Cell Therapy with Treg Cells Obtained from Thymic Tissue (thyTreg) to Control the Immune Hyperactivation Associated with COVID-19 And/or Acute Respiratory Distress Syndrome (THYTECH2)

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 trial to evaluate the safety and efficacy of the adoptive transfer of autologous thyTreg to prevent rejection in heart transplant children (NCT04924491), with preliminary results indicating the feasibility and safety of the therapy.

In addition, thyTreg cells have shown low immunogenicity in the pre-clinical setting, indicating that allogeneic use of these thyTreg cells (allo-thyTreg) would have a low risk of adverse effects. These thyTreg cells could inhibit an excessive inflammation in SARS-CoV-2 infection, or ameliorate the immunological affection underlying Acute respiratory distress syndrome, improving life-threatening manifestations, restoring immune balance, and protecting affected tissues.

This clinical trial is an open-label Sequential Parallel Group Phase I/II study to evaluate the safety and efficacy of allogeneic thymus derived Tregs (thyTreg) (thyTreg) in controlling the immune dysregulation associated with SARS-CoV-2 infection and/or Acute Respiratory Distress Syndrome.

The immune system is the body's defense 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 respiratory infections like COVID-19, 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 severe COVID-19 and ARDS, it has been shown that an alteration in the frequency and functionality of Tregs. In addition, it has been described that the increased oxygen therapy requirements 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 or ARDS, including dexamethasone and other approved therapies from institutional guidelines.

Eligibility Criteria:
Inclusion Criteria:

1. Patient over 18 to 65 years of age
2. Patient Informed and non-opposed to the research by his medical doctor during hospitalization
3. Patient with clinical, radiological, gasometric and immunological criteria defined as:

   1. Acute respiratory failure secondary to acute lung injury of noncardiogenic cause
   2. Pulmonary abnormalities compatible with bilateral alveoloinsterstitial infiltrates by chest imaging (radiograph or scan)
   3. PaO2/FiO2≤ 300 Presence of at least one of the following markers of inflammation: IL6 \> 40 pg/ml or ferritin \>300 ng/ml or CRP \>3 mg/dl or increasing over the last 24 hours

Exclusion Criteria:

1. Pregnancy or breast feeding
2. Body mass index \>35
3. Patients not expected to survive 48 hours after enrolment based on clinical assessment
4. Patients with an extracorporeal respiratory support
5. Neutropenia (absolute neutrophil count \<1000/uL)
6. Thrombocytopenia (absolute neutrophil count \<50000/uL)
7. Positive serology for HBV, HCV, or HIV at Screening
8. Life expectancy of less than 6 months due to other pathologies
9. History of significant underlying pulmonary disease requiring oxygen therapy prior to inclusion.
10. Patients with a history of autoimmune diseases
11. Patients with a history of hematopoietic neoplasia or oncology disease
12. Patients with a history of hematopoietic or solid organ transplant
13. Patients with a congenital or induced immunodeficiency
14. Patients received thymoglobulin, basiliximab or any anti-T-cell therapies within 6 moths prior to the screening visit
15. Patients received other cell therapy in the last 12 months
16. Patients received intravenous immunoglobulin (IVIg) within 5 moths prior to the screening visit
17. Patients who have participated or is participating in a clinical research study evaluating COVID-19 or ARDS within 30 days prior to the screening visit