Viability assessment of human peripheral blood-derived stem cells after three methods of nebulization

Background and objectives: Drug delivery by nebulization has become a crucial strategy for treating different respiratory and lung diseases. Emerging evidence implicates stem cell therapy as a promising tool in treating such conditions, not only by alleviatingthe related symptoms but by improving the prognosis. However, delivery of human peripheral blood-derived stem cells (hPBSCs) to the respiratory airways remains an innovative approach yet to be realized. This study is an analytic, translational, and in vitro research to assess the viability and morphological changes of identified cell populations in hPBSCs cocktail derived from COVID-19 patients. Methods and results: Peripheral blood (PB) samples were obtained from patients enrolled in the SENTAD-COVID Study (ClinicalTrials.gov Reference: NCT04473170). hPBSCs cocktails (n=15) were provided by the Cells Processing Laboratory of Abu Dhabi Stem Cells Center, and were nebulized by three different methods of nebulization: compressor (jet), ultrasonic, and mesh. Our results reported that nucleated CD45(dim) cell count was significantly lower after the three nebulization methods, but nucleated CD45 - cells show a significant decrease only after mesh nebulization. Mesh-nebulized samples had a significant reduction in viability of both CD45(dim) and CD45 cells. Conclusions: This study provides evidence that stem cells derived from PB of COVID-19 patients can be nebulized without substantial loss of cell viability, cell count, and morphological changes using the compressor nebulization. Therefore, we recommend compressor nebulizers as the preferable procedure for hPBSCs delivery to the respiratory airways in further clinical settings.

REGISTRI: Regorafenib in first-line of KIT/PDGFR wild type advanced GIST: Capatalize the A Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial

Background: Around 15% of adult GIST are wild type for KIT/PDGFRA mutations (KPWT), usually have SDH deficiencies, and are resistant to imatinib (IM). The underlying mechanisms include overexpression of HIF1α in SDH deficient-GIST, high IGFR signaling through MAPK, BRAF mutation or STAT3 activation. Regorafenib (RE), targeting these pathways, could be more active as upfront therapy in KPWT GIST. Methods: Patients (pts) >18, with advanced non pretreated KPWT GIST were eligible after central confirmation by next-generation sequencing (NGS). Eligible pts received RE at 160mg/d for 21/28d cycles. Primary end-point was disease control rate (DCR) at 12 weeks (RECIST 1.1 ) by central radiological assessment (CRA). Secondary objectives were PFS, OS, ORR (RECIST,Choi), safety and QoL. An amendment allowed previous IM (adjuvant). Statistical assumptions [H0 73% and H1 90% (α 0.1 and β 0.2)], defined a sample size of 20 pts. Results: From May 2016 to October 2020, 30pts with KPWT GIST (by Sanger) underwent central molecular screening. Among the 15 non-eligible pts, 8 harbored KIT exon 11 mutations, 3 exon 9 and 3 PDGFRA exon 18 by NGS. The remaining 16 (53.3%) molecularly eligible pts were enrolled and started RE except one pt due to COVID-19 pandemic. The trial was prematurely closed due to low recruitment, especially after COVID outbreak. Demographics and treatment details in the table. Based on CRA, 12w-DCR was 86.7%. With a median (m) FU of 26 (5-44) months (mo), 10/15 pts progressed, with a mPFS of 10.8 mo (95% CI 6.9-14.8). 6 mo, 9 mo and 12 mo PFS rates were 65%, 48% and 29% respectively. 2 pts were PD-free at 25 and 43 mo from start of RE. 6/15 pts died, with a mOS of 33.5 mo (95% CI NR). [Formula presented] Conclusions: The study results approach the prespecified activity threshold. The low recruitment rate could have affected this attainment. Other analysis of secondary endpoints are ongoing. The high percentage of overlooked mutant GIST by Sanger raises the need of NGS in presumed KPWT GIST. Clinical trial identification: NCT02638766. Legal entity responsible for the study: Spanish Group for Research on Sarcoma (GEIS). Funding: Bayer. Disclosure: J. Martin Broto: Financial Interests, Personal, Expert Testimony, Honoraria: Lilly;Financial Interests, Personal, Expert Testimony, Honoraria: PharmaMar;Financial Interests, Personal, Expert Testimony, Honoraria: Eisai;Financial Interests, Personal, Expert Testimony, Honoraria: Bayer;Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Institutional, Invited Speaker: PharmaMar;Financial Interests, Institutional, Invited Speaker: Eisai;Financial Interests, Institutional, Invited Speaker: Novartis;Financial Interests, Institutional, Invited Speaker: IMMIX Biopharma;Financial Interests, Institutional, Invited Speaker: Lixte;Financial Interests, Institutional, Invited Speaker: Karyopharm;Financial Interests, Institutional, Invited Speaker: Bayer;Financial Interests, Institutional, Invited Speaker: Celgene;Financial Interests, Institutional, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker: BMS;Financial Interests, Institutional, Invited Speaker: Blueprint;Financial Interests, Institutional, Invited Speaker: Deciphera;Financial Interests, Institutional, Invited Speaker: Nektar;Financial Interests, Institutional, Invited Speaker: FORMA;Financial Interests, Institutional, Invited Speaker: Amgen;Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo;Financial Interests, Institutional, Invited Speaker: Lilly;Financial Interests, Institutional, Invited Speaker: AROG;Financial Interests, Institutional, Invited Speaker: Adaptimmune;Financial Interests, Institutional, Invited Speaker: GSK. N. Hindi: Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Personal, Advisory Board: PharmaMar;Financial Interests, Institutional, Research Grant: PharmaMar;Financial Interests, Institutional, Sponsor/Funding: PharmaMar;Financial Interests, Institutional, Research Grant: Nova tis;Financial Interests, Institutional, Research Grant: Eisai;Financial Interests, Institutional, Research Grant: Immix Bio;Financial Interests, Institutional, Sponsor/Funding: Bayer;Financial Interests, Institutional, Sponsor/Funding: Deciphera;Financial Interests, Institutional, Sponsor/Funding: Daychii;Financial Interests, Institutional, Sponsor/Funding: Blueprint;Financial Interests, Institutional, Sponsor/Funding: Adaptimmune;Financial Interests, Institutional, Sponsor/Funding: GSK;Financial Interests, Institutional, Sponsor/Funding: Karyopharm;Financial Interests, Institutional, Sponsor/Funding: Celgene;Financial Interests, Institutional, Sponsor/Funding: AROG. J. Lavernia: Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Personal, Invited Speaker: BMS. C. Serrano: Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Institutional, Research Grant: Bayer. D. Moura: Financial Interests, Institutional, Research Grant: Novartis;Financial Interests, Institutional, Research Grant: Eisai;Financial Interests, Institutional, Research Grant: PharmaMar;Financial Interests, Institutional, Research Grant: Immix Bio. J. Blay: Financial Interests, Institutional, Research Grant: Bayer;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Institutional, Research Grant: Novartis;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Institutional, Research Grant: Deciphera;Financial Interests, Personal, Research Grant: Deciphera. E.R. Fumagalli: Financial Interests, Institutional, Research Grant: Bayer. All other authors have declared no conflicts of interest.