Induction of Anti-Tumor Immune Response in Murine Models

The rationale of tumor-specific immunotherapeutic strategies relies on the capability of the immune system to recognize and specifically kill neoplastic cells. Several immunotherapeutic approaches to boost natural immune response to tumors have been developed, including cellular vaccines, recombinant or naked DNA vaccines, peptide/protein vaccines and the administration of biologic response modifiers like GM-CSF, [alpha]-IFN and other cytokines involved in modulating the immune responses. Here, we describe a novel approach to cancer vaccination based on the delivery of tumor antigens to immunological priming sites. The novelty of this approach is represented by the use of T lymphocytes expressing a defined tumor antigen, which do expand antigen specific cells that could, indeed, have an active role in controlling tumor growth. The rationale underlying our vaccination approach derives from clinical and experimental results of an adoptive immunotherapeutic study carried out in the context of hematologie malignancies by our group. We observed that genetically modified T cells could induce a highly specific immune response against the transgene products (i.e.: HSV-TK and neo) when injected into immunocompetent patients. Aim of this study is to investigate in murine models the cellular mechanism(s) responsible for the induction of antigen-specific immune response following T cell- engineered based vaccination. We have hypothesized 2 different mechanisms: 1) antigen-expressing lymphocytes may directly prime host CDS+ effectors within the secondaiy lymphoid organs (SLO); 2) antigen-expressing lymphocytes, may undergo cell death within SLO and behaving as antigen carriers may “transfer” antigenic material to host APCs, which in turn cross-present the antigens to CDS4″ effectors. To address this issue C57BL/6 mice were given intravenous infusions of syngeneic genetically modified T-lymphocytes expressing either the murine tumor antigen TRP-2 or the model antigen ovalbumin (OVA). LNs and spleen from the infused mice were collected at different time points and analysed by FACS in order to evaluate the number of transduced T-lymphocytes reaching SLO. Approximately 1-3% of the infused cells migrated to SLO and were deetectable within the SLO for about 10 days. Antigen-specific activation, proliferation and ?-IFN release has been observed in C57BL/6 recipient mice adoptively transferred with OT-1 T-cells and vaccinated with ovalbumin transduced T-lymphocytes. Moreover vaccination with transduced T-cells obtained from C57BL/6 [beta]2 microglobulin^sup – /-^ mice in the same experimental settings, shows antigen-specific activation/expansion suggesting the involvment of a “cross- presentation” pathway in the generation of the immune response.

A. Cipponi, A. De Laurentiis, C. Traversari, V. Russo

Cancer Immunotherapy and Gene Therapy Programm, DIBIT, H. San Raffaele Scientific Institute, Milan, Italy

Copyright Edizioni Minerva Medica Mar 2004