Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), with cetuximab (C) as reference.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3035-3035
Author(s):  
Christoph Mancao ◽  
Lilla Di Scala ◽  
Paul Delmar ◽  
Stéphane Temam ◽  
Jean-Charles Soria ◽  
...  
Keyword(s):  
Statistical Methods ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
Immune Markers ◽  
Open Label ◽  
Immune Effector ◽  
Bivariate Correlation ◽  
Cell Counts ◽  
Biomarker Analysis ◽  
Tumor Biopsies

3035 Background: GA201 is a novel humanized anti-epidermal growth factor receptor (EGFR) mAb with a dual MoA: glycoengineered to enhance ADCC on top of inhibition of EGFR signaling. In an open-label, multi-center trial of pts with HNSCC, an exploratory biomarker analysis of sequential tumor biopsies was performed to investigate the single/duplex marker correlation structure. Methods: Pts received 2 doses of 700 or 1,400 mg GA201 or C (day 1, 8). Tumor biopsies were taken at baseline (BL) and pre-surgery (day 15). Immunohistochemistry immune-cell counts (single/duplex markers), EGFR-pathway markers and intra-tumoral cytokines (LUMINEX) were assessed. Advanced exploratory statistical methods were used to analyse inter-relationship between BL and on treatment markers, and with response (as determined by FDG-PET). Results: All immune markers (single and duplex) presented highly heterogeneous median values at BL, but cluster analysis emphasized their strong inter-correlation. These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201. Intra-tumoral cytokines like CXCL12 showed good correlation with BL CD3, 16 and 68 infiltration. Principle component analysis also confirmed a good association between most BL immune markers and was able to differentiate strongest PET responders in the 700 mg GA201 cohort. Conclusions: Multivariate statistical methods were used to demonstrate strong interdependencies between immune-effector markers and to highlight their promising associations with response to GA201 treatment, likely due to ADCC processes in the tumors. Clinical trial information: NCT01046266.

A phase II, multicenter, open-label, single-arm trial of famitinib in patients with advanced recurrent and/or metastatic nasopharyngeal carcinoma (NPC) after two previous treatment regimens.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6026-6026 ◽  
Author(s):  
Yan Huang ◽  
Li Zhang ◽  
Jian-ji Pan ◽  
Guoqing Hu ◽  
Wu Gang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nasopharyngeal Carcinoma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Previous Treatment ◽  
Open Label ◽  
Primary Object ◽  
Biomarker Analysis ◽  
Metastatic Nasopharyngeal Carcinoma

6026 Background: Famitinib is an oral, small molecular multiple tyrosine-kinase inhibitor (TKI), targeting stem cell growth factor receptor (c-Kit), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). So far, few target therapies show acceptable efficiency in advanced recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC) patients. The primary object of this study is to determine the safety and efficacy of famitinib in patients with RM-NPC. Methods: This study recruited histologically diagnosed RM-NPC patients who failed more than two lines of systemic chemotherapy. Other eligible criteria included ECOG PS≤2, adequate organ function and no prior exposure to other c-Kit, PDGFR or VEGFR TKIs. The patients received famitinib orally at a dose of 25 mg once daily until the disease progression or intolerable toxicity. Results: From May 2011 to Sep 2012, 58 patients (Simon’s two-stage design, 28+30) were recruited at 8 sites in China. The clinical benefit rate (partial response or stable disease maintained≥12 weeks, tumor response was evaluated every 4 weeks) is 32.8%, including 5 PR and 16 SD patients. Median PFS was 3.2 months. The most frequently observed hematologic toxicities included thrombocytopenia, leucopenia and neutropenia; non-hematologic AEs were hypertension, proteinuria, and hand-foot syndrome. All adverse events were generally mild-to-moderate (grade 1/2) and manageable with supportive treatment; grade 3/4 incidence was relatively low. Conclusions: This phase II study shows that famitinib demonstrates substantial clinical benefits in patients with advanced RM-NPC and the drug-related adverse reactions were most predictable and tolerable, no special toxicity was reported. Biomarker analysis for responder and non-responder is still ongoing and will be present at the meeting. Clinical trial information: NCT01392235.

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 492-492 ◽  
Author(s):  
Sang Joon Shin ◽  
Jeeyun Lee ◽  
Ik-Joo Chung ◽  
Tae Won Kim ◽  
Hoo Geun Chun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Open Label ◽  
Baseline Serum ◽  
Biomarker Analysis ◽  
Group A ◽  
Group B

492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.

Long-term efficacy and pharmacodynamic parameter analysis in pretreated KRAS-mutant metastatic colorectal carcinoma (mCRC) patients treated with RG7160 (GA201), an antibody-dependent cellular cytotoxicity (ADCC)-enhanced monoclonal anti-EGFR antibody.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 379-379
Author(s):  
Jean-Pierre Delord ◽  
Josep Tabernero ◽  
Rocio Garcia-Carbonero ◽  
Andres Cervantes-Ruiperez ◽  
Carlos Alberto Gomez-Roca ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Immune Cell ◽  
Single Agent ◽  
Parameter Analysis ◽  
Term Survival ◽  
Cell Counts ◽  
Tumor Biopsies ◽  
Egfr Antibody

379 Background: EGFR-positive, KRAS-mutant mCRC patients (pts) do not benefit from anti-EGFR treatment. In this pt population we investigated the efficacy of single-agent GA201, a novel dual acting, anti-EGFR antibody which was glycoengineered to enhance ADCC on top of signaling blockage. This stimulation of immune effector cells may improve long term clinical outcomes. Methods: In an open-label, multicenter, non-randomized study, KRAS-mutant mCRC pts (1-2 prior chemotherapy lines) were treated with GA201 (1400 mg on day 1 and 8 then by 1400 mg q2W). The primary endpoint was to investigate tumor response. Here we report response rates, overall survival (OS) and pharmacodynamics analyses from archival, pre- and on-treatment biopsies and blood samples. Results: 25 pts received a median of 5 GA201 infusions (range 2–24), for up to 414 days. Median overall survival was 9.3 months (range 1.2 – 21.2). Best overall response was stable disease (40% of patients at 8 weeks), which was maintained in 24% of pts at 16 weeks, in 2 patients (8%) at 24 weeks and 1 pt (4%) at 42 weeks. Treatment-related adverse events were all manageable with rash (20% grade3), hypomagnesaemia (20% g3/4) and infusion-related reactions (4% g3) being the most common adverse events; none led to discontinuation or dose reduction. Comparison of pre- and post-treatment tumor biopsies evaluable for 11 pts revealed that tumor-infiltrating cell counts increased notably after one cycle of therapy (median composite immune reactive score of 1491 vs 898 cells/mm3 at baseline). In addition, it was noted that EGFR H-score in baseline tumor biopsies was notably higher than in archival tumors (median [range] 52 [13–161] vs 3 [1–81], respectively). High tumor immune cell infiltration at baseline might be associated with better treatment outcome and long-term survival. Conclusions: Encouraging OS is achieved with GA201 monotherapy in patients with KRAS-mutant tumors. The pharmacodynamics analyses support the hypothesis of triggering an enhanced long term immune response in this pretreated patient population. Clinical trial information: NCT00721266.

A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: Final results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4598-4598 ◽  
Author(s):  
V. Gruenwald ◽  
L. Wilkens ◽  
M. Gebel ◽  
T. F. Greten ◽  
S. Kubicka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Chromosome 1 ◽  
Preliminary Evaluation ◽  
Open Label ◽  
Prior Therapy ◽  
Egfr Expression ◽  
Tumor Biopsies

4598 Background: Hepatocellular carcinoma (HCC) express the epidermal growth factor receptor (EGFR), and EGFR-targeting therapies are known to block tumor growth. We tested the activity of cetuximab (CET) in HCC and evaluated serial tumor biopsies for biomarker analyses. Methods: Patients (pts) with advanced or metastatic HCC with ECOG = 2 and adequate organ function were eligible. Prior therapy was permitted. CET was given iv weekly (400 mg/m2 loading dose, 250 mg/m2 thereafter). The primary endpoint was the rate of progression-free survival (PFS) at 24 wks. Serial tumor biopsies were performed prior to treatment, after 4 wks and at time of progression. 32 pts were enrolled. 27 pts are evaluable for tumor response. Results: Stable disease (SD) was achieved in 44.4% (12 pts) for at least 8 weeks of treatment. 55.6% failed to respond to CET (15 pts). The median time to progression (TTP) for all pts was 8.0 wks. Pts, which were stable for more than 8 wks achieved a median TTP of 22.5 wks (11–48 wks) compared to a median TTP of 6.0 wks (3–8 wks) in progressive pts. No treatment-related severe adverse events were noted throughout the study. Preliminary evaluation of surrogate markers showed no correlation with cytogenetic abnormalities based on FISH analyses for chromosome 1 and 8. Furthermore, only 5 of 21 tumor specimens were positive for EGFR expression without gene amplification, evaluated by FISH analyses. Serial tumor specimens are available in 5 responding and in 7 non-responding pts for changes of p27 and p21 expression. p27 and p21 were upregulated simultaneously in 60% (3/5 pts) of responding pts, whereas in pts with treatment failure p27 and p21 expression was detectable in 14% (1/7 pts) only. Conclusions: Cytogenetic aberrations of chromosome 1 and 8 failed to predict response to CET. In a subgroup of pts with SD >8 weeks, induction of p21 and p27 were associated with prolonged TTP >20 wks. Further evaluation of p21 and p27 as early molecular tumor response is warranted to identify pts, which benefit from anti-EGFR therapies. [Table: see text] No significant financial relationships to disclose.

A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5502-5502 ◽  
Author(s):  
Jordi Giralt ◽  
Andre Fortin ◽  
Ricard Mesia ◽  
Heikki Minn ◽  
Michael Henke ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Mucosal Inflammation ◽  
Open Label ◽  
Hpv Status ◽  
Biomarker Analysis ◽  
Grade 3 ◽  
Fatal Adverse Events ◽  
Ecog Ps

5502 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m2, both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of >10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.

scholarly journals 528 Correlation of baseline circulating Vg9Vd2 T cell counts and pharmacodynamic activity of ICT01 in cancer patients: preliminary results from EVICTION and a novel patient enrichment strategy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A558-A558
Author(s):  
Emmanuel Valentin ◽  
Aude de Gassart ◽  
Patrick Brune ◽  
Clément Ghigo ◽  
Sophie Agaugué ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Count ◽  
T Cell Activation ◽  
Immune Cell ◽  
Selection Criterion ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Cell Counts ◽  
Tumor Biopsies

BackgroundICT01, a novel, anti-BTN3A immunotherapeutic mAb for activating g9d2T cells, is currently evaluated in a Phase 1/2a clinical trial in patients with advanced-stage, relapsed/refractory cancer (NCT04243499, EVICTION). ICT01 indirectly activates g9d2 T cells that secrete inflammatory cytokines and migrate into tumors to coordinate antitumor immune responses. Therefore, the baseline number of g9d2 T effector cells constitutes a biomarker of interest and a potential selection criterion for target patients.MethodsFull immunophenotyping (cell counts and activation state) was performed by flow cytometry on fresh blood collected pre- and on-treatment. Serum cytokines were monitored at baseline and post-treatment. Tumor biopsies were harvested at baseline and on Day 28, and multiplex IHC coupled with digital pathology was used to quantify g9d2T cell, CD8 T cell, NK cell, and T reg infiltration and activation stateResultsBaseline circulating g9d2 T cell count was highly variable in solid tumor patients enrolled in the monotherapy arm of EVICTION (median 6918 cell/mL, n=26). Melanoma and colorectal patients displayed respectively the highest (median 42277 cell/mL, n=3) and the lowest (median 3040 cell/mL, n=9) baseline number. During the dose escalation phase, g9d2 T cell activation (CD69+) and migration from the blood was observed 30 min post-ICT01 administration. Serum cytokine levels showed variability within ICT01 dose cohorts. IFNg, TNFa, IL-6 and IL-8 levels post-ICT01 dosing were ICT01 dose dependent and clearly related to baseline number of circulating g9d2 T cells. Activation of peripheral blood NK cells, granulocytes and CD8 T cells was observed post-dosing at ICT01 doses ≥7 mg, which was significantly correlated with baseline g9d2 T cell counts, but not with other immune subsets (Spearman r=0.51, 0.47 and 0.65 for CD69+NK, CD69+CD8 and PD-L1+granulocytes respectively, p<0.05, n=19). Baseline circulating g9d2 T cell count was positively correlated with gdTCR+ T cell density in baseline tumor biopsies (Spearman r=0.76, p=0.0086, n=11). Finally, a trend was observed between baseline g9d2 T cell counts and overall tumor immune cell infiltration and activation post-ICT01 treatment, with 4 patients (out of 13 with available biopsy pairs) with g9d2 T cell counts above the median displaying the highest tumor immune cell infiltration and activation.ConclusionsThese results suggest the utility of measuring baseline g9d2 T cells as part of the patient selection process for ICT01 clinical trials. Patient enrichment based on this biomarker will be tested in EVICTION expansion arms where a minimum baseline threshold of g9d2 T cells counts will be one of the eligibility criteria.Trial RegistrationNCT04243499Ethics ApprovalThe study has obtained Competent Authority and Ethics Committee approvals. Informed consent forms were obtained from all enrolled patients.

scholarly journals Phase I first-in-human study of HLX07, a novel and improved recombinant anti-EGFR humanized monoclonal antibody, in patients with advanced solid cancers

2021 ◽  
Author(s):  
Ming-Mo Hou ◽  
Ching-Liang Ho ◽  
Hsuan-Yu Lin ◽  
Yunting Zhu ◽  
Xiaodi Zhang
Keyword(s):  
Phase I ◽  
Standard Therapy ◽  
Human Study ◽  
Growth Factor Receptor ◽  
Systemic Exposure ◽  
Open Label ◽  
Dose Escalation Study ◽  
Clinical Trial Registration ◽  
Humanized Monoclonal Antibody ◽  
Open Label Phase

SummaryPurpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a ‘3 + 3’ escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov: NCT02648490 (Jan 7, 2016).

scholarly journals Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study

2021 ◽  
Author(s):  
Ravi Savarirayan ◽  
Louise Tofts ◽  
Melita Irving ◽  
William R. Wilcox ◽  
Carlos A. Bacino ◽  
...  
Keyword(s):  
Growth Velocity ◽  
Bone Growth ◽  
Growth Factor Receptor ◽  
Extension Study ◽  
Controlled Study ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Pathogenic Variants ◽  
Growth Promoting

Abstract Purpose Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. Methods After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day. Results In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. Conclusion Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

scholarly journals Combination of umbilical cord mesenchymal stem cells and standard immunosuppressive regimen for pediatric patients with severe aplastic anemia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Lan ◽  
Fang Liu ◽  
Lixian Chang ◽  
Lipeng Liu ◽  
Yingchi Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Aplastic Anemia ◽  
Umbilical Cord ◽  
Pediatric Patients ◽  
Statistical Significance ◽  
Severe Aplastic Anemia ◽  
Control Group ◽  
Open Label ◽  
Cell Counts

Abstract Background Defects of bone marrow mesenchymal stem cells (BM-MSCs) in proliferation and differentiation are involved in the pathophysiology of aplastic anemia (AA). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) may improve the efficacy of immunosuppressive therapy (IST) in childhood severe aplastic anemia (SAA). Methods We conducted an investigator-initiated, open-label, and prospective phase IV trial to evaluate the safety and efficacy of combination of allogenic UC-MSCs and standard IST for pediatric patients with newly diagnosed SAA. In mesenchymal stem cells (MSC) group, UC-MSCs were injected intravenously at a dose of 1 × 106/kg per week starting on the 14th day after administration of rabbit antithymocyte globulin (ATG), for a total of 3 weeks. The clinical outcomes and adverse events of patients with UC-MSCs infusion were assessed when compared with a concurrent control group in which patients received standard IST alone. Results Nine patients with a median age of 4 years were enrolled as the group with MSC, while the data of another 9 childhood SAA were analysed as the controls. Four (44%) patients in MSC group developed anaphylactic reactions which were associated with rabbit ATG. When compared with the controls, neither the improvement of blood cell counts, nor the change of T-lymphocytes after IST reached statistical significance in MSC group (both p > 0.05) and there were one (11%) patient in MSC group and two (22%) patients in the controls achieved partial response (PR) at 90 days after IST. After a median follow-up of 48 months, there was no clone evolution occurring in both groups. The 4-year estimated overall survival (OS) rate in two groups were both 88.9% ± 10.5%, while the 4-year estimated failure-free survival (FFS) rate in MSC group was lower than that in the controls (38.1% ± 17.2% vs. 66.7% ± 15.7%, p = 0.153). Conclusions Concomitant use of IST and UC-MSCs in SAA children is safe but may not necessarily improve the early response rate and long-term outcomes. This clinical trial was registered at ClinicalTrials.gov, identifier: NCT02218437 (registered October 2013).

scholarly journals Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽  
2021 ◽  
Author(s):  
Audrey Lequeux ◽  
Muhammad Zaeem Noman ◽  
Malina Xiao ◽  
Kris Van Moer ◽  
Meriem Hasmim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Transcriptional Activity ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Combination Strategy ◽  
Immune Effector ◽  
Effector Cells ◽  
Melanoma Patients ◽  
The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

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