Targeting TCR in the immunotherapy of T cell tumors

Torrey Pines Inst For Molecular Studies, San Diego CA

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Abstract

DESCRIPTION (provided by applicant): T cell lymphomas remain largely untreatable and fatal in the majority of cases despite current therapies, including chemotherapy. Most T cell malignancies comprise a clonal to oligoclonal proliferation of T cells with respect to the usage of the TCR V-beta-gene segments. Recent experiments have shown that the induction of immunity against a TCR idiotype (antigen-combining site) can result in rejection of T cell lymphomas. We have considered targeting the conserved region of the TCR V-beta molecule rather than the idiotype because it avoids the necessity of establishing a different agent for each individual T cell tumor, thereby facilitating widespread application. Since the TCR V- beta-genes are not somatically mutated and are relatively small in number, a panel of V beta-region-specific therapeutic agents could be generated individually and combined as required. Based upon our extensive experience in the induction of TCRV-beta-peptide-reactive T cell responses with profound therapeutic effects in experimentally induced autoimmune diseases, we propose that targeting the V-beta region of the TCR on T cell tumors represents a realistic approach for selective immunotherapy. To determine the efficacy of the anti-TCR immunity, we will use the V-beta 8.2+ EL-4 T cell tumor line as an experimental model. Preliminary data suggest that challenge of mice with the TCR V-beta 8.2 DNA results in the rejection of a V-beta 8.2+ T cell lymphoma. We will use three different modalities to optimize the induction of most robust anti-TCR immunity capable of rejecting T-cell tumors: the V-beta 8.2 plasmid DNA, adenoviral vector encoding the TCR V-beta 8.2 gene, and dendritic cells ex vivo transduced with the V-beta 8.2 adenoviral vector. We will treat established tumors using these reagents alongwith anti-CD40 treatment as well as adenoviral delivery of IL-12 into the tumor mass. To further optimize the immunotherapeutic strategy, we will characterize the immune mechanism(s) responsible for tumor rejection. We have already identified TCRV-beta 8.2-derived peptides which expand both CD4 and CD8 T cells. The CD8 response to one of the TCR-determinant induces lysis of the V- beta 8.2+ tumor in vitro, suggesting processing and presentation of the TCR-peptide in a class I-context on the surface of the tumor. We will further characterize these anti-TCR responses and examine whether both cell types either individually or together are able to reject a V-beta 8.2-expressing T cell lymphoma. These studies are crucial in establishing the proof-of-principle for targeting TCR-V beta chains for the selective immunotherapy of T cell tumors in humans.