Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering

Derek Lee; Zachary Spencer Dunn; Wenbin Guo; Carl J Rosenthal; Natalie E Penn; Yanqi Yu; Kuangyi Zhou; Zhe Li; Feiyang Ma; Miao Li; Tsun-Ching Song; Xinjian Cen; Yan-Ruide Li; Jin J Zhou; Matteo Pellegrini; Pin Wang; Lili Yang

doi:10.1038/s41467-023-42619-2

Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering

Nat Commun. 2023 Nov 8;14(1):6942. doi: 10.1038/s41467-023-42619-2.

Authors

Derek Lee^#¹, Zachary Spencer Dunn^#^{1

2}, Wenbin Guo^#³, Carl J Rosenthal¹, Natalie E Penn¹, Yanqi Yu¹, Kuangyi Zhou¹, Zhe Li¹, Feiyang Ma⁴, Miao Li¹, Tsun-Ching Song¹, Xinjian Cen¹, Yan-Ruide Li¹, Jin J Zhou⁵, Matteo Pellegrini^{3

4

6}, Pin Wang², Lili Yang^{7

8

9

10}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA.
² Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
³ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
⁴ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, USA.
⁵ Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA.
⁶ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA.
⁷ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. [email protected].
⁸ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. [email protected].
⁹ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. [email protected].
¹⁰ Molecular Biology Institute, University of California, Los Angeles, CA, USA. [email protected].

^# Contributed equally.

Abstract

Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16^Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16^Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16^Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biomarkers
Female
Hematopoietic Stem Cell Transplantation*
Humans
Interleukin-15 / genetics
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / therapy

Substances

Interleukin-15
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding