Novel NK cell-like phenotype expressing CCR5 and its ligands elicits tumor-specific acquired immunity to carcinomatous peritonitis via host NK-derived IFN-{gamma}

Background
Natural killer (NK) cell-based immunotherapies remain largely ineffective against solid tumors and strategies that directly enhance NK cell cytotoxicity often fail to establish durable tumor control. To address this limitation, we developed…

Novel NK cell-like phenotype expressing CCR5 and its ligands elicits tumor-specific acquired immunity to carcinomatous peritonitis via host NK-derived IFN-{gamma}

Background
Natural killer (NK) cell-based immunotherapies remain largely ineffective against solid tumors and strategies that directly enhance NK cell cytotoxicity often fail to establish durable tumor control. To address this limitation, we developed…

RASA2 deletion rescues immune synapse dysfunction, enhancing CAR T cell efficacy against DMGs

Background
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated safety and modest efficacy against diffuse midline gliomas (DMGs), a highly aggressive pediatric brain tumor. However, mechanisms of CAR T-cell resistance in DMG settings remai…

IL-12-secreting CAR-T cells reprogram the tumor microenvironment and improve efficacy against heterogeneous models of glioblastoma

Background
Glioblastoma (GBM) remains uniformly lethal due to pronounced intratumoral heterogeneity and a highly immunosuppressive microenvironment that limits the efficacy of targeted therapies.

Methods
We engineered chimeric antigen receptor (CAR) …

Phase I trial of locoregional administration of autologous tumor-infiltrating lymphocytes in patients with uveal melanoma and liver metastases (the HAITILS trial)

Background
Uveal melanoma is a rare melanoma subtype characterized by a liver-dominant pattern of metastasis which is associated with a lack of durable responses to immunotherapies. Adoptive cell transfer of autologous tumor-infiltrating lymphocytes (…

CD79A/CD40 intracellular domain uses a 4-1BB-like metabolic pathway driven by cholesterol biosynthesis

Background
Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has transformed the treatment of hematologic malignancies. The costimulatory domain (CSD) of CAR constructs plays a crucial role in determining T cell metabolism, persistence, an…

Targeting endosomal trafficking-mediated antigen escape to resensitize myeloma to CAR-T therapy

Background
Antigen escape is one of the leading causes of relapse following chimeric antigen receptor (CAR)-T therapy, particularly in multiple myeloma. A critical gap persists in understanding the tumor-intrinsic pathways that trigger antigen loss, i…

Enhanced antitumoral activity of the academic CAR-T ARI0002h against normal and low BCMA-expressing myeloma cells after incorporating a transmembrane CD28 domain

Background
B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin’s…

Effective allogeneic natural killer cell therapy for pancreatic adenocarcinoma avails conserved activating receptors and evades HLA I-driven inhibition

Background
At diagnosis, ~80% of pancreatic ductal adenocarcinomas (PDAC) have metastasized. Relapse is thus common even among patients who undergo surgical resection, the only curative option. PDAC progresses rapidly, and existing immunotherapies hav…

Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2R{alpha}

Background
Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T p…

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