A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy

Article Article scientifique Article A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy eng 2024-10-18 2024-12-19 author Wenes Mathias 0000-0001-8478-8592 AGORA Cancer Research Center, 1005 Lausanne, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, 1206 Geneva, Switzerland.,MPC Therapeutics, 1206 Geneva, Switzerland. 983986 Département de médecine (DEMED) author Lepez Anouk AGORA Cancer Research Center, 1005 Lausanne, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, 1206 Geneva, Switzerland. 960733 author Arinkin Vladimir Department of Molecular and Cellular Biology, University of Geneva, 1206 Geneva, Switzerland. 980415 Département de biologie moléculaire et cellulaire (MOCEL) author Maundrell Kinsey MPC Therapeutics, 1206 Geneva, Switzerland.,Department of Molecular and Cellular Biology, University of Geneva, 1206 Geneva, Switzerland. author Barabas Orsolya Department of Molecular and Cellular Biology, University of Geneva, 1206 Geneva, Switzerland. 938832 Département de biologie moléculaire et cellulaire (MOCEL) author Simonetta Federico Center for Translational Research in Onco-Hematology, University of Geneva, 1206 Geneva, Switzerland.,Division of Hematology, Department of Oncology, Geneva University Hospitals (HUG), 1206 Geneva, Switzerland. 936876 Département de médecine (DEMED) author Dutoit Vallotton Valérie 0000-0002-3469-4237 AGORA Cancer Research Center, 1005 Lausanne, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, 1206 Geneva, Switzerland. 668630 Département de médecine (DEMED) author Romero Pedro Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.,Novigenix SA, 1066 Epalinges, Switzerland. author Martinou Jean-Claude MPC Therapeutics, 1206 Geneva, Switzerland.,Department of Molecular and Cellular Biology, University of Geneva, 1206 Geneva, Switzerland. 27293 Département de biologie moléculaire et cellulaire (MOCEL) author Migliorini Denis AGORA Cancer Research Center, 1005 Lausanne, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, 1206 Geneva, Switzerland.,Department of Oncology, Geneva University Hospitals (HUG), 1206 Geneva, Switzerland. 838158 Département de médecine (DEMED) 200897 10.1016/j.omton.2024.200897 39559715 2950-3299 PMC11570499 https://www.sciencedirect.com/science/article/pii/S2950329924001395 Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell <i>in vivo</i> expansion and long-term persistence. We previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma. Here, we use a novel MPC inhibitor, MITO-66, which robustly induces a stem cell-like memory phenotype in CD19-CAR T cells generated from healthy donors and patients with relapsed/refractory B cell malignancies. MITO-66-conditioned CAR T cells were superior in controlling human pre-B cell acute lymphoblastic leukemia in mice. Following adoptive cell transfer, MITO-66-conditioned CAR T cells maintained a memory phenotype and protected cured mice against tumor rechallenge. Furthermore, in an <i>in vivo</i> B cell leukemia stress model, CD19-CAR T cells generated in the presence of MITO-66 largely outperformed clinical-stage AKT and PI-3Kδ inhibitors. Thus, we provide compelling preclinical evidence that MPC inhibition with MITO-66 during CAR T cell manufacturing dramatically enhances their antitumor efficacy, thereby paving the way to clinical translation. CAR T cell manufacture CAR T cell therapy MT: Regular Issue Immunometabolism Memory T cell differentiation Mitochondrial pyruvate carrier Dewey 616 Dewey 570 56 Département de médecine 221 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 1310 Tumeurs cérébrales 1016 1347 Groupe Barabas 1216 Leucémie et transplantation allogénique de cellules souches hématopoïétiques 982 Molecular therapy. Oncology 32 4 83fc4d8d-419b-4e66-83b8-314ad392fe46 Article (Published version) Public Wenes_Mol_Ther_Oncol._2024.pdf 2939810 application/pdf CC BY-4.0 d4962021fdc0d22bc24d24636a10423df6593961a26102496bd068898f79c04a f03a34a0-97c9-4b44-9fe3-2a941806ec5e Supplemental data Public 1-s2.0-S2950329924001395-mmc1.pdf 549282 application/pdf 3288bac97d48e2e16cd1a4f4a3639d58cd9dad029942657d9fca916d5c3a0365 Vignette Public 1-s2.0-S2950329924001395-fx1_lrg.jpg 155775 image/png openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

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Arinkin, Vladimir