Dataset Information

MiNK-215: Allogeneic FAP-CAR-IL15 iNKT therapy remodels tumor stroma to enhance anti-tumor immunity

ABSTRACT: Cellular immunotherapies show remarkable efficacy against hematological malignancies; but face challenges against solid tumors largely attributed to the lack of tumor-specific antigens and immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), expressing fibroblast activation protein (FAP) are key contributors in shaping this immunosuppressive landscape, yet effective targeting strategies remain an ongoing challenge. Here, we describe MiNK-215, a novel allogeneic human invariant natural killer T (iNKT) cell therapy, engineered to express a FAP-targeting chimeric antigen receptor (CAR) and secrete interleukin-15 (IL-15) to remodel the TME and enhance anti-tumor activity. MiNK-215 modulated multifunctional immune responses by enhancing T cell responsiveness, dendritic cell activation, M1 macrophage polarization, and tumor killing. In a lung tumor mouse model, MiNK-215 depleted FAP+ CAFs, enhanced antigen-specific T cell infiltration, and promoted durable anti-tumor immunity without off-target toxicity. These findings extended to human organoid models of treatment-refractory Microsatellite Stable Colorectal Cancer (MSS-CRC) liver metastases, establishing FAP-CAR iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294754 | GEO | 2025/04/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Ionizing radiation (IR) is a double-edge sword for immunotherapy as it may cause both immunosuppressive and immunostimulatory effects. The interactions of IR with the tumor microenvironment (TME) is a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of CAFs in many cancer types and its presence is associated with poor immune response to immune checkpoint blockade in patients. We hypothesize that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic FAP-4-1BBL bispecific antibody fusion protein could enhance the immune-mediated antitumoral effect of these treatments given in combination. Methods: Murine transplantable TS/A tumor cells line was used to investigate increases in FAP expression in tumors after irradiation by IHQ and RT-PCR. We treated bilateral tumor-bearing mice in which only one of the lesions was locally irradiated (2 × 6 Gy) given alone or in combination with a systemic administration of the FAP-4-1BBL bispecific construct. Tumor sizes were followed over time and in the cellular composition microenvironment (TME) was assessed by immunochemistry and multiplex tissue immunofluorescence. Selective depletions of immune cell populations were used to delineate the immune system requirements for efficacy. Antibody of interest was labeled and tracked its distribution by CT. Colorectal carcinoma samples were also validated. Results: Irradiation of TS/A+CAF tumors showed clear increases of FAP expression levels after local irradiation. The suboptimal radiotherapy regimen in combination with FAP targeted 4-1BBL worked to attain primary tumor control as well as partial abscopal effect. Immune landscape analysis showed an effector and proinflammatory phenotype with an increased infiltration of immune cells. The antitumoral mechanism relied on CD8+ T cells, IFN-I, IFN-γ and CD137 expression. Biodistribution studies of bispecific antibody performed indicated enhanced tumor targeting after tumor irradiation. Human sample results confirmed enhanced immune infiltration and FAP expression after radiotherapy treatment. Conclusion: Our data provides a proof- of- concept and mechanistic insights pertaining the therapeutic efficacy of bispecific FAP-41BBL combined with local radiotherapy.

Dataset Information

MiNK-215: Allogeneic FAP-CAR-IL15 iNKT therapy remodels tumor stroma to enhance anti-tumor immunity

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets