Type: Oral
Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Determinants of Venetoclax Resistance and Response
Hematology Disease Topics & Pathways:
Combination therapy, Research, MDS, Translational Research, Chronic Myeloid Malignancies, Diseases, Immunology, Myeloid Malignancies, Biological Processes, Technology and Procedures, Omics technologies
To explore the contribution of T-cell phenotypic states to venetoclax-induced responses and assess clonality and antigen recognition prediction, we performed transcriptomic and T-cell receptor (TCR) analyses using different single-cell multi-omics platforms. Single-cell proteo-genomic analyses (with a panel of 32 antibodies) of CD3+ cells isolated at different times during venetoclax therapy (15 samples from 5 patients; 34,229 sequenced T cells) allowed us to develop specific transcriptomic signatures for each T-cell subtype, which we applied to interrogate a larger cohort of sequential samples analyzed by scRNA- and/or scTCR-sequencing analyses (64 CD3+ samples from 12 patients; 124,871 sequenced T cells). This comprehensive approach confirmed the significant expansion of SCM CD4+ T cells at treatment response and the reduction of these cells at disease relapse, previously observed by flow cytometry analysis. SCM CD4+ T cells had significantly upregulated gene expression programs associated with cytokine secretion and cytotoxicity at disease response but expressed increased levels of exhaustion-related genes at disease relapse.
MDS patients whose disease responded to venetoclax-based therapy showed a higher count of CD4+ EM T-cell clonotypes and greater T-cell diversity at baseline, whereas a reduction in these clonotypes during therapy predicted disease progression. SCM and EM CD4+ T cells had the highest rates of TCR sharing, which suggests a close interplay between these subsets. Cytokine secretion assays showed that compared with naïve and CM CD4+ T cells, SCM CD4+ T cells cocultured with MDS cells secreted higher levels of IFN-γ, TNF-α, and granzyme B (GZMB), a cytokine profile resembling that of EM and TE cells. Upon tumoral challenge, venetoclax also significantly increased IFN-γ, TNF-α, and GZMB levels in SCM and EM CD4+ T cells.
Our study demonstrates that a subset of CD4+ T cells with SCM features contributes to the outcomes of MDS patients enrolled in trials of venetoclax-based therapy. SCM cells are transcriptionally and functionally similar to EM and TE cells and undergo the greatest improvement in cytotoxic capabilities and pro-inflammatory cytokine secretion upon venetoclax exposure. Thus, adoptive immunotherapy strategies have a potential role in enhancing venetoclax efficacy and preventing immune-mediated venetoclax resistance.
Disclosures: Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Garcia-Manero: Onconova: Research Funding; Helsinn: Research Funding; Astex: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Curis: Research Funding; Merck: Research Funding; Novartis: Research Funding; Aprea: Research Funding; Forty Seven: Research Funding; H3 Biomedicine: Research Funding; Astex: Other: Personal fees; Bristol Myers Squibb: Other: Personal fees, Research Funding; Janssen: Research Funding; Amphivena: Research Funding; Helsinn: Other: Personal fees; Genentech: Other: Personal fees. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy.