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

Phase 1

• Conditions: Acute Myeloid Leukemia; High Risk Acute Myeloid Leukemia; High Risk Acute Lymphoblastic Leukemia; Acute Biphenotypic Leukemia in Relapse; Non-hodgkin Lymphoma; Myelodysplastic Syndromes; Acute Lymphoblastic Leukemia, in Relapse
• Interventions: Biological: boost anti-viral immunity after T-cell depleted HSCT

• Registration Number: NCT05066958
• Lead Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology

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).

Detailed Description

Not available

Study Timeline

• Status Verified: 2021-09
• Study Start: 2021-09-16
• Study First Submitted: 2021-09-22
• Study First Submitted QC: 2021-10-01
• Last Update Submitted: 2021-10-01
• Study First Posted: 2021-10-04
• Last Update Posted: 2021-10-04
• Primary Completion: 2022-09-01
• Study Completion: 2022-12-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

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

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
boost anti-viral immunity after T-cell depleted HSCT	boost anti-viral immunity after T-cell depleted HSCT	-

Primary Outcome Measures

Name	Time	Method
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
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

Secondary Outcome Measures

Name	Time	Method
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
Cumulative Incidence of developing chronic GVHD	after HSCT up to 2 years	Cumulative Incidence of developing chronic GVHD
OS	after HSCT up to 2 years	Overall survival

Trial Locations

Locations (1)

Federal Research Center for pediatric hematology, oncology and immunology; 🇷🇺 Moscow, Russian Federation