scholarly journals T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

2020 ◽  
Author(s):  
Katie J. Ewer ◽  
◽  
Jordan R. Barrett ◽  
Sandra Belij-Rammerstorfer ◽  
Hannah Sharpe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
T Cell ◽  
Phase 1 ◽  
Antibody Responses

scholarly journals Author Correction: T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

2021 ◽  
Author(s):  
Katie J. Ewer ◽  
◽  
Jordan R. Barrett ◽  
Sandra Belij-Rammerstorfer ◽  
Hannah Sharpe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
T Cell ◽  
Phase 1 ◽  
Antibody Responses

scholarly journals Assessing the Progress of Various Novel SARS-CoV-2 Vaccine Tests and Clinical Trials

2020 ◽  
Author(s):  
Yasmin Khajenoori ◽  
Ayesha Aslam-Mir ◽  
Arezo Ahmadi ◽  
Risa Iwazaki ◽  
Shiv Puliady
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Clinical Trials ◽  
T Cell ◽  
Phase 1 ◽  
T Cell Response ◽  
Antibody Responses ◽  
Spike Protein ◽  
Post Inoculation ◽  
Pharmaceutical Manufacturers

The SARS-CoV-2 outbreak of winter 2019 and 2020 has boomed into a global pandemic of a highly contagious respiratory illness, COVID-19. This affliction causes severe acute respiratory distress and, for many with pre-existing conditions, can threaten to be fatal. Many pharmaceutical manufacturers have been allowed to accelerate their vaccination development, an otherwise lengthy and several stage process. Vaccines being developed are both novel and traditional; some target the spike protein, an agent in SARS-CoV-2 contagion, as recent studies showed that it produced polyclonal antibody responses and neutralized SARS-CoV-2 S-mediated entry, as well as the receptor binding domain. Animal testing used pre-clinical trial in Sinovac’s PiCoVacc show promise to create SARS-CoV-2–specific antibody responses targeting S-specific and RBD-specific IgG in mice, which is why PiCoVacc was shown to mitigate the severity of the virus’s symptoms in all rhesus macaques tested. Additionally, testing of Novavax’s NVX-CoV2373 used live mice and baboon models and has shown promising results of high affinity antibody responses targeting SARS-CoV-215. In this pre-clinical trial, the spleens of animal models who received NVX-CoV2373 followed by a Matrix-M adjuvant, or an immune response boosting agent, showed increased frequencies of TFH cells and GC B cells, encouraging Novavax to continue into clinical trial stages15. Vaccine candidates have already produced post-clinical trial results. INO-4800, a DNA vaccine made by INOVIO, has passed phase 1 clinical trials, while demonstrating general safety in all volunteers and generating immunological response rates and T cell immune responses in 94% of the participants. Moderna and Pfizer show promise with mRNA vaccines, both for the spike protein and receptor domain12; these follow a novel approach and have currently moved into their phase two trials due to increased immune response and reduced adverse effects initially in clinic; Moderna’s spike protein vaccine showed titers of antibody 2.1 times higher than those convalescent with the 100ug dosage, in addition to elevated T-cell response post inoculation for all tested doses.3, 9 Another vaccine, known as ChAdOx1 nCoV-19, a chimpanzee adenovirus-vectored vaccine, has been tested on 1077 healthy adults through single and double doses. The results have shown that the single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunization augmenting antibody titers. Within the ChAdOx1 nCoV-19 groups, local and systemic reactions were more common5. Patients were randomly assigned single intramuscular injections of ChAdOx1 nCoV-19 at doses of 5 × 1010 viral particles or MenACWY5. After the vaccination procedure, participants were observed in the clinic for 30-50 minutes and asked to take note of any abnormal events during the 28-day follow up period5. Evaluating the adenovirus, mRNA, DNA, inactivated, and subunit vaccines currently in accelerated development by pharmaceutical manufacturers will allow for a comprehensive review of which vaccine is most ready for widespread use and can successfully and safely curtail further spread of SARS-CoV-2.

Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 734-734
Author(s):  
Joanne Shaw ◽  
Brandon Ballard ◽  
Xiaohui Yi ◽  
Aditya Malankar ◽  
Matthew R. Collinson-Pautz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Phase 1 ◽  
Metastatic Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Fixed Dose ◽  
Serum Cytokines

734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.

A phase 1 multicenter clinical trial of alemtuzumab and CHOP chemotherapy for peripheral T-cell lymphomas.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 8551-8551
Author(s):  
Rena Buckstein ◽  
Michael Crump ◽  
Graeme A Fraser ◽  
Matthew C. Cheung ◽  
Eugenia Piliotis ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase 1 ◽  
Multicenter Clinical Trial ◽  
Chop Chemotherapy ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T-cell based toxicity and preliminary efficacy in advanced uveal melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9531-9531 ◽  
Author(s):  
Takami Sato ◽  
Paul D. Nathan ◽  
Leonel Fernando Hernandez-Aya ◽  
Joseph J Sacco ◽  
Marlana M. Orloff ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Uveal Melanoma ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Dismal Prognosis ◽  
Dosing Strategy ◽  
Expansion Cohort ◽  
Clinical Trial Information

9531 Background: IMCgp100 is a bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100. In the first-in-human (FIH) clinical trial, preliminary efficacy of IMCgp100 in advanced uveal melanoma (UM) was observed; however, cases of severe T cell-mediated toxicities with the first 2 doses limited dosing to 50 mcg QW. This phase 1 study was designed to implement intra-patient escalation to mitigate toxicity and maximize exposure of IMCgp100. Methods: Using a 3+3 design, HLA-A2+ pts with metastatic UM were treated with low weekly (QW) dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1) (20 mcg) and C1D8 (30 mcg), followed by the escalated cohort dose administered at C1D15 and beyond. Results: Nineteen metastatic UM pts with a median of 3 prior lines of therapy (range 0 - 8) were treated across 4 target dose cohorts (60, 70, 80, and 75 mcg). Fifteen of 19 pts remain on treatment at the data cutoff (25Nov16). Enrollment completed 15Sep16. DLT was observed in 1 of 6 pts in the 70-mcg cohort (LFT elevation), and 2 of 4 pts treated at 80 mcg QW (LFT and bilirubin elevation). The 80 mcg dose level was not tolerated and a 75 mcg cohort was enrolled. Six pts were treated at 75 mcg without DLT; this dose was identified as the MTD and RP2D. All 3 DLT resolved without corticosteroids and all pts resumed IMCgp100. Frequent related AE included pruritus (84%), pyrexia (84%), fatigue (74%), hypotension (74%) and peripheral edema (63%). Gr 3/4 drug-related AE include AST increased (15%), erythema (15%) and hypotension (15%). Preliminary efficacy data (RECIST v1.1) from 17 evaluable pts (2 pts had insufficient follow-up) showed no objective responses; 12 pts had a BOR of SD (63%) including 4 pts (24%) with a ≥10% reduction in target lesions. With median follow-up of 1.8 mo, the disease control rate (16 wks) was 32%. Conclusions: The intra-patient escalation regimen of IMCgp100 results in a 50% increase in dose above the FIH Phase 1, acceptable safety profile, and preliminary efficacy in UM pts. Considering the dismal prognosis of metastatic UM, the PFS observed in this study is encouraging. A Phase 2 expansion cohort and separate pivotal trial of IMCgp100 in advanced UM are ongoing. Clinical trial information: NCT02570308.

A phase 1 trial of JS001, a monoclonal antibody targeting programmed death-1 (PD-1) in patients with advanced or recurrent malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14581-e14581 ◽  
Author(s):  
Sheng Yang ◽  
Jianliang Yang ◽  
Ying Han ◽  
Yan Qin ◽  
Xiaohong Han ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Effector Memory ◽  
Dose Escalation Study ◽  
Biomarker Analysis ◽  
Grade 3 ◽  
Clinical Trial Information

e14581 Background: JS001, a humanized IgG4 anti-PD-1 antibody, showed potent anti-cancer activity in preclinical models. Notably, in vivo study suggests it promotes the proliferation of CD62L-CD45RA- effector memory cell effectively. A phase 1 dose escalation study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy. Methods: This trial used a 3+3 design across 3 dose levels: 1, 3, 10 mg/kg/dose. At each level, two schedules were assessed: single dose and repeated doses every 2 weeks (up to 6 doses). JS-001 was administered as a 60-minute i.v. infusion. A dose limiting toxicity (DLT) was defined as a Grade≥3 drug-related adverse event (AE) occurring within 28 days of last dosing. Results: At the time of analysis, among 19 patients (pts) enrolled (single dose: 9 pts; multiple doses: 10 pts), no DLT was reported. Most treatment-related AEs were grade 1-2, including fever, diarrhea, rash, influenza-like symptoms, fatigue, mucositis, elevated transaminase and decreased lymphocyte count. One patient experienced grade 3 pneumonia. Although the cause of pneumonia is difficult to determine, and further assessment is ongoing, it resolved after prompt management. No treatment-related death occurred. The preliminary PK profile supports a biweekly schedule, and results in detail are under analyzing. 15 pts with evaluable lesions received response evaluation. Best responses were 1 CR (Hodgkin lymphoma, HL), 5 PR (HL: 3; soft tissue sarcoma, STS: 1; diffuse large B-cell lymphoma: 1) and 5 SD (non-small cell lung cancer: 3; head and neck cancer: 2), yielding a disease control rate of 11/15. Remarkably, a patient with STS achieved dramatic tumor shrinkage after a single injection of JS001. Biomarker analysis is in progress. Conclusions: JS001 is well tolerated and the preliminary efficacy results are promising. Updated data on the expansion cohorts at 3mg/kg and 10mg/kg will be presented. Clinical trial information: NCT02836834. Clinical trial information: NCT02836834.

Novel anti-EGFRvIII bispecific T cell engager (BiTE) antibody construct in glioblastoma (GBM): Trial in progress of AMG 596 in patients with recurrent or newly diagnosed disease.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2071-TPS2071
Author(s):  
Mark Rosenthal ◽  
Carmen Balana ◽  
Myra Ellen Van Linde ◽  
Cyrus Sayehli ◽  
Walter M. Fiedler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Medical Information ◽  
Group Performance ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Newly Diagnosed ◽  
Bispecific T Cell Engager

TPS2071 Background: GBM is the most aggressive primary brain tumor in adults and is extremely difficult to treat. Patients with GBM tend to progress rapidly within weeks or months. Median overall survival is only 12–15 months despite aggressive treatment, and less than 5% of patients survive 5 years. GBM also severely impacts quality of life and cognitive function. Approximately 50% of GBM tumors test positive for amplification or mutation of the epidermal growth factor receptor (EGFR), the most common of which is the EGFRvIII gain-of-function mutation. AMG 596 is a bispecific T cell engager (BiTE®) antibody construct designed to crosslink and engage CD3-positive T cells to EGFRvIII-positive tumor cells, inducing tumor cell lysis and T cell proliferation. A clinical trial is being conducted for this novel immunotherapy agent in patients with EGFRvIII-positive GBM. Methods: NCT03296696 is a phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study evaluating the safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of AMG 596 in patients with EGFRvIII-positive GBM. AMG 596 is administered via continuous intravenous infusion. The study is expected to enroll approximately 82 patients total and comprises two groups (Group 1: patients with recurrent GBM; Group 2: patients with newly diagnosed GBM in the maintenance treatment phase after standard of care). Key inclusion criteria include: male or female; ≥ 18 years of age; with pathologically documented and diagnosed grade IV GBM; Eastern Cooperative Oncology Group performance status ≤ 1; life expectancy ≥ 3 months per study investigator; and acceptable renal, hematological, and hepatic function. The primary endpoint evaluates the safety and tolerability of AMG 596 via collection of treatment-emergent adverse events. Additional endpoints include objective response rate per modified Response Assessment in Neuro-Oncology Criteria and PK/PD analyses of AMG 596 in serum. The study began enrolling patients in April 2018 and enrollment is ongoing. For more information, please contact Amgen Medical Information: [email protected]. Clinical trial information: NCT03296696.

A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced-stage solid tumors (ACRONYM: GDFATHER).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2658-TPS2658
Author(s):  
Ignacio Melero ◽  
Emiliano Calvo ◽  
Reinhard Dummer ◽  
Elena Garralda ◽  
Martin H. Schuler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Advanced Stage ◽  
Open Label ◽  
Effector T Cell

TPS2658 Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study [Haake et al. AACR2020; Abstract #5597] elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [reviewed in Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.

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