TY - JOUR
T1 - A Bispecific γδ T-cell Engager Targeting EGFR Activates a Potent Vγ9Vδ2 T cell-Mediated Immune Response against EGFR-Expressing Tumors
AU - King, Lisa A.
AU - Toffoli, Elisa C.
AU - Veth, Myrthe
AU - Iglesias-Guimarais, Victoria
AU - Slot, Manon C.
AU - Amsen, Derk
AU - van de Ven, Rieneke
AU - Derks, Sarah
AU - Fransen, Marieke F.
AU - Tuynman, Jurriaan B.
AU - Riedl, Thilo
AU - Roovers, Rob C.
AU - Adang, Anton E. P.
AU - Ruben, Jurjen M.
AU - Parren, Paul W. H. I.
AU - de Gruijl, Tanja D.
AU - van der Vliet, Hans J.
N1 - Funding Information: This research was funded by Lava Therapeutics NV, Utrecht, The Netherlands. M. C. Slot and D. Amsen were supported by a grant from the Landsteiner Foundation for Blood Cell Research (LSBR1818). The authors would like to thank the patients for participation, Tara Muijlwijk, Tessa van Schooten, Micaela Harrasser, Milon de Jong, Publisher Copyright: © 2023 American Association for Cancer Research.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.
AB - Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.
UR - http://www.scopus.com/inward/record.url?scp=85169504511&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/2326-6066.CIR-23-0189
DO - https://doi.org/10.1158/2326-6066.CIR-23-0189
M3 - Article
C2 - 37368791
SN - 2326-6066
VL - 11
SP - 1237
EP - 1252
JO - Cancer immunology research
JF - Cancer immunology research
IS - 9
ER -