Targeting CD2 for immunotherapy: Results of a phase 1 trial with a LFA-3/IgG Fc fusion protein

1998 ◽  
Vol 16 ◽  
pp. S210
Author(s):  
Daniel Magilavy ◽  
Paul Norman ◽  
Gerard Maieau ◽  
Steven Knox ◽  
Gunther Winkler ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Phase 1 ◽  
Phase 1 Trial ◽  
Fc Fusion Protein

scholarly journals 380 GS-3583, a novel FLT3 agonist Fc fusion protein, expands conventional dendritic cells in healthy volunteers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A413-A414
Author(s):  
Nishanthan Rajakumaraswamy ◽  
Anees Dauki ◽  
Michelle Kuhne ◽  
Torsten Trowe ◽  
Winnie Weng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Protein ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Vital Role ◽  
Controlled Study ◽  
Therapeutic Effects ◽  
Fc Fusion Protein ◽  
Quantitative Changes ◽  
Dose Dependent

BackgroundConventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. We sought to evaluate the pharmacodynamic (PD) effect of a single dose of GS-3583 in healthy volunteers alongside its safety. Herein, we present the updated results of the study.MethodsThis was a first-in-human, placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, pharmacokinetics (PK), and PD of escalating single doses (ranging from 75 micrograms to 2000 micrograms) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8–12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1 and cDC2 cells.ResultsAs of 2nd July 2021, selected safety, PK and PD data from all 4 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in temporary, dose-dependent increases in cDC1/cDC2 cells that peaked between days 5–11 (higher doses resulted in later peaks) and returned to baseline within 3 weeks of drug administration (table 1, figure 1).Abstract 380 Table 1Selected subject characteristics and pharmacodynamic resultsAbstract 380 Figure 1A) Comparison of cDC1 cell quantitative changes in cohorts 1–4; B) Comparison of cDC2 cell quantitative changes in cohorts 1–4ConclusionsGS-3583 infusion was well tolerated and induced dose dependent expansion of dendritic cells in the periphery in healthy volunteers. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor therapeutic effects of immuno-oncology therapies.AcknowledgementsFunding provided by Gilead Sciences, Inc.Ethics ApprovalThe study received study site IRB/Ethics Committee approval prior to enrollment of subjects.

Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 227-236 ◽  
Author(s):  
Andres Forero ◽  
Paul L. Weiden ◽  
Julie M. Vose ◽  
Susan J. Knox ◽  
Albert F. LoBuglio ◽  
...  
Keyword(s):  
Fusion Protein ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase 1 ◽  
Whole Body ◽  
Single Chain ◽  
Phase 1 Trial ◽  
Non Hodgkin Lymphoma ◽  
Pretargeted Radioimmunotherapy ◽  
Anti Cd20

Abstract Pretargeted radioimmunotherapy (PRIT) has the potential to increase the dose of radionuclide delivered to tumors while limiting radiation to normal tissues. The purpose of this phase 1 trial is to assess safety of this multistep approach using a novel tetrameric single-chain anti-CD20–streptavidin fusion protein (B9E9FP) as the targeting moiety in patients with B-cell non-Hodgkin lymphoma (NHL), and to characterize its pharmacokinetics and immunogenicity. All patients received B9E9FP (160 mg/m2 or 320 mg/m2); either 48 or 72 hours later, a synthetic clearing agent (sCA) was administered (45 mg/m2) to remove circulating unbound B9E9FP. 90Yttrium (90Y; 15 mCi/m2)/111In (5 mCi)–DOTA-biotin was injected 24 hours later. There were 15 patients enrolled in the study. B9E9FP had a mean plasma half-life (T½) of 25 ± 6 hours with a reduction in plasma level of more than 95% within 6 hours of sCA administration. 90Y/111In-DOTA-biotin infusion resulted in rapid tumor localization and urinary excretion. The ratio of average tumor to whole-body radiation dose was 49:1. No significant hematologic toxicities were noted in 12 patients. There were 2 patients who had hematologic toxicity related to progressive disease. There were 2 complete remissions (90 and 325 days) and one partial response (297 days). B9E9FP performs well as the targeting component of PRIT with encouraging dosimetry, safety, and efficacy. A dose escalation trial of 90Y-DOTA-biotin in this format is warranted.

GS-3583, a novel FLT3 agonist Fc fusion protein, to expand conventional dendritic cells in healthy volunteers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Nishanthan Rajakumaraswamy ◽  
Anees Dauki ◽  
Michelle R. Kuhne ◽  
Torsten Trowe ◽  
Jing He ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Protein ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Vital Role ◽  
Controlled Study ◽  
Patients With Cancer ◽  
Fc Fusion Protein ◽  
Grade 3 ◽  
Dose Dependent

2559 Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]

Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3006-3006 ◽  
Author(s):  
James L. Gulley ◽  
Christopher Ryan Heery ◽  
Jeffrey Schlom ◽  
Ravi Amrit Madan ◽  
Liang Cao ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase 1 Trial ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

3006 Background: M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-β (TGF-β) receptor II, which acts as a TGF-β trap. We report preliminary data from a phase 1 trial of M7824 in patients (pts) with advanced solid tumors. Methods: NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible pts receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. Results: 16 heavily pretreated pts with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, and colitis with associated anemia); there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Conclusions: Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in pts with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. Clinical trial information: NCT02517398.

354 A phase 1 trial of CUE-101 a novel HPV16 E7-pHLA-IL2-Fc fusion protein in patients with recurrent/metastatic HPV16+ head and neck cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A379-A379
Author(s):  
Sara Pai ◽  
Douglas Adkins ◽  
Lori Wirth ◽  
Christine Chung ◽  
Michael Gibson ◽  
...  
Keyword(s):  
T Cells ◽  
Fusion Protein ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Tumor Antigen ◽  
Phase 1 ◽  
Cancer Center ◽  
School Of Medicine ◽  
Fc Fusion Protein ◽  
Anti Tumor Activity

BackgroundImmuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. Human papillomavirus (HPV) associated cancers serve as a model system to assess the safety and efficacy of the Immuno-STAT platform. CUE-101 is comprised of human leukocyte antigen (HLA) complex, HLA A*0201, a peptide epitope derived from the HPV type 16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL2) designed to bind and activate HPV-specific T cells for eradication of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, which translated into anti-tumor activity.1MethodsCUE-101-01 is a first-in-human (FIH) phase 1 study in patients diagnosed with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) refractory to one or more lines of therapy. Trial eligibility includes MHC class I type HLA-A*0201 and a diagnosis of an HPV16+ HNSCC, as assessed by p16 IHC and confirmed by HPV16 mRNA ISH. CUE-101 is administered intravenously over 60 minutes every 21 days. Objectives include determination of safety, pharmacodynamics (PD), pharmacokinetics (PK), recommended phase 2 dose (RP2D), and preliminary anti-tumor activity. The safety results from treated participants will be presented.Results19 participants have received CUE-101 monotherapy as of August 7, 2020. Doses ranging from 0.06 to 1 mg/kg were determined to be safe and well-tolerated, enabling dose escalation to 2 mg/kg. Preliminary PK data demonstrate dose-dependent increases in drug exposure which are sustained upon repeat dosing, and low inter-subject variability. Preliminary data from systemic blood analyses show early signals of expansion of HPV-16 E711-20-specific CD8+ T cells. Stable disease (SD), as determined by RECIST 1.1, was observed in several participants in these early dose cohorts, with one subject maintaining SD up to 19 weeks. The maximum tolerated dose (MTD) has not yet been reached. As of May 14, 2020 (the development safety update report (DSUR) data-lock date), no dose limiting toxicities and the following adverse events were observed in the first 12 patients treated with CUE-101: fatigue (n=3), decreased appetite (n=1), arthralgia (n=1), muscular weakness (n=1), parasthesia (n=1), bullous pemphigoid (n=1), and infusion-related reactions (n=1).ConclusionsCUE-101 is a novel agent that is demonstrating acceptable tolerability, favorable PK, and preliminary PD signals that support selective activation of tumor-specific T cells. Neither the MTD nor the monotherapy RP2D have been established. PD and PK analyses are ongoing as dose escalation continues.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma.Trial RegistrationClinicalTrials. gov NCT03978689Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites; IRB reference numbers: DF/HCC IRB# 19-374 (Massachusetts General Hospital), HRPO# 201905108 (Washington University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), Advarra Pro00037736 (Moffitt Cancer Center), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), 2019-087 (Karmanos Cancer Institute), WIRB IRB00112341(Winship Cancer Institute/Emory University), WIRB 2000026098 (Yale Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle ), WIRB 1908869642 (University of Arizona Cancer Center, IRB 20-073 (Memorial Sloan Kettering Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), IRB 52744 (Stanford University School of Medicine).ReferenceQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies. Clin Cancer Res 2020;26:1953–64.

Sign in / Sign up

Export Citation Format

Share Document