TIGIT blockade in the context of BCMA-CART cell therapy does not augment efficacy in a multiple myeloma mouse model

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• BCMA-directed CAR-T therapies offer promise for multiple myeloma (MM) but face challenges with patient relapse.
• T cell exhaustion, marked by increased TIGIT expression, is a key resistance mechanism identified in CAR-T cells.
• ARI0002h is an academic CAR-T therapy developed for MM.

Purpose of the Study:

• To investigate the impact of blocking TIGIT on the efficacy of ARI0002h CAR-T cells.
• To evaluate three distinct strategies for TIGIT blockade in preclinical MM models.

Main Methods:

• Three TIGIT blockade strategies were employed: anti-TIGIT antibody addition, a 4th generation CAR-T (ARITIGIT) secreting a soluble TIGIT-blocking scFv, and TIGIT knock-out (KO) using CRISPR/Cas9.
• Each strategy was assessed through in vitro assays and in vivo studies using murine models.
• In vivo models included standard tumor challenge and a relapse model with secondary tumor cell infusion.

Main Results:

• Addition of anti-TIGIT antibody improved in vitro cytotoxicity but did not enhance in vivo survival.
• The ARITIGIT 4th generation CAR-T showed no survival benefit, although a trend was observed in a relapse model.
• TIGIT knock-out ARI0002h (KO-ARI0002h) demonstrated similar in vitro activity to ARI0002h, with a significant but not superior survival benefit in an in vivo stress model.

Conclusions:

• This study did not demonstrate a significant therapeutic benefit of TIGIT blockade on ARI0002h CAR-T cell efficacy across three different approaches.
• The findings suggest that targeting a single immune checkpoint like TIGIT may be insufficient to overcome resistance mechanisms in BCMA-directed CAR-T therapy for MM.
• Further research may be needed to explore combination strategies or alternative targets to enhance CAR-T therapy effectiveness in relapsed MM.