Adoptively Transferred Immune T Cells Eradicate Established Tumors despite Cancer-Induced Immune Suppression

Arina, Ainhoa; Schreiber, Karin; Binder, David; Karrison, Theodore; Liu, Rebecca B.; Schreiber, Hans

doi:10.4049/jimmunol.1202498

Cited by 17 publications

(17 citation statements)

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“…YFP×1D9×Rag −/− double-transgenic mice were generated as a pure source of fluorescently labeled 1D9tg T cells. YFP-transgenic Rag −/− mice have been described (29). OTIxRag −/− mice (B6.129S7- Rag1 tm1Mom Tg(TcraTcrb)1100Mjb) were obtained by breeding Rag −/− and TCR OT-I-transgenic mice (provided by Matthew Mescher, University of Minnesota, Minneapolis, MN).…”

Section: Methodsmentioning

confidence: 99%

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Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

Leisegang

Engels

Schreiber

et al. 2016

Clinical Cancer Research

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Purpose Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic non-synonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T cell receptor (TCR) that is specific for a single AAS. Experimental Design By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. Results When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intra-tumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. Conclusions Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape.

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Section: Methodsmentioning

confidence: 99%

“…Implantation of windows, cancer cell injection, confocal microscopy and data analysis were done as described (29,32). Detailed information are provided in Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

Leisegang

Engels

Schreiber

et al. 2016

Clinical Cancer Research

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“…Many tumors are highly infiltrated with suppressive cells such as regulatory T cells (Tregs), MDSCs, and so-called M2 suppressive macrophages. In addition, tumors cells and the associated stroma can express inhibitory molecules such as PD-L1, FAS, or TGF-β that can kill or inhibit transferred cells (Arina et al, 2014). One advantage of adoptive transfer protocols is that T cells can be manipulated ex vivo and strategies to overcome tumor-induced immune suppression can be directly engineered into them.…”

Section: Car Therapymentioning

confidence: 99%

The New Era of Cancer Immunotherapy

Khalil¹,

Budhu²,

Gasmi³

et al. 2015

Advances in Cancer Research

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“…Other barriers to the success of ACT include tumor stroma associated immunosuppression (Phan and Disis, 2008). Cellular components in tumor stroma, including cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSC), and tumorassociated macrophages (TAMs) inhibit T cell function (Arina and Bronte, 2015;Arina et al, 2014;PhanLai et al, 2013). However, reports have shown the…”

Section: Act Trials: Cd8+ Versus Cd4+mentioning

confidence: 99%

Adoptive immunotherapy via CD4+ versus CD8+ T cells

Phan-Lai

2016

Biomed Res Ther

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Abstract-The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT) has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets) which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT.

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Adoptively Transferred Immune T Cells Eradicate Established Tumors despite Cancer-Induced Immune Suppression

Cited by 17 publications

References 50 publications

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

The New Era of Cancer Immunotherapy

Adoptive immunotherapy via CD4+ versus CD8+ T cells

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