Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Mohammed, Somala; Sukumaran, Sujita; Bajgain, Pradip; Watanabe, Norihiro; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Fisher, William E.; Leen, Ann M.; Vera, Juan F.

doi:10.1016/j.ymthe.2016.10.016

Cited by 218 publications

(166 citation statements)

References 52 publications

(76 reference statements)

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“…These engineering approaches are also applicable to cytokine receptors. T cells engineered to express a dominant negative TGFβ receptor (Foster et al, 2008) or a chimeric cytokine receptor such as a one with GM-CSF or IL-4 receptor ectodomains and IL-2R or IL-7R endodomains (Cheng and Greenberg, 2002; Leen et al, 2014; Mohammed et al, 2017; Wilkie et al, 2010) could allow T cells to co-opt suppressive cues within the tumor milieu to enhance function. Combining many of these approaches, such as cell engineering with reagents that improve T cell infiltration, modify the immunosuppressive TME, and/or enhance the endogenous immune response may yield synergistic effects on tumor control and overall survival.…”

Section: Final Thoughts: Emerging Strategies To Overcome Obstacles Pomentioning

confidence: 99%

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

2017

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T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

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Section: Final Thoughts: Emerging Strategies To Overcome Obstacles Pomentioning

confidence: 99%

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

2017

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“…The use of combinatorial antigen sensing circuits, i.e., synthetic Notch, where engagement of a tissue-specific antigen by a surface receptor induces transcription of a CAR recognising a tumour-associated antigen [42][43][44] Reduction of CAR T cell affinity [45] Designing CAR T cells targeting antigens that contain tumour-specific modifications/mutations (i.e., mutated variant III of epidermal growth factor receptor; EGFRvIII) [46][47][48] Overcoming immunosuppressive tumour microenvironment (TME) CAR T cell transduction with dominant-negative transforming growth factor β receptor II (dnTGF-βRII)-a decoy receptor for immunosuppressive TGFβ produced by tumour [49] Introducing switch receptors transforming inhibitory cytokine signals into a stimulus (i.e., fusing immunosuppressive IL-4 receptor exodomain to the immunostimulatory IL-7 receptor endodomain) [50,51] Introduction of hypoxia-inducible factor 1-alpha (HIF-1α), a transcription factor stabilised in response to hypoxia, to CAR T cells resulting in increased CAR expression specifically in hypoxic TME [52] Co-expression of catalase to protect CAR T cells, as well as bystander T cells, from reactive oxygen species (ROS) in TME [53] Inhibition of adenosine receptors with their antagonists or shRNA to prevent immunosuppressive effects exerted by tumour derived adenosine [54] The remaining issue of CAR T cell therapy is the loss of expression of targeted antigen by the tumour during the treatment [39,47]. It has been suggested that only patients with homogenous antigen expression on all cancer cells should be treated with this approach to avoid recurrence.…”

Section: Possible Solution Referencesmentioning

confidence: 99%

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

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In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

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“…Thus, the introduction of a CAR while simultaneously silencing NK cell inhibitory receptors (such as NKG2A or TIM-3) may improve the efficacy of CAR-NK cells. To protect CAR-T cells from impairment by the immunosuppressive cytokine IL-4 in the tumor environment, an inverted cytokine receptor (ICR) in which the IL-4 receptor exodomain is fused to the IL-7 receptor endodomain (4/7 ICR) has been transgenically expressed in PSCA-targeted CAR-T cells [84] . This 4/7 ICR attenuated inhibition by tumor-derived IL-4 and instead promoted T cell proliferation.…”

Section: Improvements In the Anti-tumor Effects Of Car-nk Cellsmentioning

confidence: 99%

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

2017

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Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy.

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Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Cited by 218 publications

References 52 publications

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

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