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The stud will evaluate whether infusions of CD45RA-depleted lymphocytes from the donor early post-transplant is a safe way to improve immunity to common infections in recipients of TCR-alpha/beta depleted hematopoietic stem cell grafts.
Graft-versus-host disease (GVHD) remains the most important direct complication of hematopoietic stem cell transplantation. Methods used to prevent GVHD include diverse pharmacologic interventions and ex vivo methods of T-cell depletion, the latter being the most effective ones. Historically depletion of T-cells from the graft is associated with increased rate of graft failure, relapse of malignant disease and prolonged immune deficiency. Selective depletion of TCR-alpha/beta T-lymphocytes is a new method of hematopoietic stem cell graft manipulation which is thought to conserve important cell populations, e.g. NK cells and gamma/delta T cells within the graft. Preliminary results suggest that TCR alpha/beta depletion ensures high engraftment rate, low early mortality and good control of GVHD. The problem of delayed immune reconstitution and life-threatening viral infections remains incompletely resolved.
Depletion of naive (CD45RA-positive) T-cells was developed as a new method of graft manipulation to prevent GVHD. Research data indicate that alloreactivity is associated mainly with naive T-cell fraction. In vitro depletion of CD45RA lowers significantly the alloreactive response while retaining reactivity to pathogens.
In the current protocol we plan to test whether relatively low doses of CD45RA-depleted mononuclear cells can be safely infused after TCR-alpha/beta depleted transplantation. The biologic readout for the protocol will be quantitative assessment of T-cell reactivity to common pathogens after infusion.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CD45RA-depleted peripheral blood mononuclear cells | Biological | Infusion of escalating doses of CD45RA-depleted donor-derived allogeneic peripheral blood mononuclear cells |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative incidence of grade 2-4 acute graft-versus-host disease | Cumulative incidence (competing risk model) of acute graft-versus-host disease | 100 days |
| Immune reconstitution (Quantitative evaluation of lymphocyte subsets in the peripheral blood, quantitative evaluation of pathogen-specific immune response by ELISPOT assay) | Quantitative evaluation of lymphocyte subsets in the peripheral blood, quantitative evaluation of pathogen-specific immune response by ELISPOT assay | 120 days |
| Measure | Description | Time Frame |
|---|---|---|
| 1-year survival | Kaplan-Meyer estimate of overall survival | 1 year |
| Transplant-related mortality | Cumulative incidence (competing risk model) of transplant-related mortality |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Maschan, MD | Fedaral Research Center for pediatric hematology, oncology and immunology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Federal Research Center for pediatric hematology, oncology and immunology | Moscow | 117997 | Russia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23933765 | Background | Teschner D, Distler E, Wehler D, Frey M, Marandiuc D, Langeveld K, Theobald M, Thomas S, Herr W. Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. Bone Marrow Transplant. 2014 Jan;49(1):138-44. doi: 10.1038/bmt.2013.114. Epub 2013 Aug 12. | |
| 24525279 | Background |
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| 1-year |
| Incidence of chronic graft-versus-host disease | Cumulative incidence (competing risk model) of chronic graft-versus-host disease | 1 year |
| Bleakley M, Heimfeld S, Jones LA, Turtle C, Krause D, Riddell SR, Shlomchik W. Engineering human peripheral blood stem cell grafts that are depleted of naive T cells and retain functional pathogen-specific memory T cells. Biol Blood Marrow Transplant. 2014 May;20(5):705-16. doi: 10.1016/j.bbmt.2014.01.032. Epub 2014 Feb 11. |
| ID | Term |
|---|---|
| D054218 | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma |
| D015470 | Leukemia, Myeloid, Acute |
| C565469 | Immune Deficiency Disease |
| D000080983 | Bone Marrow Failure Disorders |
| D009894 | Opportunistic Infections |
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D007951 | Leukemia, Myeloid |
| D001855 | Bone Marrow Diseases |
| D007239 | Infections |
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