TY - JOUR

T1 - Methods to Improve Adoptive T-Cell Therapy for Melanoma

T2 - IFN-γ Enhances Anticancer Responses of Cell Products for Infusion

AU - Donia, Marco

AU - Hansen, Morten

AU - Sendrup, Sarah L

AU - Iversen, Trine Zeeberg

AU - Ellebæk, Eva

AU - Andersen, Mads H

AU - Straten, Per Thor

AU - Svane, Inge Marie

PY - 2013

Y1 - 2013

N2 - Further development of adoptive T-cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) has the potential to markedly change the long-term prognosis of patients with metastatic melanoma, and modifications of the original protocol that can improve its clinical efficacy are highly desirable. In this study, we demonstrated that a high in vitro tumor reactivity of infusion products was associated with clinical responses upon adoptive transfer. In addition, we systematically characterized the responses of a series of TIL products to relevant autologous short term-cultured melanoma cell lines from 12 patients. We provide evidence that antitumor reactivity of both CD8(+) and CD4(+) T cells could be enhanced in most TIL products by autologous melanoma sensitization by pretreatment with low-dose IFN-γ. IFN-γ selectively enhanced responses to tumor-associated antigens other than melanoma differentiation antigens. In addition, IFN-γ treatment was invariably associated with restored/increased cancer immunogenicity as demonstrated by upregulation of major histocompatibility complex molecules. These findings suggest a potential synergism between IFN-γ and ACT, and have important implications for clinical development of combination strategies for the treatment of metastatic melanoma.

AB - Further development of adoptive T-cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) has the potential to markedly change the long-term prognosis of patients with metastatic melanoma, and modifications of the original protocol that can improve its clinical efficacy are highly desirable. In this study, we demonstrated that a high in vitro tumor reactivity of infusion products was associated with clinical responses upon adoptive transfer. In addition, we systematically characterized the responses of a series of TIL products to relevant autologous short term-cultured melanoma cell lines from 12 patients. We provide evidence that antitumor reactivity of both CD8(+) and CD4(+) T cells could be enhanced in most TIL products by autologous melanoma sensitization by pretreatment with low-dose IFN-γ. IFN-γ selectively enhanced responses to tumor-associated antigens other than melanoma differentiation antigens. In addition, IFN-γ treatment was invariably associated with restored/increased cancer immunogenicity as demonstrated by upregulation of major histocompatibility complex molecules. These findings suggest a potential synergism between IFN-γ and ACT, and have important implications for clinical development of combination strategies for the treatment of metastatic melanoma.

U2 - 10.1038/jid.2012.336

DO - 10.1038/jid.2012.336

M3 - Journal article

C2 - 23014345

VL - 133

SP - 545

EP - 552

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 2

ER -