Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.
Jin Ng, Yue You, Tina Zhang et al.· Cancer Cell· 0 citations
Current cell and gene therapies lack clinically practical mechanisms to selectively promote or suppress therapeutic cells in vivo, a limitation that is particularly acute in patients requiring ongoing immunosuppression. This includes gene therapy for immune dysregulation syndromes, and antigen-specific or chimeric antigen receptor (CAR) T-cell therapy for patients requiring immunosuppression (e.g., transplant recipients), where both pathogenic and therapeutic cells may be suppressed. Here, we develop a multiplex prime-editing platform that converts commonly used immunosuppressive drugs into tools for in vivo control of T-cell therapies via defined, pathway-specific drug resistance. Focusing initially on gene therapy, prime editing efficiently edited loci of multiple pathogenic variants associated with immune dysregulation in primary human T-cells and corrected the HAVCR2 driver mutation in T-cells from multiple patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Comprehensive genomic, transcriptional, immunophenotypic, and clonal analyses demonstrated minimal off-target perturbation. Multiplexed gene correction and drug-resistance editing of T-cells from patients with SPTCL enabled selective in vivo expansion of corrected cells under immunosuppressive pressure in humanized mouse models and exhibited retained sensitivity to alternative agents permitting rapid in vivo suppression. Extending this approach, prime edited, drug-resistant antigen-specific and CAR T-cells retained effector function despite pharmacologic immunosuppression, demonstrating the generalizability of this platform to diverse cellular therapies. Together, these findings establish multiplex prime editing as a promising preclinical framework for generating drug-controllable T-cell therapies, enabling selective in vivo modulation in settings where immunosuppression cannot be withdrawn.
E. Bandala-Sanchez, Emma V. Petley, K. Ramsay et al.· Blood· 0 citations
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