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Corona Virus InfectionPhase 1/2RELEASENCT04578210

Safety Infusion of NatuRal KillEr celLs or MEmory T Cells as Adoptive Therapy in COVID-19 pnEumonia or Lymphopenia

A Phase 1/2 study testing T memory cells and NK cells in people with Corona Virus Infection, run by Instituto de Investigación Hospital Universitario La Paz at 1 site in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a phase I/II clinical trial using adoptive cell therapy with NK cells or memory T cells in patients affected by COVID-19. Severe cases with COVID-19 present a dysregulated immune system with T cell lymphopenia, specially NK cells and memory T cells, and a hyper-inflammatory state. Read more about this study

Who is it for?
Ages Up to 80 years
Conditions the study is for
Corona Virus Infection
What is being tested?
T memory cells and NK cells
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
84 participants
Where
1 siteSpain
Study dates
4 Sep 2020to 30 Mar 2022
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 80 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Male or female patients ≤ 80 years of age.
  • Patient with diagnosis of COVID-19 infection with laboratory confirmation by reverse-transcription PCR (RT-PCR) of SARS-CoV-2 <72 hours prior to study entry.
  • Onset of symptoms < 10 days prior to administration of study treatment.
  • No more than 72 hours (3 days) of hospitalization before study treatment administration.
  • Phase I criteria: Patients requiring hospitalization for COVID-19, with pneumonia diagnosed with chest radiograph or computed tomography imaging or lymphopenia (absolute lymphocyte counts below 1.2 x 109cells /L) AND O2Sat ≤ 94% on room air at screening, no oxygen requirement or with an oxygen need of ≤ 2.5 lpm in nasal cannula.
  • Phase II criteria: Patients requiring hospitalization with pneumonia diagnosed with chest radiograph or computed tomography imaging or lymphopenia (absolute lymphocyte counts below 1.2 x 109cells /L) AND O2Sat ≤ 94% on room air at screening, requiring or not oxygen supplementation (nasal cannula, oxygen mask with reservoir, non-invasive ventilation, etc), but excluding mechanical ventilation.
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  • Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
  • Be willing and able to comply with study procedures.
  • Patients with the ability to comprehend and sign the informed consent
  • Written informed consent obtained prior to any screening procedures.

Who cannot join

  • Enrolled in another Clinical Trial for COVID19.
  • Rapidly progressive disease with anticipated life-expectancy <72 hours.
  • Patients requiring mechanical ventilation.
  • Patients with multiorgan failure.
  • Mild-moderate (grade ≥ 3) organ impairment (liver, kidney, respiratory), according to criteria from the National Cancer Institute (NCI CTCAE version 5.0).
  • Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol.
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  • Have a known history of human immunodeficiency virus infection, Hepatitis B or Hepatitis C; testing is not required in the absence of prior documentation or known history.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
  • Any other condition that, in the opinion if the Investigator, may interfere with the efficacy and/or safety evaluation of the trial.

Trial locations and contacts

1 site in 1 country.

Spain1 site

  • Hospital Universitario La Paz

    Madrid, 28046

Other trials in Spain

About this study

Official title: 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

This is a phase I/II clinical trial using adoptive cell therapy with NK cells or memory T cells in patients affected by COVID-19.

Severe cases with COVID-19 present a dysregulated immune system with T cell lymphopenia, specially NK cells and memory T cells, and a hyper-inflammatory state.

This clinical trial proposes the use of cell therapy for the treatment of patients with worse prognosis due to SARS-CoV-2 infection (those with pneumonia and/or lymphopenia). This is an innovative and a non-pharmacological intervention.

Read the detailed description

In this phase I/II trial natural killer (NK) cells or memory T lymphocytes will be infused from donors who have recovered from COVID-19 and have complete resolution of symptoms for at least 14 days.

There will be two arms based on the biology of the donor and the patient:

Arm 1. Infusion of memory T cells from HLA partially match donors which have the SARS-COV-2 memory T cell repertoire.

Arm 2. Infusion of NK cells which are cells of the innate immune system that can eliminate virally infected cells.

The investigators expect a quick recovery of the patients with pneumonia or lymphopenia for two reasons:

  1. The pool of memory T cells will increase in patients. Memory T cell levels are low in these patients. These lymphocytes have long-life memory, which upon reencountering SARS-CoV-2 will induce enhanced effector function resulting in greater protection of the patient.
  2. NK cells act quickly after a viral infection. The number and function of NK cells correlates with the severity of another coronavirus infection, Severe Acute Respiratory Syndrome (SARS), originated in China in 2002.

Moreover, the investigators have previous successful experience with other viruses such as CMV, EBV and HHV-6.

Patients who have recovered from COVID-19 are the ideal donor candidates because they have immune cells with memory against SARS-CoV-2. Therefore, the infusion of NK and memory T cells from these donors will increase the pool of cells with cytotoxicity to virally infected cells, and will increase the pool of memory cells that respond quicker to a previously encountered stimulus.

This will impact in saving thousands of lives, releasing hospital beds, reducing the costs of a national health system and improving the economy of a locked-down country.

Cell therapies are safe and cost-effective and successfully used in other diseases. The investigators need new innovative treatments where others have failed.

We have performed the phase I:

Arm 1.Phase I single-center dose-escalation in 9 patients infused with memory T cells from a HLA partially match convalescent donor.

Arm 2. Phase I single-center dose-escalation in 6 patients infused with NK cells from convalescent donors.

We evaluate the safety, and feasibility, and obtained the RP2D of a single infusion.

We have performed the phase II with memory T cells:

The phase II for the infusion of memory T cells from HLA partially match convalescent donors has been carried out. 84 patients have been enrolled and randomized into the SoC treatment or the SoC plus the infusion of memory T cells.

Being tested
T memory cells and NK cells
Medical subject headings
Coronavirus Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • T memory cells and NK cellsBiological

    Single infusion of NK or memory T cells from a healthy donor recovered from COVID-19 (dose escalation).

Study groups in NCT04578210
Study groupRoleWhat they receive
Arm A: allogeneic T memory cellsExperimentalpatients will receive memory T cells
Receives: Biological: T memory cells and NK cells
Arm B: allogeneic NK cellsExperimentalpatients will receive NK cells
Receives: Biological: T memory cells and NK cells

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase I: Occurrence of DLTs in all patients during the study treatment, until 21 days after cell infusion and the MTD

    Any grade 3 or higher toxicity with an attribution of definitely or probably related to the infusion of the cells and any lower grade toxicity that increases to a grade 3 or higher as a direct result of the cell infusion.

    Measured: 3 months

  2. Phase II

    Phase II primary outcome is the incidence of patient recovery infusing adoptive NK cells or adoptive memory T cells. Recovery is defined as the proportion of participants in each group with normalization of fever and oxygen saturation (criteria for normalization: temperature < 38°C armpit, and SpO2 > 94%, sustained for at least 24 h) or lymphopenia recovery through day 14.

    Measured: 3 months

Secondary outcomes (1)

  1. Secondary Outcomes

    Time (days) to normal level of lymphocytes. Proportion of patients showing clinical improvement at day 7 according to the investigator (based on respiratory status and blood-result tests).

    Proportion of patients receiving a second cycle. Time (days) to first negative SARS-CoV-2 PCR after infusing adoptive NK cells or adoptive memory T cells.

    The incidence of treatment-related adverse events (new or worsening from baseline) Duration (days) of hospitalization. Time (days) to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever comes first.

    Time to improvement by one category on a 7-point ordinal scale. Subject clinical status (on a 7-point ordinal scale) at day 14. Proportion of patients requiring intensive care unit. All-cause mortality at Day 28.

    Measured: 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Oct 2020
  2. Study start4 Sep 2020
  3. Primary completion13 Jan 2022
  4. Study completion30 Mar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Phase I/II escalating-dose clinical trial, randomized study to determine safety, tolerability, alloreactivity and efficacy of cell therapy with adoptive cell therapy of NK cells or memory T cells in patients affected by COVID-19 Donors will be patients recovered from COVID-19 Will be 2 arms * A: allogeneic T memory cells * B: allogeneic NK cells Two consecutive phases: * The first dose escalation focuses on determining safety and the recommended dose for the phase II Phase I: Patients with SARS-CoV-2+ pneumonia and/or lymphopenia and O2Sat ≤ 94% on room air at screening, with no oxygen required or with an oxygen need of ≤ 2.5 lpm in nasal cannula, will be selected This phase has a single ascending dose design with up to 3 planned dose levels for each arm. * The second phase extends the safety study Phase II: Patients with SARS-CoV-2+ pneumonia and/or lymphopenia and O2Sat ≤ 94% on room air at screening, requiring or not oxygen supplementation
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
84 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04578210
Sponsor's protocol ID
RELEASE
Acronym
RELEASE
Status last verified
May 2022
First submitted
1 Oct 2020
Last updated
1 Jun 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Martin-Antonio B, Blanco B, Gonzalez-Murillo A, Hidalgo L, Minguillon J, Perez-Chacon G; Next Generation CART MAD Consortium. Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations. Front Immunol. 2024 May 8;15:1386856. doi: 10.3389/fimmu.2024.1386856. eCollection 2024.

    PubMed 38779672

  • Ferreras C, Hernandez-Blanco C, Martin-Quiros A, Al-Akioui-Sanz K, Mora-Rillo M, Ibanez F, Diaz-Almiron M, Cano-Ochando J, Lozano-Ojalvo D, Jimenez-Gonzalez M, Goterris R, Sanchez-Zapardiel E, de Paz R, Guerra-Garcia P, Queiruga-Parada J, Molina P, Briones ML, Ruz-Caracuel B, Borobia AM, Carcas AJ, Planelles D, Vicario JL, Moreno MA, Balas A, Llano M, Llorente A, Del Balzo A, Canada C, Garcia MA, Calvin ME, Arenas I, Perez de Diego R, Eguizabal C, Soria B, Solano C, Perez-Martinez A. Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210). Cytotherapy. 2024 Jan;26(1):25-35. doi: 10.1016/j.jcyt.2023.10.002. Epub 2023 Oct 29.

    PubMed 37897472

  • Herrera L, Martin-Inaraja M, Santos S, Ingles-Ferrandiz M, Azkarate A, Perez-Vaquero MA, Vesga MA, Vicario JL, Soria B, Solano C, De Paz R, Marcos A, Ferreras C, Perez-Martinez A, Eguizabal C. Identifying SARS-CoV-2 'memory' NK cells from COVID-19 convalescent donors for adoptive cell therapy. Immunology. 2022 Feb;165(2):234-249. doi: 10.1111/imm.13432. Epub 2021 Dec 2.

    PubMed 34775592

  • Garcia-Garcia I, Guerra-Garcia P, Ferreras C, Borobia AM, Carcas AJ, Queiruga-Parada J, Vicario JL, Mirones I, Solano C, Eguizabal C, Soria B, Perez-Martinez A. 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 study protocol. Trials. 2021 Oct 2;22(1):674. doi: 10.1186/s13063-021-05625-7.

    PubMed 34600562

  • Perez-Martinez A, Mora-Rillo M, Ferreras C, Guerra-Garcia P, Pascual-Miguel B, Mestre-Duran C, Borobia AM, Carcas AJ, Queiruga-Parada J, Garcia I, Sanchez-Zapardiel E, Gasior M, De Paz R, Marcos A, Vicario JL, Balas A, Moreno MA, Eguizabal C, Solano C, Arribas JR, Buckley RM, Montejano R, Soria B. 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. 2021 Sep;39:101086. doi: 10.1016/j.eclinm.2021.101086. Epub 2021 Aug 13.

    PubMed 34405140

  • Del Pozo Martin Y. 47th Annual Meeting of the EBMT. Lancet Haematol. 2021 May;8(5):e317-e318. doi: 10.1016/S2352-3026(21)00104-6. Epub 2021 Mar 31. No abstract available.

    PubMed 33811823

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing T memory cells and NK cells in people with Corona Virus Infection, run by Instituto de Investigación Hospital Universitario La Paz at 1 site in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Occurrence of DLTs in all patients during the study treatment, until 21 days after cell infusion and the MTD (time frame: 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04578210, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2023.

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