Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.
Background Magrolimab (previously named 5F9) is a first-in-class antibody targeting CD47, a macrophage immune checkpoint and "don't eat me" signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with magrolimab by inducing "eat me" signals on AML, to enhance phagocytosis. A Phase 1b trial of magrolimab+AZA was initiated in MDS/AML patients with preliminary reported results mainly from the safety cohort demonstrating high response rates in both diseases. Here we report data from the expansion cohort of this ongoing trial. Methods Results from this Phase 1b reported here focus on treatment of magrolimab+AZA in untreated intermediate to very high risk MDS patients by IPSS-R and untreated AML (induction chemotherapy ineligible) patients. A magrolimab priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was utilized to mitigate on target anemia. AZA dosing was 75mg/m2 days 1-7 on a 28 day cycle. Responses were assessed by IWG 2006 and ELN 2017 criteria for MDS and AML patients, respectively. Results 43 patients (18 MDS and 25 AML) with a median of 73 years of age were treated with magrolimab+AZA. 19% were intermediate cytogenetic risk with 63% poor risk (19% unknown). 28% of patients harbored a TP53 mutation. Magrolimab+AZA was well-tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (>15% of patients) for magrolimab+AZA were anemia (37%), neutropenia (26%), and thrombocytopenia (26%). Treatment-related febrile neutropenia occurred in only 1 (2%) patient. Only 1 patient discontinued due to an AE. 29 patients were evaluable for efficacy at time of data cut. 13/13 (100%) untreated MDS patients had an objective response with 7 patients (54%) achieving a CR, 5 (39%) with marrow CR (3/5 also had hematologic improvement (HI)), and 1 (7%) with HI alone. In AML, 11/16 (69%) had an objective response; 8/16 (50%) with CR or CRi, 2 (13%) with PR, 1 (6%) with MLFS, and 5 (31%) with stable disease. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. For those with abnormal cytogenetics at baseline, 40% and 44% of MDS and AML patients achieved a cytogenetic CR, respectively. 4/8 (50%) AML patients with CR/CRi and 2/12 (17%) MDS patients with CR or marrow CR were MRD negative by flow cytometry. 11/16 (69%) AML patients became RBC transfusion independent and 11/13 (85%) MDS patients had hematologic improvement. Given that CD47 is an LSC marker on leukemic cells, CD34+CD38- putative LSC frequency was measured by flow cytometry in the bone marrow in 5F9+AZA treated AML/MDS patients. In data available for analysis, LSCs were completely eliminated in 10/16 (63%) of AML/MDS patients who had a clinical response. Lastly, mutational analyses are ongoing to correlate subgroups with response. Interestingly, 7/8 (88%) evaluable TP53 mutant patients (5/6 AML patients [5 CR/CRi], 2/2 MDS [1 CR, 1 marrow CR]) achieved an objective response, highlighting efficacy in a poor prognosis and therapy-refractory population. No median duration response or overall survival has been reached for either MDS or AML patients with a median follow-up of 4.9 months (range 3.1 - 8.8 months) for MDS and 5.8 months (range 1.9 - 9.5 months) for AML. Conclusions Magrolimab+AZA is a novel immunotherapy regimen that blocks a key macrophage checkpoint. The combination therapy continues to be well tolerated with robust activity in MDS and AML patients with an ORR of 100% and 69%, respectively. High rates of putative LSC eradication suggest potential durable responses, with no median duration of response yet reached. Initial data indicate that 5F9+AZA may be particularly effective in TP53 mutant patients, a treatment-refractory subgroup. Expansion cohorts are ongoing (NCT03248479) with registrational studies in MDS being initiated. Additional patients, follow-up, and mutational characterization will be reported at time of presentation. Funded by Forty Seven and the California Institute for Regenerative Medicine. Disclosures Sallman: Celyad: Membership on an entity's Board of Directors or advisory committees. Lee:Bayer: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Forty Seven, Inc.: Research Funding; Tolero: Research Funding. Daver:Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; NOHLA: Research Funding; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Komrokji:Novartis: Speakers Bureau; Incyte: Consultancy; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Van Elk:Forty Seven, Inc.: Employment, Equity Ownership. Lin:Forty Seven, Inc.: Employment, Equity Ownership. Takimoto:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Chao:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Vyas:Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Abbvie: Speakers Bureau; Astellas: Speakers Bureau.
MDS is characterized by ineffective hema- IntroductionThe myelodysplastic syndromes (MDSs) are clonal stem cell disorders characterized by cytologic dysplasia and ineffective hematopoiesis. [1][2][3] Although approximately one third of patients may progress to acute leukemia, refractory cytopenias are the principal cause of morbidity and mortality in patients with MDS. 4 In fact, approximately two-thirds of patients present with lower risk disease characterized by hypercellular marrows with increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] Ineffective hematopoiesis arising from abortive maturation leads to peripheral cytopenias. Higher grade or more advanced disease categories are associated with a significant risk of leukemia transformation, with a corresponding lower apoptotic index and higher percentage of marrow blasts.Cytokines play important roles in the regulation of normal hematopoiesis, and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. Excess production of inhibitory cytokines amplifies ineffective hematopoiesis inherent to the MDS clone. Transforming growth factor- (TGF-) is a myelosuppressive cytokine that has been implicated in the hematopoietic suppression in MDS. The plasma levels of TGF- have been reported to be elevated in some [9][10][11][12][13] but not all studies [14][15][16][17] and are supported by greater TGF- immunohistochemical staining in selected studies. In addition to direct myelosuppressive effects, TGF- has also been implicated in the autocrine production of other myelosuppressive cytokines (TNF, IL-6, and IFN␥) in MDS. 18 Conflicting data may arise from technical limitations of bone marrow immunohistochemical analyses of a secreted protein as well as the biologic heterogeneity of the disease itself. In addition, plasma levels of TGF- may not be an accurate reflection of the biologic effects of this cytokine in the MDS bone marrow microenvironment. Thus we investigated the role of TGF- in MDS by direct examination of receptor signal activation to conclusively determine its role in the pathogenesis of ineffective hematopoiesis in MDS.Our previous studies have shown that signaling pathways activated by myelosuppressive cytokines can serve as therapeutic targets in low-risk MDS. We showed that interferons (IFN␣, IFN, and IFN␥), TGF-, and tumor necrosis factor ␣ (TNF␣) can all activate the p38 mitogen-activated protein kinase (MAPK) in primary human hematopoietic progenitors and that activation of p38 is required for myelosuppressive actions of these cytokines on hematopoiesis. 19,20 We subsequently confirmed overactivation of p38 MAPK in the bone marrow progenitors of low-risk MDS patients. Our data showed that inhibition of this cytokinestimulated p38 MAPK pathway partially rescues hematopoiesis in MDS progenitors. This led to a clinical trial of a p38 inhibitor, SCIO-469, in low-risk MDS; the ...
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