Sánchez Martínez et al. generated CD123-directed second generation CAR-Delta One T cells (CAR-DOTs), which highly expressed HLA-independent Vδ1+γδ TCRs and NK cell receptors, and lacked PD-1. CD123-CAR-DOTs released antitumor effectors and chemokines in response to primary AML cells and, compared to mock-DOT controls, mediated augmented elimination of syngeneic and allogeneic AML cell lines and primary samples both in vitro and in mouse xenograft models. Daily i.p. treatment of mice with rhIL-15 completely sustained AML control over 70 days after a single infusion of CD123-CAR-DOTs and protected mice upon tumor rechallenge.
Contributed by Paula Hochman
Background: Chimeric antigen receptor (CAR)-T cells have emerged as a breakthrough treatment for relapse/refractory hematological tumors, showing impressive complete remission rates. However, around 50% of the patients relapse before 1-year post-treatment. T-cell 'fitness' is critical to prolong CAR-T persistence and activity. Allogeneic T cells from healthy donors are less dysfunctional or exhausted than autologous patient-derived T cells; in this context, Delta One T cells (DOTs), a recently described cellular product based on MHC/HLA-independent Vδ1+γδ T cells, represent a promising allogeneic platform.
Methods: Here we generated and preclinically validated, for the first time, 4-1BB-based CAR-DOTs directed against the interleukin-3α chain receptor (CD123), a target antigen widely expressed on acute myeloid leukemia (AML) blasts.
Results: CD123CAR-DOTs showed vigorous, superior to control DOTs, cytotoxicity against AML cell lines and primary samples both in vitro and in vivo, even on tumor rechallenge.
Conclusions: Our results provide the proof-of-concept for a DOT-based next-generation allogeneic CAR-T therapy for AML.
Author Info: (1) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain dsanchez@carrerasresearch.org bssantos@med
Author Info: (1) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain dsanchez@carrerasresearch.org bssantos@medicina.ulisboa.pt pmenendez@carrerasresearch.org. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). (2) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). (3) Instituto de Medicina Molecular Joo Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal. (4) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). (5) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). (6) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). (7) Instituto de Medicina Molecular Joo Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal. (8) Instituto de Medicina Molecular Joo Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal dsanchez@carrerasresearch.org bssantos@medicina.ulisboa.pt pmenendez@carrerasresearch.org. (9) Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain dsanchez@carrerasresearch.org bssantos@medicina.ulisboa.pt pmenendez@carrerasresearch.org. Red Espaola de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029). Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, Barcelona, Spain. Instituci Catalana de Recerca i Estudis Avanats (ICREA), Barcelona, Spain.
