RESUMO
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.
Assuntos
Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/imunologia , Transdução Genética , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Antígenos Virais de Tumores/biossíntese , Antígenos Virais de Tumores/genética , Células Clonais , Imunoterapia Adotiva/métodos , Vírus da Influenza A/imunologia , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Vírus 40 dos Símios/imunologia , Linfócitos T/virologia , Transdução Genética/métodos , Vacínia/imunologiaRESUMO
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.