Interleukin-23 engineering improves CAR T cell function in solid tumors

Ma, Xingcong; Shou, Peishun; Smith, Christof C.; Chen, Yuhui; Du, Hongwei; Sun, Chuang; Kren, Nancy P.; Michaud, Daniel; Ahn, Sarah; Vincent, Benjamin G.; Savoldo, Barbara; Pylayeva-Gupta, Yuliya; Zhang, Shuqun; Dotti, Gianpietro; Xu, Yingxin

doi:10.1038/s41587-019-0398-2

Cited by 181 publications

(126 citation statements)

References 67 publications

(87 reference statements)

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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%

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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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Section: Discussionmentioning

confidence: 99%

“…CAR-T cells with self-secreting cytokines, or taking use of auxiliary therapy to reverse the immunosuppressive tumor microenvironment [5,6].…”

mentioning

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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“…The success of this strategy is progressing onto human phase I clinical trials. Similar efforts have also been studied in upregulating the expression of IL-23 receptors in CAR T cells [34]. In another recent study, switchable CAR T cells have been used to target receptors expressed across several cancers but also across normal tissue.…”

Section: Solid Tumours-challenges and Developmentsmentioning

confidence: 98%

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

Alard

Butnariu

Grillo

et al. 2020

Cancers

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Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.

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“…[193][194][195] Transgenic expression of these cytokines, demonstrated in numerous preclinical studies, improves the ability of CAR T cells to expand and/or persist, resulting in improved antitumor activity. [196][197][198] Investigators have not only explored secretory but also membrane-bound versions of cytokines, which might be advantageous since they have the potential to improve cytokine activity (e.g., IL-15) and also restrict most of the cytokine's action to the genetically modified cell. 199,200 To mitigate systemic side effects of secreted cytokines, investigators have engineered T cells in which cytokine expression is controlled by the nuclear factor of activated T cells (NFAT) promoter.…”

Section: Reviewmentioning

confidence: 99%