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Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.

ABSTRACT: Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53. Activation of this DNA damage response pathway also occurred upon antigen-specific restimulation in TCR-transduced TIL1383I T cells prepared for adoptive transfer to patients as part of a clinical trial. Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker ?H2AX, subsequent ATM activation, and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T-cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth, and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T-cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients. Cancer Res; 76(20); 6006-16. ©2016 AACR.

SUBMITTER: Scheffel MJ

PROVIDER: S-EPMC5074089 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.

Scheffel Matthew J MJ Scurti Gina G Simms Patricia P Garrett-Mayer Elizabeth E Mehrotra Shikhar S Nishimura Michael I MI Voelkel-Johnson Christina C

Cancer research 20161001 20

Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of ...[more]

PMID: 27742673

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Project description:Cancer immunotherapy including adoptive T cell therapy (ACT) is widely used in the clinic and is highly beneficial for patients with hematological malignancies; however, it remains a challenge to develop effective immunotherapy strategies for the treatment of solid cancers, due to the inefficiency of the immune response and the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulate a systemic antigen-specific antitumor immune response, which can effectively subvert the immunosuppressive TME and enhance the efficiency of immune responses, relative to conventional immunotherapeutic regimens. However, the application of traditional inducers of ICD in anti-cancer immunotherapy has been limited because of low levels of ICD induction and a lack of tumor-targeting accumulation. Mitochondria are important for tumor-targeting strategies and have emerged as organelles with key roles in the immune system. We hypothesized that the alteration of mitochondria in cancer cells could be an important target for the development of an efficient ICD inducer for use in cancer immunotherapy. Here, we report the evaluation of a mitochondria-targeted small molecule, IR-780, that acts as an ICD inducer and exhibits exceptional antineoplastic activity. IR-780 specifically accumulated in tumor cells to elicit ICD in vitro and in vivo, effectively suppressed tumor growth and lung metastasis, and enhanced adoptive T-cell therapy effects against solid tumors in mouse models. These anticancer effects were linked to dendritic cell maturation and synergistic effector T cell priming and infiltration into tumors. The underlying mechanism involves the direct targeting of the mitochondria by IR-780, to destroy cancer cells, including drug-resistant cancer cells, leading to the full exposure of tumor-associated antigens (TAAs), thereby enhancing antigen-specific antitumor immune responses. These features of IR-780 suggest that it has the advantage of leading to complete TAA exposure and the stimulation of efficient antitumor immune responses in the TME. IR-780 has potential for use as a preparative ICD inducer, in combination with conventional immunostimulatory regimens for cancer immunotherapy, particularly in the context of solid tumor treatment.

Dataset Information

Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.

Publications

Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.

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