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

Study Overview
=================
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).

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

Conditions
-----------------
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

Intervention / Treatment
-----------------
* Biological: boost anti-viral immunity after T-cell depleted HSCT


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: boost anti-viral immunity after T-cell depleted HSCT<br> | Biological: boost anti-viral immunity after T-cell depleted HSCT<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of developing chronic GVHD | Cumulative Incidence of developing chronic GVHD | after HSCT up to 2 years | 
| Cumulative Incidence of recurrence of leukemia CI of relapse | Cumulative Incidence of recurrence of leukemia | after HSCT up to 2 years | 
| TRM | Cumulative Incidence of transplant-related mortality | after HSCT up to 2 years | 
| OS | Overall survival | after HSCT up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hematopoietic stem cell transplantation, alpha/beta T cell depletion, CD45RA depletion, immune reconstitution, viral infections, ELISPOT