Delfanti et al. transduced CD1d-restricted iNKT cells derived from a iVα14-Jα18 TCR Tg mouse with a second TCR specific for an MHC-I restricted surrogate TAA (OVA) and selected dual-reactive TCR-iNKT effectors. Tumor infiltration and antitumor activity of adoptively transferred TCR-iNKT cells in mice bearing tumors expressing the cognate antigen surpassed that of transferred non-transduced iNKT cells or CD8+ T cells engineered to express the same TCR. In the TME, TCR-iNKT cells modulated myeloid cells toward an inflammatory phenotype and killed tumor cells. Efficacy was boosted by microparticulate delivery of α-galactosyl ceramide agonist.
Contributed by Paula Hochman
ABSTRACT: Adoptive immunotherapy with T cells engineered with tumor-specific T cell receptors (TCRs) holds promise for cancer treatment. However, suppressive cues generated in the tumor microenvironment (TME) can hinder the efficacy of these therapies, prompting the search for strategies to overcome these detrimental conditions and improve cellular therapeutic approaches. CD1d-restricted invariant natural killer T (iNKT) cells actively participate in tumor immunosurveillance by restricting suppressive myeloid populations in the TME. Here, we showed that harnessing iNKT cells with a second TCR specific for a tumor-associated peptide generated bispecific effectors for CD1d- and major histocompatibility complex (MHC)-restricted antigens in vitro. Upon in vivo transfer, TCR-engineered iNKT (TCR-iNKT) cells showed the highest efficacy in restraining the progression of multiple tumors that expressed the cognate antigen compared with nontransduced iNKT cells or CD8+ T cells engineered with the same TCR. TCR-iNKT cells achieved robust cancer control by simultaneously modulating intratumoral suppressive myeloid populations and killing malignant cells. This dual antitumor function was further enhanced when the iNKT cell agonist α-galactosyl ceramide (α-GalCer) was administered as a therapeutic booster through a platform that ensured controlled delivery at the tumor site, named multistage vector (MSV). These preclinical results support the combination of tumor-redirected TCR-iNKT cells and local α-GalCer boosting as a potential therapy for patients with cancer.
Author Info: (1) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (2) Experimental Immunolog
Author Info: (1) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (2) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (3) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (4) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (5) IDSIA-SUPSI/USI, CH-6928 Manno, Switzerland. (6) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (7) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (8) Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan 20132, Italy. (9) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (10) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (11) BioNanoMedicine Center NANOMIB, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, Italy. (12) BioNanoMedicine Center NANOMIB, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, Italy. (13) Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. (14) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy. (15) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20132, Italy.
