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Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.

ABSTRACT: Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a ?-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this problem, a vector was designed where IL-12 expression was directed by a composite promoter-containing binding motifs for nuclear factor of activated T-cells (NFAT.hIL12.PA2). The NFAT-responsive promoter was activated to drive IL-12 expression upon the recognition of tumor-specific antigen mediated by a T cell receptor (TCR) that was engineered into the same lymphocytes. We tested the efficacy of the inducible IL-12 vector in vivo in a murine melanoma model. Adoptive transfer of pmel-1 T cells genetically engineered with NFAT-murineIL12 (NFAT.mIL12.PA2) significantly enhanced regression of large established B16 melanoma. Notably, this targeted and controlled IL-12 treatment was without toxicity. Taken together, our results suggest that using the NFAT.hIL12.PA2 vector might be a promising approach to enhance adoptive cancer immunotherapy.

SUBMITTER: Zhang L

PROVIDER: S-EPMC3070103 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.

Zhang Ling L Kerkar Sid P SP Yu Zhiya Z Zheng Zhili Z Yang Shicheng S Restifo Nicholas P NP Rosenberg Steven A SA Morgan Richard A RA

Molecular therapy : the journal of the American Society of Gene Therapy 20110201 4

Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a γ-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this probl ...[more]

PMID: 21285960

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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

Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.

Publications

Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.

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