Immunotherapy of hematologic malignancies is a rapidly evolving approach to eradication of residual disease following chemotherapy and/or radiation. Aberrant expression of normal proteins, fusion proteins and numerous point mutations have been identified in association with hematologic malignancies suggesting a variety of potential immmunotherapeutic targets. However, many human malignancies are believed to induce a state of immunological """"""""tolerance"""""""" which renders immune approaches ineffective. In prior studies we have used the combined approach of effector cell recruitment using chemokines, in tandem with specific T-cell activation using costimulatory ligands to successfully eradicate pre-existing T-cell lymphoma in a mouse model.
We aim to further develop this strategy using a less immunogenic B-cell lymphoma model, in which the development of tolerance poses a major barrier to immune based therapies. We will explore the utility of recruitment using three constitutively expressed chemokines, specifically, SDF-1beta, DC-CK1, and SLC, to preferentially recruit naive T-cells, which have not been rendered anergic through prior exposure to tumor associated antigens. The chemokines will be studied alone or when used in combination with the CD40L costimulatory molecule. We will attempt to overcome T- cell anergy induced by exposure to tumor cells in the absence of co-stimulatory signals through recruitment of an expanded repertoire of naive T-cells, followed by exposure of the recruited T-cells to tumor cells which express the CD40L costimulatory molecule. We will use Herpes Simplex amplicon vectors, which have been extensively used in our laboratory and which are highly efficient for purposes of gene transfer and expression in vivo. We will study the composition and evolution of immune infiltrates resulting from chemokine transduction and the antitumor activity of the chemokines when used alone and/or in combination with CD40L in the A20 murine B-cell lymphoma model. Using transgenic T-cells with specificity for the influenza Hemagglutinin antigen (HA) and a model system in which HA antigens are presented via A20 B-cells, (A20-HA) we will formally test whether immunologic tolerance to the HA target antigen can be overcome through selective recruitment and costimulation of a naive T-cell population. Optimal dosage and temporal sequencing of chemokine administration will be ascertained in preparation for potential Phase I trials.
