide DC that produce bioactive IL-12p70 and foster innate immunity and Th1-polarized immune responses. It is hoped that third generation DC vaccines based on these properties will improve anti-tumor responses and clinical efficacy.

We have also utilized RNA-pulsed DC to overcome a critical bottleneck in generating high-avidity T cells specific for tumor-associated antigens that are over-expressed self-proteins by using co-expression of ivt-RNA encoding an antigen and an allogeneic MHC molecule to create new ligands for recognition by allo-restricted peptide-specific T cells. By tapping a non-selected T cell repertoire when self-antigens are presented by allogeneic MHC molecules, one can bypass negative selection and obtain T cells expressing TCR with higher affinities. As model antigens we have used tyrosinase and survivin together with HLA-A2 as an allogeneic MHC molecule. Allo-restricted peptide-specific T cells showed functional superiority and higher functional avidities compared to self-restricted T cells recognizing the same ligand. We generated TCR-transgenic PBL of healthy donors using cloned TCR sequences of self- and allo-restricted tyrosinase-specific T cell clones and observed that allo-restricted TCR allowed transduced PBL to recognize lower peptide concentrations and to better recognize tumor cells, demonstrating the superiority of the allo-restricted TCR. Transfer of survivin-specific TCR led to a big surprise to be discussed.

Link:

Dolores J. Schendel's CV (download PDF)