A phase I/II clinical trial of autologous CMV-specific cytotoxic T cells (CMV-TC) for glioblastoma: Dose escalation results.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 2035-2035
Author(s):  
Marta Penas-Prado ◽  
Katayoun Rezvani ◽  
Shiao-Pei S. Weathers ◽  
Shouhao Zhou ◽  
Carlos Kamiya-Matsuoka ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Phase I ◽  
Dose Escalation ◽  
Cytotoxic T Cells

scholarly journals ATIM-10. A PHASE I/II CLINICAL TRIAL OF AUTOLOGOUS CMV-SPECIFIC CYTOTOXIC T CELLS (CMV-TC) FOR GLIOBLASTOMA: DOSE ESCALATION AND CORRELATIVE RESULTS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi2-vi3
Author(s):  
Marta Penas-Prado ◽  
Shiao-Pei Weathers ◽  
Shouhao Zhou ◽  
Carlos Kamiya-Matsuoka ◽  
Barbara O’Brien ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Phase I ◽  
Dose Escalation ◽  
Cytotoxic T Cells

scholarly journals A Phase I/II Dose-Escalation Multi-Center Study to Evaluate the Safety of Infusion of Natural Killer Cells or Memory T Cells As Adoptive Therapy in Coronavirus Pneumonia and/or Lymphopenia: (RELEASE NCT04578210)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1765-1765
Author(s):  
Antonio Pérez-Martínez ◽  
Alejandro Martín-Quirós ◽  
Cristina Ferreras ◽  
Karima Al-Akioui ◽  
Marta Mora-Rillo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Phase I ◽  
Nk Cells ◽  
Dose Escalation ◽  
Memory T Cells ◽  
Preliminary Evidence ◽  
Specific Memory

Abstract Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. Figure 1 Figure 1. Disclosures Soria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.

scholarly journals Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE)

2021 ◽  
Vol 39 ◽  
pp. 101086
Author(s):  
A. Pérez-Martínez ◽  
M. Mora-Rillo ◽  
C. Ferreras ◽  
P. Guerra-García ◽  
B. Pascual-Miguel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Phase I ◽  
Dose Escalation ◽  
Memory T Cells ◽  
Single Centre ◽  
Adoptive Therapy

scholarly journals Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

BMJ ◽  
2020 ◽  
pp. m3734
Author(s):  
Andy Roemhild ◽  
Natalie Maureen Otto ◽  
Guido Moll ◽  
Mohamed Abou-El-Enein ◽  
Daniel Kaiser ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Kidney Transplantation ◽  
Regulatory T Cells ◽  
Adverse Effects ◽  
Phase I ◽  
Kidney Transplant ◽  
Dose Escalation ◽  
Reference Group ◽  
High Dose

AbstractObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.DesignInvestigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).SettingCharité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).ParticipantsRecipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).InterventionsCD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.Main outcome measuresThe primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.ResultsFor all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.ConclusionsThe application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.Trial registrationNCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

Clinical scale facs-sorting and expansion of regulatory t cells (TREGS) for phase i clinical trial

Cytotherapy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. S196
Author(s):  
A. Ekwe ◽  
R. Au ◽  
B. McEnroe ◽  
M. Tan ◽  
A. Saldan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Regulatory T Cells ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Clinical Scale ◽  
Facs Sorting

scholarly journals Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034629 ◽  
Author(s):  
Philip George ◽  
Nathaniel Dasyam ◽  
Giulia Giunti ◽  
Brigitta Mester ◽  
Evelyn Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Third Generation ◽  
Car T Cells ◽  
Car T

IntroductionAutologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.Methods and analysisEligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.Ethics and disseminationEthical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.Trial registration numberNCT04049513

scholarly journals PS1034 PHASE I DOSE ESCALATION CLINICAL TRIAL OF H3B-8800, A SPLICING MODULATOR, IN PATIENTS WITH ADVANCED MYELOID MALIGNANCIES

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 467 ◽  
Author(s):  
D. Steensma ◽  
V. Klimek ◽  
J. Yang ◽  
A. Brunner ◽  
P. Font Lopez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Malignancies
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