Cell Therapy With Treg Cells Obtained From Thymic Tissue (thyTreg) to Control the Immune Hyperactivation Associated With COVID-19 (THYTECH2)

Study Overview
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Brief Summary
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The investigators developed a GMP protocol to isolate Treg cells from thymic tissue (thyTreg). The thyTreg cells are being evaluated in a Phase I/II clinical tria l to evaluate the safety and efficacy of the adoptive transfer of autologous thyTreg to prevent rejection in heart transplant children. The preliminary results of the ongoing clinical trial indicate that this therapy is not immunogenic, indicating that allogeneic use of these thyTreg cells would be feasible and safe . The goal of this open-label Phase I/IIa study is to evaluate the safety, tolerability and efficacy of allogeneic thymus derived Tregs (thyTreg) in controlling the Immune Hyperactivation in SARS-CoV-2 infected-patients. These thyTreg cells could inhibit an excessive inflammation, improving life-threatening manifestations, restoring immune balance, and protecting infected tissues.

Detailed Description
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The immune system is the body's defence system against pathogens and other harmful agents, but it is also responsible for transplant rejection or autoimmune diseases. Another scenario of disproportionate immune response is the Immune Hyperactivation, an exaggerated systemic inflammatory response such as that caused by severe SARS-CoV-2 infection, a major cause of acute respiratory distress syndrome (ARDS) in critically ill patients. The standard treatment to prevent these immune responses is the use of immunosuppressive and immunomodulatory therapy, which produces a pleotropic inhibition on the immune system and have a high cost. However, a widespread feeling among the scientific community is that only re-educating immune system to promote immune tolerance will decline the harmful immune responses without prejudice to the functional integrity of the immune system. In the context of COVID-19, it has been shown that in parallel to a general lymphopenia, there is an alteration in the frequency and functionality of Tregs. In addition, it has been described that the progression of the COVID-19 infection is not due to the viral effect, but to the triggered immune hyperinflammation that can lead to multi-organ failure and death. Therefore, although the adoptive transfer of Treg is a promising cell therapy for the treatment of this type of disease, the characteristics of the patients make it unfeasible to obtain enough Treg from the patient to produce a therapeutic dose and, if achieved, the quality of these cells does not allow a prolonged therapeutic effect to be obtained over time. Tregs are a subset of CD4+ T cells with suppressive function that maintain the immune system balance. Adoptive Treg cell therapy has shown efficacy in a variety of immune-mediated diseases in preclinical and clinical studies. To date, most of the clinical trials employing Treg cell therapy have been limited due to a small Treg numbers obtained (Treg cells represent less than 10% of CD4+ T cells) and the low quality of infused Treg (in terms of purity, survival, and suppressor capacity). The investigators have developed an innovative Treg manufacturing protocol, that overcome the existing difficulties by employing a new source of cells, which is the thymic tissue routinely removed and discarded in paediatric cardiac surgeries. The protocol allows to produce massive amounts of thymus derived Treg cells (thyTreg), with improved survival, high suppressive capacity and suitable for therapeutic use. The study will evaluate escalating doses of thyTreg administrated as a single IV dose. The study will include up to 2 cohorts of 4 to 8 subjects per each arm (control group and thyTreg group) followed for a total of 24 months. All subjects will receive standard of care treatment for COVID-19, including dexamethasone and other approved therapies associated with SARS-CoV-2 infection per institutional guidelines.

Official Title
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Open Phase I/IIa Clinical Trial to Evaluate the Safety and Efficacy of Allogenic Administration of Treg Cells Obtained From Thymic Tissue (thyTreg) to Control The Immune Hyperactivation Associated With COVID-19

Conditions
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Systemic Inflammatory Response Syndrome

Intervention / Treatment
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* Biological: Allogeneic thyTreg 5.000.000
* Biological: Allogeneic thyTreg 10.000.000


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient over 18 to 60 years of age Patient Informed and non-opposed to the research by his medical doctor during hospitalization Patient diagnosed with severe COVID-19 pneumonia with Diagnosis of infection with SARS-CoV-2 virus by C-reactive Protein (CRP) Pulmonary abnormalities consistent with pneumonia by chest imaging (radiograph or scan) Who have one or more of the following requirements: SpO2≤94% on room air, PaO2/FiO2≤ 300 or SaO2/FiO2≤ 350 Patients with signs of cytokine release or macrophage activation syndrome with one of the following conditions: or leukopenia <800/ul or D-dimer >1500 ng/ml or IL6 > 40 pg/ml or ferritin >300 ng/ml or CRP >3 mg/dl or LDH >300 UI/L Exclusion Criteria: Pregnancy or breast feeding Body mass index >35 Patients not expected to survive 48 hours after enrolment based on clinical assessment Patients with an extracorporeal respiratory support Neutropenia (absolute neutrophil count <1000/uL) Thrombocytopenia (absolute neutrophil count <50000/uL) Positive serology for HBV, HCV, or HIV at Screening Sepsis or severe pneumonia bacterial or suspected serious infection Life expectancy of less than 6 months due to other pathologies History of significant underlying pulmonary disease requiring oxygen therapy prior to COVID-19 infection. Patients with a history of autoimmune diseases Patients with a history of hematopoietic neoplasia or oncology disease Patients with a history of hematopoietic or solid organ transplant Patients with a congenital or induced immunodeficiency Patients received thymoglobulin, basiliximab or any anti-T-cell therapies within 6 moths prior to the screening visit Patients received other cell therapy in the last 12 months Patients received intravenous immunoglobulin (IVIg) within 5 moths prior to the screening visit Patients who have participated or is participating in a clinical research study evaluating COVID-19 within 30 days prior to the screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase A: 5.000.000 thyTreg /kg<br>Allogeneic thyTreg 5.000.000 | Biological: Allogeneic thyTreg 5.000.000<br>* Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and stimulated with Interleukin (IL-) 2 (thyTreg)<br>* Other names: Allogeneic thyTreg cells;|
| No Intervention: Phase A: standard of care<br>Standard of care | |
| Experimental: Phase B: 10.000.000 thyTreg /kg<br>Allogeneic thyTreg 10.000.000 | Biological: Allogeneic thyTreg 10.000.000<br>* Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and stimulated with Interleukin (IL-) 2 (thyTreg)<br>* Other names: Allogeneic thyTreg cells;|
| No Intervention: Phase B: standard of care<br>Standard of care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Incidence of infusion-related adverse events (safety) by type, frequency, severity, and causality |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of intensive care unit stay |  | 24 months | 
| Oxygenation improvement as assessed using PaO2/FiO2 and SaO2/FiO2 |  | 24 months | 
| Change in clinical status as assessed using Sequential Organ Failure Assessment Score |  | 24 months | 
| Change in clinical status as assessed using Acute Physiology and Chronic Health disease Classification System (APACHE) III |  | 24 months | 
| Change in clinical status as assessed using Barthel score |  | 24 months | 
| Change in myocardial function as measured by mitral and tricuspid regurgitation using doppler echocardiography |  | 24 months | 
| Change in myocardial function as measured by mitral and tissue mitral doppler using doppler echocardiography |  | 24 months | 
| Change in myocardial function as measured by tricuspid and tissue tricuspid using doppler echocardiography |  | 24 months | 
| Change in SARS-CoV-2 positivity as assessed using diagnostics test |  | 24 months | 
| CChange From Baseline in ferritin parameter |  | 24 months | 
| Change From Baseline in D-dimer parameter |  | 24 months | 
| Change From Baseline in Lactate dehydrogenase (LDH) parameter |  | 24 months | 
| Change From Baseline in interleukin 6 (IL-6) |  | 24 months | 
| Change From Baseline in C-Reactive Protein (PCR) |  | 24 months | 
| Change From Baseline in Treg cells number in peripheral blood |  | 24 months | 
| Number of T cells, B cells, NK cells, monocytes, dendritic cells, and granulocytes in peripheral blood |  | 24 months | 
| Change From Baseline in cytokines levels of interferon gamma, tumor necrosis factor alpha and interleukins (IL-6 and IL-10). |  | 24 months | 
| Overall patient survival rate at 24 months |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune Hyperactivation, Regulatory T cell, COVID-19, Advanced therapy, Immunotherapy, Th1-Th2 Balance