T‐cell receptor gene therapy targeting melanoma‐associated antigen‐A4 inhibits human tumor growth in non‐obese diabetic/SCID/γc^null mice

Abstract

Adoptive cell therapy with lymphocytes that have been genetically engineered to express tumor-reactive T-cell receptors (TCR) is a promising approach for cancer immunotherapy. We have been exploring the development of TCR gene therapy targeting cancer ⁄ testis antigens, including melanoma-associated antigen (MAGE) family antigens, that are ideal targets for adoptive T-cell therapy. The efficacy of TCR gene therapy targeting MAGE family antigens, however, has not yet been evaluated in vivo. Here, we demonstrate the in vivo antitumor activity in immunodeficient non-obese diabetic ⁄ SCID ⁄ cc null (NOG) mice of human lymphocytes genetically engineered to express TCR specific for the MAGE-A4 antigen. Polyclonal T cells derived from human peripheral blood mononuclear cells were transduced with the ab TCR genes specific for MAGE-A4, then adoptively transferred into NOG mice inoculated with MAGE-A4 expressing human tumor cell lines. The transferred T cells maintained their effector function in vivo, infiltrated into tumors, and inhibited tumor growth in an antigen-specific manner. The combination of adoptive cell therapy with antigen peptide vaccination enhanced antitumor activity, with improved multifunctionality of the transferred cells. These data suggest that TCR gene therapy with MAGE-A4-specific TCR is a promising strategy to treat patients with MAGE-A4-expressing tumors; in addition, the acquisition of multifunctionality in vivo is an important factor to predict the quality of the T-cell response during adoptive therapy with human lymphocytes. (Cancer Sci 2012; 103: 17-25)

Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8+ T cells

“…We previously described the importance of effector T-cell multifunctionality in the antitumor immune response [17][18][19], consistent with clinical observations reported by other groups [45,46]. The differences in the qualities of T-cell responses defined by different combinations of functions remain largely unknown.…”

“…The mobilization of CD107a, a marker for the release of cytotoxic granules, was also elevated in cells stimulated with CH-296. We previously reported that the multifunctionality of effector CTLs, as assessed by the combination of these three measurements, is a critical determinant of the quality of the T-cell response [17][18][19]. The acquisition of multifunctionality by effector T cells is one mechanism by which these cells resist immunosuppression mediated by tumor progression in a model of adoptive transfer of tumor-specific T cells [17][18][19].…”

“…We previously reported that the multifunctionality of effector CTLs, as assessed by the combination of these three measurements, is a critical determinant of the quality of the T-cell response [17][18][19]. The acquisition of multifunctionality by effector T cells is one mechanism by which these cells resist immunosuppression mediated by tumor progression in a model of adoptive transfer of tumor-specific T cells [17][18][19]. We therefore evaluated multifunctionality by calculating the relative frequency of several distinct populations: cells with all three functional characteristics, cells with varying combinations of two functions, cells displaying only one function, and cells without any of these functions.…”

Limited expression of cancer-testis antigens in renal cell carcinoma patients

“…MAGE, NY-ES0-1 and SAGE genes exhibit a similar expression pattern, and their immunogenicity as targets for cancer immunotherapy has been well-studied (12)(13)(14)(15)(16). In a recent study, we assessed the efficacy of immunotherapy for several types of cancer-targeting CTAs (17,18). As a first step towards the development of effective immunotherapy for RCC patients, it is crucial to evaluate the expression level of CTA in the targeted cancer.…”

Harnessing autophagy for cell fate control gene therapy

“…In terms of efficacy, T cells expressing T cell receptors or chimeric antigen receptors specific for tumor or viral antigens can enhance anti-cancer or anti-infection effects. [6][7][8][9][10][11] And, as we will focus on in this study, T cells expressing suicide genes, which we prefer to refer to as cell-fate control genes, can be utilized to increase the safety of T cell therapy. In this approach, T cells expressing a cell-fate control gene can be adoptively transferred to mediate a therapeutic effect, with subsequent deletion of the gene-modified T cell population in vivo for prevention or treatment of T cell-mediated adverse effects.…”