IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype

Alizadeh, Darya; Wong, Robyn A.; Yang, Xin; Wang, Dongrui; Pecoraro, Joseph R.; Kuo, Cheng-Fu; Aguilar, Brenda; Qi, Yue; Ann, David K.; Starr, Renate; Urak, Ryan; Wang, Xiuli; Forman, Stephen J.; Brown, Christine E.

doi:10.1158/2326-6066.cir-18-0466

Cited by 312 publications

(253 citation statements)

References 53 publications

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“…Recently, Ghassemi et al reported that decreasing the time of in vitro T cell expansion increased its antitumor activity in vivo, and lower doses of CAR T cell were able to control leukemia growth (25). This report goes in line with the literature, showing that considerable T cell differentiation occur after in vitro expansion, with less differentiated, central memory-like T cells being associated with improved antitumor activity in preclinical models (26)(27)(28) and patients (29). In this proof-of-principle paper, we take this concept one step further and show that, by using SB transposon system and electroporation-based gene delivery, CAR-T cells can be generated and directly used for therapy, without the need of ex vivo activation and expansion protocols.…”

Section: Introductionsupporting

confidence: 68%

Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach

Abdo

Barros

Viegas

et al. 2019

Preprint

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AbstractRecently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 hours of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggests that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries.

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Section: Introductionsupporting

confidence: 68%

Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach

Abdo

Barros

Viegas

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Decreased mTORC1 activity due to IL15, which is used to expand CAR-T cells, also enhances CAR-T cell antitumor activity by preserving their stem cell memory phenotype. CAR-T cells that are less differentiated or less exhausted are more effective [348]. mTOR inhibition is also being exploited for improvement of vaccine strategies.…”

Section: Immunotherapymentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

171

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…In vivo CRS studies used female SCID-Beige mice injected using 310 6 Raji GFP/Luc cells, following with intraperitoneal injections of C-miR146a (5mg/kg) or PBS daily for three days before transfer of 12.510 6 mock-transfected or CD19-specific CAR-T-cells described before. 15,23,24 Human AML xenotransplants NSG-SGM3 mice were injected intravenously with 210 6 of HL-60 LUC cells and tumor progression was monitored using BLI/AmiX (Spectral Instruments). Mice were injected retro-orbitally with 10mg/kg of C-miR146a or C-scrRNA every other day.…”

Section: Cytokine Release Syndrome Modelsmentioning

confidence: 99%

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

Wang

Mann

et al. 2020

Blood

Self Cite

108

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NF-κB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-κB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell–selective NF-κB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-κB in target cells. IV injections of C-miR146a mimic to miR-146a–deficient mice prevented excessive NF-κB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell–induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-κB–related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell–targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.

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IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype

Cited by 312 publications

References 53 publications

Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach

Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

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