Ex-vivo Primed Memory Donor Lymphocyte Infusion to Boost Anti-viral Immunity After T-cell Depleted HSCT

Sponsor

Federal Research Institute of Pediatric Hematology, Oncology and Immunology (Other)

Overall Status

Recruiting

CT.gov ID

NCT05066958

Collaborator

(none)

Enrollment

Location

Arm

14.5

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

HSCT from an allogeneic donor is the standard therapy for high-risk hematopoietic malignancies and a wide range of severe non-malignant diseases of the blood and immune system. The possibility of performing HSCT was significantly limited by the availability of donors compatible with the MHC system. However, modern ex-vivo and in vivo technologies for depletion of T lymphocytes have made it possible to improve the outcomes of HSCT from partially compatible related (haploidentical) donors. In representative groups, it was shown that the success of HSCT from haploidentical donors is not inferior to standard procedures of HSCT from HLA-compatible unrelated donors. HSCT from haploidentical donors in children associated with the deficit of the adaptive immune response, which persists up to 6 months after HSCT and can be an increased risk of death of the patient from opportunistic infections. To solve this problem, the method of infusion of low doses of donor memory T lymphocytes was introduced. This technology is based on the possibility of adoptive transfer of memory immune response to key viral pathogens from donor to recipient. Such infusions have been shown to be safe and to accelerate the recovery of the pathogen-specific immune response. The expansion of virus-specific T lymphocytes in the recipient's body depends on exposure to the relevant antigen in vivo. Thus, in the absence of contact with the viral antigen, the adoptive transfer of memory T lymphocytes is not accompanied in vivo by the expansion of virus-specific lymphocytes and does not form a circulating pool of memory T lymphocytes, that can protect the patient from infections. Therefore the investigators assume that ex-vivo priming of donor memory lymphocytes with relevant antigens can provide optimal antigenic stimulation and may solve the problem of restoring immunological reactivity in the early stages after HSCT. Technically ex-vivo primed memory T lymphocytes will be generated by short incubation of CD45RA-depleted fraction of the graft (a product of T lymphocyte depletion) with a pool of GMP-quality peptides representing a number of key proteins of the viral pathogens. The following are proposed as targeted antigens: CMV pp65, EBV EBNA-1, EBV LMP12A, Adeno AdV5 Hexon, BKV LT, BKV VP1. An infusion of donor memory lymphocytes will be performed on the day +1 after transplantation. Parameters of the assessment will be safety and efficacy (immune response by day 60 and stability (responses by day 180).

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia High Risk Acute Myeloid Leukemia Acute Lymphoblastic Leukemia, in Relapse High Risk Acute Lymphoblastic Leukemia Acute Biphenotypic Leukemia in Relapse Non-hodgkin Lymphoma Myelodysplastic Syndromes	Biological: boost anti-viral immunity after T-cell depleted HSCT	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Safety and Efficacy Study of an Ex-vivo Antigen-primed Donor Memory Lymphocyte Infusion for the Enhancement of Immunity to Viral Infections Among Recipients of Allogeneic Hematopoietic Stem Cell Transplantation on the Platform of Selective Immunomagnetic Depletion of T-lymphocytes

Actual Study Start Date :

Sep 16, 2021

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: boost anti-viral immunity after T-cell depleted HSCT	Biological: boost anti-viral immunity after T-cell depleted HSCT Registration and informed consent sign Screening clinical and laboratory examination, assessment of compliance with inclusion criteria Survey of the recipient and potential donors Donor selection The study of the immune response to relevant antigens in the donor and recipient Pre-transplant conditioning Stimulation of the donor and apheresis of peripheral blood mononuclear cells Graft processing The manufacturing of cell product Transplant Infusion Antigen-primed memory DLI infusion Inpatient care until day +30 Outpatient monitoring and screening

Arm

Intervention/Treatment

Experimental: boost anti-viral immunity after T-cell depleted HSCT

Biological: boost anti-viral immunity after T-cell depleted HSCT

Registration and informed consent sign Screening clinical and laboratory examination, assessment of compliance with inclusion criteria Survey of the recipient and potential donors Donor selection The study of the immune response to relevant antigens in the donor and recipient Pre-transplant conditioning Stimulation of the donor and apheresis of peripheral blood mononuclear cells Graft processing The manufacturing of cell product Transplant Infusion Antigen-primed memory DLI infusion Inpatient care until day +30 Outpatient monitoring and screening

Outcome Measures

Primary Outcome Measures

acute Graft Versus Host Disease [100 days after HSCT]
Cumulative risk of developing of acute Graft Versus Host Disease (aGVHD) (evaluation period is 100 days) stage II-IV
The proportion of patients with detectable T-cell response (IFNgamma ELISPOT) to CMV [after HSCT by day + 30 and by day + 180]
The proportion of patients with detectable peripheral blood T-lymphocytes specific for CMV antigens
The proportion of patients with detectable T-cell response (IFNgamma ELISPOT) to ADV [after HSCT by day + 30 and by day + 180]
The proportion of patients with detectable peripheral blood T-lymphocytes specific for ADV antigens
The proportion of patients with detectable T-cell response (IFNgamma ELISPOT) to EBV [after HSCT by day + 30 and by day + 180]
The proportion of patients with detectable peripheral blood T-lymphocytes specific for EBV antigens

Secondary Outcome Measures

Cumulative Incidence of developing chronic GVHD [after HSCT up to 2 years]
Cumulative Incidence of developing chronic GVHD
Cumulative Incidence of recurrence of leukemia CI of relapse [after HSCT up to 2 years]
Cumulative Incidence of recurrence of leukemia
TRM [after HSCT up to 2 years]
Cumulative Incidence of transplant-related mortality
OS [after HSCT up to 2 years]
Overall survival

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Informed consent signed by the patient (ages 14 to 18) and / or his legal representative (ages 0 to 18).
The patient has an indication for allogeneic transplantation of hematopoietic stem cells established in accordance with the current regulatory framework
Planned HSCT selective immunomagnetic depletion of alpha/betta T lymphocytes
Karnovsky or Lansky index more than 50%
Life expectancy at least 4 weeks
Heart function: ejection fraction of at least 40%
Consent to continue follow-up for 5 years

Exclusion Criteria:

Acute viral hepatitis or acute HIV infection
Hypoxemia with SaO2 <90%
Bilirubin> 3 norms
Creatinine> 3 norms
Pregnancy and lactation
Severe uncontrolled infection
Severe (>?) pathology of the central nervous system (epilepsy, dementia, organic damage to the central nervous system, psychosis)