ABSTRACT
Analogous to the clinical use of recombinant high-affinity Abs, transfer of TCR genes may be used to create a T cell compartment specific for self-Ags to which the endogenous T cell repertoire is immune tolerant. In this study, we show in a spontaneous prostate carcinoma model that the combination of vaccination with adoptive transfer of small numbers of T cells that are genetically modified with a tumor-specific TCR results in a marked suppression of tumor development, even though both treatments are by themselves without effect. These results demonstrate the value of TCR gene transfer to target otherwise nonimmunogenic tumor-associated self-Ags provided that adoptive transfer occurs under conditions that allow in vivo expansion of the TCR-modified T cells.
Subject(s)
Immunotherapy, Adoptive , Lymphocyte Activation/immunology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Receptors, Antigen, T-Cell/therapeutic use , T-Lymphocytes/immunology , Transduction, Genetic , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Animals , Antigens, Viral, Tumor/biosynthesis , Antigens, Viral, Tumor/genetics , Clone Cells , Immunotherapy, Adoptive/methods , Influenza A virus/immunology , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , Receptors, Antigen, T-Cell/administration & dosage , Simian virus 40/immunology , T-Lymphocytes/virology , Transduction, Genetic/methods , Vaccinia/immunologyABSTRACT
Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCR-modified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigen-specific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHC-mismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of "off the shelf" T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical setting.
