Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells

TY - JOUR

T1 - Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells

AU - Obajdin, Jana

AU - Larcombe-Young, Daniel

AU - Glover, Maya

AU - Kausar, Fahima

AU - Hull, Caroline M.

AU - Flaherty, Katie R.

AU - Tan, Ge

AU - Beatson, Richard E.

AU - Dunbar, Phoebe

AU - Mazza, Roberta

AU - Bove, Camilla

AU - Taylor, Chelsea

AU - Bille, Andrea

AU - Spillane, Katelyn M.

AU - Cozzetto, Domenico

AU - Vigilante, Alessandra

AU - Schurich, Anna

AU - Davies, David M.

AU - Maher, John

N1 - Publisher Copyright: © 2024 The Author(s)

PY - 2024/11/19

Y1 - 2024/11/19

N2 - NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain. NKG2D/Dap10-12 T cells elicit compelling efficacy, eradicating or controlling NKG2DL-expressing tumors in several established xenograft models. Importantly, durable responses, long-term survival, and rejection of tumor re-challenge are reproducibly achieved. Efficacy is markedly superior to a clinical stage CAR analog, comprising an NKG2D-CD3ζ fusion. Structure-function analysis using an extended CAR panel demonstrates that potency is dependent on membrane proximity of signaling units, high NKG2D cell surface expression, adaptor structure, provision of exogenous Dap10, and inclusion of one rather than three immune tyrosine activation motifs per signaling unit. Potent therapeutic impact of NKG2D/Dap10-12 T cells is also underpinned by enhanced oxidative phosphorylation, reduced senescence, and transcriptomic re-programming for increased ribosomal biogenesis.

AB - NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain. NKG2D/Dap10-12 T cells elicit compelling efficacy, eradicating or controlling NKG2DL-expressing tumors in several established xenograft models. Importantly, durable responses, long-term survival, and rejection of tumor re-challenge are reproducibly achieved. Efficacy is markedly superior to a clinical stage CAR analog, comprising an NKG2D-CD3ζ fusion. Structure-function analysis using an extended CAR panel demonstrates that potency is dependent on membrane proximity of signaling units, high NKG2D cell surface expression, adaptor structure, provision of exogenous Dap10, and inclusion of one rather than three immune tyrosine activation motifs per signaling unit. Potent therapeutic impact of NKG2D/Dap10-12 T cells is also underpinned by enhanced oxidative phosphorylation, reduced senescence, and transcriptomic re-programming for increased ribosomal biogenesis.

KW - adaptor

KW - chimeric antigen receptor

KW - Dap10

KW - Dap12

KW - NKG2D

UR - https://www.scopus.com/pages/publications/85209126297

U2 - 10.1016/j.xcrm.2024.101827

DO - 10.1016/j.xcrm.2024.101827

M3 - Article

AN - SCOPUS:85209126297

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 11

M1 - 101827

ER -