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 toevaluate the safety and efficacy of the adoptive transfer of autologous thyTreg toprevent rejection in heart transplant children (NCT04924491), with preliminary resultsindicating 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 lowrisk of adverse effects. These thyTreg cells could inhibit an excessive inflammation inSARS-CoV-2 infection, or ameliorate the immunological affection underlying Acuterespiratory distress syndrome, improving life-threatening manifestations, restoringimmune balance, and protecting affected tissues.This clinical trial is an open-label Sequential Parallel Group Phase I/II study toevaluate the safety and efficacy of allogeneic thymus derived Tregs (thyTreg) (thyTreg)in controlling the immune dysregulation associated with SARS-CoV-2 infection and/or AcuteRespiratory 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.
Biological: Allogeneic thyTreg 5.000.000
Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and
stimulated with Interleukin (IL-) 2 (thyTreg)
Other Name: Allogeneic thyTreg cells
Biological: Allogeneic thyTreg 10.000.000
Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and
stimulated with Interleukin (IL-) 2 (thyTreg)
Other Name: Allogeneic thyTreg cells
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
Hospital General Universitario Gregorio Marañon
Madrid, Spain
Investigator: Rafael Correa-Rocha, PhD
Contact: +34 915866455
rafael.correa@iisgm.com
Marta Martínez-Bonet, PhD
34 915866455
marta.mbonet@iisgm.com
Diana Hernández Flórez, PhD
34 915866455
diana.hernandez@iisgm.com
Rafael Correa-Rocha, PhD, Principal Investigator
Hospital General Universitario Gregorio Marañon