Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.
BACKGROUND No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. METHODS Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). RESULTS For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P=.02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P=.03). There was one case of Common Terminology Criteria for Adverse Events grade ≥ 3 RT-related toxicity (acute grade 3 pancytopenia). CONCLUSIONS In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques.
3086 Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.
Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien–Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk.
The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B-cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of Bcell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development.
Background: PRMT5 is overexpressed in certain myeloid malignancies and catalyzes symmetric arginine dimethylation of protein substrates that regulate expression of genes associated with disease pathogenesis (Pastore et al. Cancer Discov. 2020). PRT543 is a potent, selective, oral PRMT5 inhibitor with preclinical antitumor activity in acute myeloid leukemia and myeloproliferative neoplasm models (Bhagwat AACR 2020). An open-label phase 1 study of PRT543 in unselected patients (pts) with advanced solid tumors and hematologic malignancies (NCT03886831) is ongoing. Dose escalation results from pts with myeloid malignancies are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy per International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) and myeloproliferative neoplasm of PRT543 administered at varying schedules beginning with twice weekly (BIW) and increasing to once daily (QD) with doses ranging from 5 to 40 mg in 28-day cycles. Dose escalation followed a modified 3+3 design, allowing for accelerated titration at lower doses. Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 16 July 2021, 23 unselected pts (12 with myelofibrosis [MF] and 11 with MDS) with disease refractory to established therapies had enrolled (5 pts were dosed BIW, 6 pts 3 times per week [TIW], 5 pts 5 times per week, and 7 pts QD). The median number of prior lines of systemic therapies was 2 (range, 0 to 6). Ten of 12 MF pts had prior exposure to ruxolitinib. Median platelet counts at baseline were 176,500/µL for MF pts and 52,000/µL for MDS pts. Three of 23 pts (13%) experienced dose limiting toxicity (DLT) of thrombocytopenia, with a single occurrence at each of 3 different doses/schedules (40 mg TIW, 35 mg 5 times per week, and 20 mg QD). No other DLTs were reported. The most frequent treatment-related adverse events (TRAEs), any grade, in all regimens were nausea (n=5, 22%), thrombocytopenia (n=5, 22%), anemia (n=4, 17%), diarrhea (n=4, 17%), and fatigue (n=3, 13%). Grade ≥3 TRAEs in all regimens were limited to anemia (n=4, 17%) and thrombocytopenia (n=4, 17%). Cytopenias were reversible and managed with dose modifications. Eighteen pts discontinued treatment, primarily due to disease progression or investigator decision. One pt was discontinued due to an AE (performance status decreased/weakness). PRT543 demonstrated dose-dependent increases of C max (nM) and AUC (nM.hr). At the expansion dose (35 mg 5 times per week), half-life (T ½) was 14 hrs, and plasma drug exposures (C max, 1988 nM; AUC, 19813 nM.hr) exceeded those required for preclinical efficacy. Serum sDMA decreased in a dose-dependent manner reaching 58% reduction with the expansion dose. Increased intron retention in select transcripts was observed in peripheral blood mononuclear cells at the expansion dose. Reductions in inflammatory serum markers, including C-reactive protein and serum amyloid A and cytokines interleukin (IL)-6 and IL-8 were observed. Improvement in individual symptoms such as night sweats, fever and pruritis were noted. Of the 5 MF patients with spliceosome mutations, 1 MF pt (SF3B1) with anemia and transfusion history (8 units over the 121 days prior to baseline) experienced a substantial improvement in anemia (hemoglobin increase from 6.0 to ≥11.1 g/dL). This pt has been transfusion-free for over 300 days and remains on study. Three pts with MF exhibited stable disease per IWG for at least 1 year, with 1 MF pt demonstrating improvement in bone marrow reticulin fibrosis (+2-3 to +1-2). Conclusions: PRT543 was well tolerated with a favorable safety profile. Dose-dependent inhibition of target engagement and functional activity of PRMT5 were observed. PRT543 treatment demonstrated reduction in inflammatory markers and improvement in symptoms and anemia in select patients. Prolonged stable disease per IWG was observed in several pts with refractory MF. PRT543 is currently being evaluated as monotherapy in pts with at least one spliceosome mutation (MF and MDS pts with anemia and pts with high-risk myeloid malignancies) and in combination with ruxolitinib in MF patients demonstrating a suboptimal response to ruxolitinib. Disclosures Patel: Vigeo: Research Funding; Portola Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; AstraZeneca: Research Funding; TopAlliance: Research Funding; Tesaro: Research Funding; Vedanta: Research Funding; Curis: Research Funding; Ciclomed: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Lycera: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bicycle Therapeutics: Research Funding; Hutchinson MediPharma: Research Funding; Ignyta: Research Funding; Taiho: Research Funding; Loxo Oncology: Research Funding; Millennium Pharmaceuticals: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; H3 Biomedicine: Research Funding; Revolution Medicines: Research Funding; Hengrui: Research Funding; Cyteir Therapeutics: Research Funding; Ribon Therapeutics: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Takeda: Research Funding; Forma Therapeutics: Research Funding; Artios Pharma: Research Funding; Aileron Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Verastem: Research Funding; Phoenix Molecular Designs: Research Funding; Macrogenics: Research Funding; Mabspace: Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; GlaxoSmithKline: Research Funding; Gilead: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus: Research Funding; Checkpoint Therapeutics: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Daiichi Sankyo: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; ORIC Pharmaceuticals: Research Funding; Stemline Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; ModernaTX: Research Funding; Mirati Therapeutics: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; LSK Biopartners: Research Funding; Placon Therapeutics: Research Funding; Calithera: Research Funding; Effector Therapeutics: Research Funding; Clovis: Research Funding. Monga: Gunderson Foundation: Other; Rising Tide Foundation: Other; Amgen: Research Funding; Orbus Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; Deciphera: Research Funding; Forma Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. McKean: Ascentage Pharma Group: Research Funding; Bicycle Therapeutics: Research Funding; Dragonfly Therapeutics: Research Funding; Epizyme: Research Funding; Exelixis: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; IDEAYA Biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ikena Oncology: Research Funding; Infinity Pharmaceuticals: Research Funding; Jacobio Pharmaceuticals: Research Funding; Moderna: Research Funding; NBE Therapeutics: Research Funding; Novartis: Research Funding; Oncorus: Research Funding; Plexxikon: Research Funding; Prelude Therapeutics: Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sapience Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tizona Therapeutics: Research Funding; TMUNITY Therapeutics: Research Funding; TopAlliance Biosciences: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BicycleTX Limited: Membership on an entity's Board of Directors or advisory committees; Castle Biosciences: Membership on an entity's Board of Directors or advisory committees; MedPage Today: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mauro: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Viscusi: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhagwat: Prelude Therapeutics: Current Employment. Moore: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sun: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chiaverelli: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mintah: Prelude Therapeutics: Current Employment. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Stein: PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy; Syndax Pharmaceuticals: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy. Palmisiano: Genentech: Research Funding; Takeda: Consultancy; AbbVie: Consultancy, Research Funding; Foundation One: Consultancy. Verstovsek: Ital Pharma: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI BioPharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.
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