Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesyla...Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.展开更多
基金funded by the Sichuan Province“14th Five-Year Plan”Life and Health Major Science and Technology Project(2022ZDZX0027)Key Project of Chengdu(2021-YF08-00002-GX)+3 种基金the Incubation Program for Clinical Trials of West China Hospital(19HXFH030)the National Natural Science Foundation of China(82104211)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23020,ZYJC21007)National Key Research and Development Program of China(2022YFC2502600,2022YFC2502603).
文摘Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.
