Syamal Raychaudhuri - US grants

The main objective of this project is to develop monoclonal antibody (MoAb) anti- idiotype (anti-Id) tumor vaccines for the treatment of human cancer. The specific aims of this Phase 2 proposal are to develop anti-Id MoAb vaccines that represent internal images of neuroendocrine tumor-associated antigens (TAA) expressed by human melanoma, neuroblastoma and small cell lung carcinomas (SCLC) and by an experimental rat neuroendocrine animal tumor model. We also intend to generate synthetic peptide vaccines corresponding to the internal antigen idiotopes of whole MoAb vaccine preparations. The administration of peptide subunit idiotope vaccines may minimize potential complications associated with repeated immunization of human subjects with whole murine MoAbs. The whole MoAb and peptide anti-Id vaccine preparations will be tested for anti-tumor effects in the animal tumor model and in human subjects. The results of these in vivo studies should identify those anti-Id vaccine preparations best suited for further clinical trials in human subjects during the Phase 3 effort. In contrast to conventionally purified TAA vaccines, MoAb anti-Id preparations can be readily produced in large quantities and may be employed to enhance immune responses to weakly immunogenic TAA determinants, including carbohydrate and lipid moieties. The re- sults of the Phase 2 studies, combined with the inherent advantages of anti-Id vaccine preparations, may lead to the development of novel tumor vaccine products useful in the therapy of human cancers.

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term objective of this program is to develop novel cancer immunotherapies based upon the ability of anti-T cell receptor (TCR) monoclonal antibodies (MoAbs) to stimulate immune responses. Specifically, the applicant plans to generate anti-clonotypic and anti-TCR MoAbs to T cell clones cytotoxic for melanoma. Anti-TCR antibodies suitable for future evaluation in cancer immunotherapy will be identified by their ability to enhance in vitro tumor cytotoxicity mediated by tumor-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) obtained from cancer patients. MoAbs which demonstrate the ability to induce tumor cytotoxicity will become candidates for future clinical trials to be performed during the phase II investigation. The applicant will also commence the characterization of the stimulatory anti-TCR MoAbs with respect to their specificity for TCR constant and variable region epitopes. This information should prove useful in generating additional MoAbs during the phase II period for future clinical evaluation in human subjects.

It is now well documented that cytotoxic T cell (CTL) responses play a crucial role in the control of viral infection in vivo. While a desirable characteristic of a vaccine or immunotherapeutic reagent is that in addition to antibody, it induces a CTL response, attempts to achieve this goal have been ineffective or unsafe. The induction of class I-restricted CTL responses is almost exclusively dictated by a pathway in which cytoplasmic proteins synthesized within virus infected cells, or by soluble antigens osmotically loaded into the cytoplasm are expressed at the surface of the cell in association with major histocompatibility complex (MHC) class I molecules. The use of pure, well-defined, antigens as immunotherapeutic agents for the induction of both cellular and humoral immune responses is desirable. However, it is almost impossible to induce MHC class I-restricted CTLs in response to a soluble antigen. The objective of this proposal is to determine whether a novel, non-toxic, chemically defined, adjuvant formulation can be used to induce both class I-restricted CTLs and humoral responses against soluble protein antigens (including HIV gp120). We will also evaluate whether CTLs elicited by the adjuvant are similar to those induced by other established methods including the recombinant vaccinia virus technique or by spleen cells cytoplasmically loaded with soluble antigens. This investigation will function as a prelude to the phase II study in which we plan to test the formulation in non-human primates. Such a formulation may be used to treat, both therapeutically and prophylactically, various viral diseases, (including HIV infection) and we anticipate the work will lead to improved strategies for vaccine design.