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Poster Display session

426 - CAR-modified natural killer cell line expressing CD47/SIRPa blockers as a combined approach for solid cancer therapy

Date

14 Dec 2018

Session

Poster Display session

Presenters

Anton Chikaev

Citation

Annals of Oncology (2018) 29 (suppl_10): x11-x16. 10.1093/annonc/mdy485

Authors

A. Chikaev, A. Gorchakov, S. Kulemzin, T. Belovezhets, D. Matvienko, O. Volkova, A. Taranin

Author affiliations

  • Laboratory Of Immunogenetics, Institute of Molecular and Cellular Biology SB RAS, 630090 - Novosibirsk/RU
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Resources

Abstract 426

Background

Despite the immense potential of CAR-T cell therapy, there are several drawbacks that limit its scope, including high manufacturing costs, on-target off-tumor toxicities, induction of cytokine release syndrome, and poor efficacy against solid tumors. In order to overcome these limitations, alternative cellular platforms could be used as carriers of CARs. Here, we modified NK cell lines to express chimeric antigen receptors. Additionally, to potentiate the antitumor activity of such CAR-NK cell lines, we co-transduced them with cassettes encoding soluble CD47/SIRPa-blocking agents. This modification should eliminate the transmission of protective “don’t eat me” signal from tumor cells to macrophages thereby enhancing cancer cell phagocytosis. We refer to this universal allogeneic antitumor platform as ECAR-NK.

Methods

We designed lentiviral constructs encoding a second-generation CAR and secreted chimeric anti-CD47 chimeric mAb, scFv, as well as the extracellular domain of CD47. NK cell lines were cotransduced with the constructs coding the CAR and one of the CD47/SIRPa blockers. Transduction efficiency was assessed by flow cytometry. In vitro cytotoxic activity of ECAR-NKs against target cells was measured by FACS and using iCelligence cell viability monitoring system. To assess the effect of CD47/SIRPa blockade on the phagocytic activity, in vitro phagocytosis assay was performed.

Results

ECAR-NK cells obtained demonstrate pronounced cytotoxicity in vitro against NK-resistant target cells. We show that ECAR-NKs produce both soluble CD47-specific scFv and chimeric mAb which were able to significantly increase phagocytic activity of macrophages in vitro. Analysis of in vivo activity of ECAR-NK cells in NOD/SCID mice bearing xenografts is in progress.

Conclusions

Our findings suggest that NK cell lines may serve as a promising platform for developing allogeneic CAR-NK cell products. We believe that coaction of CD47/SIRPa blocking and CAR-mediated cytotoxicity should result in enhanced antitumor activity and help mitigate the issue of antigen escape. Supported by the RSF grant #16-14-10237.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Russian Ministry of Science.

Funding

Russian Science Foundation.

Disclosure

All authors have declared no conflicts of interest.

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