TCR-engineered iNKT cells induce robust antitumor response by dual targeting cancer and suppressive myeloid cells

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Adoptive immunotherapy using T cells engineered with tumor-specific T cell receptors (TCRs) shows promise for cancer treatment.
• The tumor microenvironment (TME) often presents suppressive cues that limit the efficacy of cellular therapies.
• Invariant natural killer T (iNKT) cells possess inherent tumor immunosurveillance capabilities, including the suppression of myeloid-derived suppressor cells.

Purpose of the Study:

• To engineer invariant natural killer T (iNKT) cells with a second TCR to create bispecific effectors targeting both CD1d-restricted and MHC-restricted antigens.
• To evaluate the in vivo efficacy of these engineered iNKT (TCR-iNKT) cells in controlling tumor progression.
• To investigate the synergistic effect of combining TCR-iNKT cells with α-galactosyl ceramide (α-GalCer) for enhanced cancer therapy.

Main Methods:

• Generation of bispecific TCR-iNKT cells capable of recognizing both CD1d-restricted and MHC-restricted antigens.
• In vivo assessment of TCR-iNKT cell efficacy against multiple tumor models expressing the target antigen.
• Evaluation of the impact of TCR-iNKT cells on suppressive myeloid populations within the TME.
• Combination therapy study involving TCR-iNKT cells and locally delivered α-GalCer using a multistage vector (MSV) platform.

Main Results:

• TCR-iNKT cells demonstrated superior efficacy in restraining tumor progression compared to non-transduced iNKT cells or CD8+ T cells engineered with the same TCR.
• TCR-iNKT cells exhibited a dual mechanism of action, simultaneously reducing intratumoral suppressive myeloid populations and directly killing malignant cells.
• Co-administration of α-GalCer via the MSV platform significantly enhanced the antitumor function of TCR-iNKT cells.

Conclusions:

• TCR-engineered iNKT cells represent a potent cellular therapy strategy for cancer, leveraging dual antitumor mechanisms.
• The combination of tumor-redirected TCR-iNKT cells and localized α-GalCer delivery offers a promising therapeutic approach for cancer patients.
• Further preclinical development of this combined strategy is warranted for clinical translation.