Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects

Zhou, Jianxia; Lin, Jin; Wang, Fuping; Zhang, Yuan; Liu, Bing; Zhao, Tongbiao

doi:10.1007/s13238-019-0643-y

Cited by 95 publications

(88 citation statements)

References 12 publications

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“…Cha et al, 2010), promote a T CM cell phenotype characterized by longer telomeres, and elevate T cell persistence and antitumor efficacy (Melchionda et al, 2005;Gattinoni et al, 2005;Zhou et al, 2005;Klebanoff et al, 2004;Le et al, 2009). Similarly, it has been shown that IL-7 and IL-15 enable enhanced human CAR-T cell effector function upon antigen recognition (Xu et al, 2014;Zhou et al, 2019) and that exogenous IL-15 can expand anti-CD19 CAR-T cells in treated patients by up to 180-fold (Ramanayake et al, 2015). Contradictory reports of lower murine T cell function in vitro following culture in IL-7/IL-15 versus IL-2 alone are presumably due to the method of T cell stimulation used, differences in the concentration of IL-2 used, and the duration of expansion (Cha et al, 2010;Gattinoni et al, 2005;Mueller et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression

Lanitis

Rota

Kosti

et al. 2020

Journal of Experimental Medicine

105

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Limited clinical benefit has been demonstrated for chimeric antigen receptor (CAR) therapy of solid tumors, but coengineering strategies to generate so-called fourth-generation (4G) CAR-T cells are advancing toward overcoming barriers in the tumor microenvironment (TME) for improved responses. In large part due to technical challenges, there are relatively few preclinical CAR therapy studies in immunocompetent, syngeneic tumor-bearing mice. Here, we describe optimized methods for the efficient retroviral transduction and expansion of murine T lymphocytes of a predominantly central memory T cell (TCM cell) phenotype. We present a bicistronic retroviral vector encoding both a tumor vasculature–targeted CAR and murine interleukin-15 (mIL-15), conferring enhanced effector functions, engraftment, tumor control, and TME reprogramming, including NK cell activation and reduced presence of M2 macrophages. The 4G-CAR-T cells coexpressing mIL-15 were further characterized by up-regulation of the antiapoptotic marker Bcl-2 and lower cell-surface expression of the inhibitory receptor PD-1. Overall, this work introduces robust tools for the development and evaluation of 4G-CAR-T cells in immunocompetent mice, an important step toward the acceleration of effective therapies reaching the clinic.

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Section: Discussionmentioning

confidence: 97%

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression

Lanitis

Rota

Kosti

et al. 2020

Journal of Experimental Medicine

105

View full text Add to dashboard Cite

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“…IL-7, IL-15, and IL-21 belong to the common γ chain cytokine family [73]. They promote the generation of the stem cell-like memory T cell (Tscm) phenotype, which is associated with increased expansion and persistence [74][75][76][77][78]. Recently, 7 × 19 CAR T cells, which are engineered to co-express IL-7 and CCL19, prolong persistence compared with conventional CAR T cells, resulting in complete control of tumor progression [79].…”

Section: Transgenic Cytokine Expressionmentioning

confidence: 99%

Gene modification strategies for next-generation CAR T cells against solid cancers

et al. 2020

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Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.

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“…Apart from the activation of CD3 and CD28 pathway, the stimulation from interleukins have long been regarded as the third necessary signal for T cell homeostasis [17]. Considering the supplement of interleukins led to the prolonged survival of T cells during the in-vitro T cell cultivation, in recent years there were a series of attempts to provide tumor-in ltrating CAR-T with different kinds of interleukins to prolong the persistence and therapeutic e cacy of the CAR-T against solid tumor [6,18]. In this research, we constructed an IL7 carrying oncolytic virus and a B7H3-targeting CAR-T therapy, and veri ed the promotive e cacy of oAD-IL7 for B7H3-CART in an orthotopic glioblastoma model.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-7 loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma

Huang

Zheng

Zhang

et al. 2020

Preprint

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Background: T cell with chimeric antigen receptors (CAR-T) has presented remarkable efficacy for blood cancer as an emerging immunotherapy. However, for solid tumors, the therapeutic efficacy is much impaired due to the lack of infiltration and persistence of CAR-T in tumor tissue. Thus, we constructed an interleukin-7-loaded oncolytic adenovirus and combined the use of oncolytic virus and CAR-T to improve the therapeutic outcome.Methods: We constructed an interleukin-7 loaded oncolytic adenovirus (oAD-IL7) and a B7H3-targeted CAR-T, and explored the efficacy of the single use of oAD-IL7, B7H3-CART or the combined therapy for glioblastoma in vitro and in vivo. The improved CAR-T anti-tumor efficacy was evaluated according to the proliferation, survival, persistence, exhaustion of T cells, and tumor regression.Results: Constructed oAD-IL7 and B7H3-CART presented moderate cytotoxicity during in vitro study, but failed to induce a thorough and persistent anti-tumor therapeutic efficacy in vivo. The combination of oAD-IL7 and B7H3-CART in vitro resulted in enhanced T cell proliferation and reduced T cell apoptosis. The joint efficacy was further confirmed using tumor-bearing xenograft mice. During in vivo study, the mice treated with both oAD-IL7 and B7H3-CART showed prolonged survival and reduced tumor burden. According to the ex vivo study, oAD-IL7 improved the proliferation and persistence of tumor-infiltrating B7H3-CART, but failed to reverse the exhaustion.Conclusions: Our results indicated that oAD-IL7 is a promising auxiliary therapy to improve the therapeutic efficacy of B7H3-CART in glioblastoma by providing the activating signals for tumor-infiltrating T cells. Our results also lay the basis for the future clinical trials for the combination of IL7-loaded oncolytic adenovirus and CAR-T therapy for glioblastoma.

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Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects

Cited by 95 publications

References 12 publications

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression

Gene modification strategies for next-generation CAR T cells against solid cancers

Interleukin-7 loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma

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