Inducible localized delivery of an anti-PD-1 scFv enhances anti-tumor activity of ROR1 CAR-T cells in TNBC.
Background: Chimeric antigen receptor (CAR)-T cells can induce powerful immune responses in patients with hematological malignancies but have had limited success against solid tumors. This is in part due to the immunosuppressive tumor microenvironment (TME) which limits the activity of tumor-infiltr...
| Publicado en: | Breast Cancer Research Vol. 24; no. 1; pp. 1 - 11 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
6/3/2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=157262100&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 157262100 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 6/3/2022 vid: 24 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 157262100 157262100 NLM35659040 157262100 10.1186/s13058-022-01531-1 NLM35659040 157262100 ppf: 1 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Inducible localized delivery of an anti-PD-1 scFv enhances anti-tumor activity of ROR1 CAR-T cells in TNBC. aug: au: Harrasser, Micaela Gohil, Satyen Harish Lau, Hiu Della Peruta, Marco Muczynski, Vincent Patel, Dominic Miranda, Elena Grigoriadis, Kristiana Grigoriadis, Anita Granger, David Evans, Rachel Nathwani, Amit Chunilal affil: Department of Academic Haematology, University College London Cancer Institute, WC1E 6DD, London, UK sug: subj: Breast Neoplasms Metabolism Breast Neoplasms Therapy Breast Neoplasms Immunoglobulins, Fab Metabolism Immunoglobulins, Fab Transferases Metabolism T Lymphocytes Mice Cell Line, Tumor Cell Physiology Animals Transferases Scales ab: Background: Chimeric antigen receptor (CAR)-T cells can induce powerful immune responses in patients with hematological malignancies but have had limited success against solid tumors. This is in part due to the immunosuppressive tumor microenvironment (TME) which limits the activity of tumor-infiltrating lymphocytes (TILs) including CAR-T cells. We have developed a next-generation armored CAR (F i-CAR) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is expressed at high levels in a range of aggressive tumors including poorly prognostic triple-negative breast cancer (TNBC). The F i-CAR-T is designed to release an anti-PD-1 checkpoint inhibitor upon CAR-T cell activation within the TME, facilitating activation of CAR-T cells and TILs while limiting toxicity.Methods: To bolster potency, we developed a F i-CAR construct capable of IL-2-mediated, NFAT-induced secretion of anti-PD-1 single-chain variable fragments (scFv) within the tumor microenvironment, following ROR1-mediated activation. Cytotoxic responses against TNBC cell lines as well as levels and binding functionality of released payload were analyzed in vitro by ELISA and flow cytometry. In vivo assessment of potency of F i-CAR-T cells was performed in a TNBC NSG mouse model.Results: F i-CAR-T cells released measurable levels of anti-PD-1 payload with 5 h of binding to ROR1 on tumor and enhanced the cytotoxic effects at challenging 1:10 E:T ratios. Treatment of established PDL1 + TNBC xenograft model with F i-CAR-T cells resulted in significant abrogation in tumor growth and improved survival of mice (71 days), compared to non-armored CAR cells targeting ROR1 (F CAR-T) alone (49 days) or in combination with systemically administered anti-PD-1 antibody (57 days). Crucially, a threefold increase in tumor-infiltrating T cells was observed with F i-CAR-T cells and was associated with increased expression of genes related to cytotoxicity, migration and proliferation.Conclusions: Our next-generation of ROR1-targeting inducible armored CAR platform enables the release of an immune stimulating payload only in the presence of target tumor cells, enhancing the therapeutic activity of the CAR-T cells. This technology provided a significant survival advantage in TNBC xenograft models. This coupled with its potential safety attributes merits further clinical evaluation of this approach in TNBC patients. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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