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

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).

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

Cytotherapy ◽

10.1016/s1465324921006150 ◽

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

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Clinical Activity of a Novel Multiple Tyrosine Kinase and Aurora Kinase Inhibitor, ENMD-2076, Against Multiple Myeloma: Interim Phase I Trial Results

Blood ◽

10.1182/blood.v116.21.1957.1957 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1957-1957 ◽

Cited By ~ 2

Author(s):

Sherif Farag ◽

Shuhong Zhang ◽

Attaya Suvannasankha ◽

Jing Liang ◽

Robyn O'Bryant ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Phase I Clinical Trial ◽

M Protein ◽

High Dose ◽

Significant Activity ◽

Dose Levels ◽

Asymptomatic Elevation

Abstract Abstract 1957 Background: Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM. Methods: An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated. Results: Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein. Conclusion: In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted. Disclosures: Farag: EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

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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 ◽

10.1182/blood-2021-150847 ◽

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.

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An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: Results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy

Journal of Immunological Methods ◽

10.1016/j.jim.2017.03.023 ◽

2017 ◽

Vol 446 ◽

pp. 21-29 ◽

Cited By ~ 7

Author(s):

Einat Almon ◽

Tawfik Khoury ◽

Ariel Drori ◽

Svetlana Gingis-Velitski ◽

Sari Alon ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Regulatory T Cells ◽

Fusion Protein ◽

Oral Administration ◽

Phase I ◽

Phase I Clinical Trial ◽

Biologically Active ◽

Tnf Alpha

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Increase of CD4+CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+CD25+ T lymphocytes

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2007.03521.x ◽

2007 ◽

Vol 150 (3) ◽

pp. 523-530 ◽

Cited By ~ 85

Author(s):

S. Audia ◽

A. Nicolas ◽

D. Cathelin ◽

N. Larmonier ◽

C. Ferrand ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Lymphocytes ◽

Regulatory T Cells ◽

Phase I ◽

Peripheral Blood ◽

Metastatic Carcinoma ◽

Phase I Clinical Trial

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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)

EClinicalMedicine ◽

10.1016/j.eclinm.2021.101086 ◽

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

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Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2048 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2048-2048 ◽

Cited By ~ 2

Author(s):

Andrew B. Lassman ◽

David A. Reardon ◽

Eudocia Quant Lee ◽

Fabio Massaiti Iwamoto ◽

Francisco Diaz-Mitoma ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Phase I ◽

Karnofsky Performance Status ◽

Performance Status ◽

Vaccine Dose ◽

High Dose ◽

Vaccine Response ◽

Dose Cohort ◽

Recurrent Gbm

2048 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. Subjects are vaccinated monthly until tumor progression, with immunomonitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. In phase I, eligible patients were age 18-70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 subjects in each cohort and DSMB safety review of the first 3 subjects in each cohort prior to enrolling additional subjects. Results: The DSMB identified no DLTs or safety concerns with any of the doses. Grade 2, 3 or 4 AEs occurred in 66%, 22% and 11% of participants, respectively, but were not related to vaccine administration. Twelve men and 6 women were enrolled with a median age 54 (range 39-66). Prior therapies included radiotherapy, temozolomide, and nivolumab. Immunological analyses demonstrate robust boosting of CMV-specific antibody titers and T cell responses against both gB and pp65 antigens in some but not all subjects, across all dose cohorts. Boosting of IFN-gsecreting T cells (measured by ELISPOT) exceeded the assay threshold for several subjects. Stable disease by MRI of 3 months or greater has been observed in 2 subjects in the high dose cohort and 1 subject in the low dose cohort and may correlate with vaccine response. Conclusions: The phase IIa extension phase of the trial planned to begin in Q2 2019 is designed to explore efficacy in an additional 10 subjects that will receive the optimal vaccine dose and includes the additional requirements of unifocal, measurable enhancing tumor 1-3 cm across at first recurrence and no prior immunotherapy. Clinical trial information: NCT03382977.

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First-in-Human Clinical Trial to Determine the Safety and Potency of Inducible T Regulatory Cells after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2018-99-113100 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2112-2112 ◽

Cited By ~ 1

Author(s):

Margaret L. MacMillan ◽

Keli Lee Hippen ◽

David H. McKenna ◽

Todd E. DeFor ◽

Erica D. Warlick ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Regulatory T Cells ◽

Dose Escalation ◽

Adoptive Transfer ◽

Research Funding ◽

Cd4 Cells ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Introduction: Adoptive transfer of thymic derived regulatory T-cells (tTregs) or Treg type I cells that arise in the periphery can ameliorate GVHD and autoimmunity in mice. However, high Treg doses (~1:1 with donor T-cells) are required to reproducibly suppress disease. In the periphery, a population of non-Treg CD4+ T-cells can be induced to acquire a Treg phenotype and function. We defined a GMP-compliant method for selecting, inducing and expanding Tregs from peripheral blood CD4+25- T cells with IL-2, sirolimus and TGFß. Sirolimus/TGFß iTregs are as suppressive as cord blood derived tTregs and the potential yield is 50-fold higher in a 2 week culture period. We hypothesized that inducible regulatory T cells (iTregs) will be effective for acute GVHD (aGVHD) prevention without concomitantly increasing the risk of opportunistic infection and relapse. Methods: We performed a phase I single center dose escalation study with an extension at the best available dose to determine the tolerability of inducible regulatory T cells (iTregs) given to adult patients undergoing reduced intensity HLA-identical sibling donor peripheral blood stem cell (PBSC) transplantation for high risk malignancy. The study used a fast track design with 1 patient per iTreg dose cohort (3.0 x 106/kg, 3.0 x 107/kg, 3.0 x 108/kg and 10.0 x 108/kg) along with CSA/MMF GVHD prophylaxis. An extension phase then occurred to total 10 patients at the best available dose, but using sirolimus/MMF as sirolimus is permissive of Treg expansion. HLA-identical sibling donors underwent 2 aphereses. On day -14, an unmobilized 15L apheresis was performed to collect cells for iTreg production. On day 0 (and +1 if needed), G-CSF mobilized 15L apheresis collected PBSCs. All patients received cyclophosphamide 50 mg/kg on day -6, fludarabine 30 mg/m2/day on days -6 to -2, and 200 cGy TBI as a single fraction on day -1. The iTregs were administered on day 0 at least 4 hours before the PBSC infusion. Results: Sixteen patients were enrolled. Two did not receive iTregs as inadequate numbers of cells were produced. 14 patients (7 male,7 female; median age 63 years) received iTregs. One patient each received 3.0 x 106/kg, 3.0 x 107/kg, 3.0 x 108/kg iTregs with a corresponding T effector:iTreg ratio of 86:1, 8:1 and 1:2. As a ratio of 1:1 was considered sufficient to suppress GVHD in mice, dose escalation was halted at 3.0 x 108/kg considering manufacturing costs despite no observed dose limiting toxicities (DLT). After 3 patients received 3.0 x 108/kg with CSA/MMF immunoprophylaxis with no DLTs, 2 patients received 3.0 x 108/kg iTregs using sirolimus/MMF. Both patients developed grade III aGVHD, resulting in suspension of the sirolimus/MMF arm. An additional 7 patients (for a total of 10) received 3.0 x 108/kg iTregs along with CSA/MMF. No severe infusional toxicities occurred in the 14 patients who received iTregs. All achieved neutrophil engraftment at a median of 7 days. Of 10 patients who received 3.0 x 108/kg iTregs using CSA/MMF, 2 developed grade II and 1 grade III aGVHD by day 100. Circulating Foxp3+iTregs were detected early after adoptive transfer, but were not detectable beyond day 28. Higher numbers of iTregs were detected at day 3 in patients who received 3.0 x 108/kg iTregs along with CSA/MMF versus 3.0 x 106/kg or 3.0 x 107/kg (21% +/-3% vs 9% +/- 3% of CD4 cells were Foxp3+CD25+). On day 7, lower numbers were seen in all patients and by day 28 only 3% of CD4+ cells were Foxp3+CD25 in all patients. In a contemporary institutional cohort of 203 adult patients with malignancies receiving the same RIC and GVHD prophylaxis, but without iTregs, the probabilities of grade II-IV aGVHD was 41% (95% CI, 34-48%) and grade III-IV GVHD was 25% (95% CI, 19-31%) suggesting iTreg administration may suppress GVHD to some extent in this small trial (Figure). Conclusions: HLA-identical sibling donor iTregs were safely administered in the setting of HLA-identical sibling PBSCT. 3 x 108/kg iTreg/kg was the best tested dose to suppress GVHD with CSA/MMF immunoprophylaxis. Sirolimus/MMF was ineffective as GVHD prophylaxis in this iTreg clinical trial. Future studies should test the combination of iTregs and tTregs which synergistically induce tolerance in mice. Figure. Figure. Disclosures MacMillan: Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Brunstein:Gamidacell: Research Funding. Weisdorf:FATE: Consultancy; SL Behring: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding.

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