Memory T-cell Infusion to Improve Immunity After TCR-alpha/Beta Depleted Hematopoietic Stem Cell Transplantation (45RA_NEG_DLI)

Memory T-cell Infusion to Improve Immunity After TCR-alpha/Beta Depleted Hematopoietic Stem Cell Transplantation

Transfusion of CD45RA-depleted Donor Lymphocytes to Improve Regeneration of Antimicrobial Immunity After TCR-alpha/Beta Depleted Hematopoietic Stem Cell Transplantation

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.

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Immune Deficiency Disease, Bone Marrow Failure Syndromes, Opportunistic Infections, Graft vs Host Disease

CD45RA-depletion, TCR-alpha/beta depletion, Hematopoietic Stem Cell Transplantation, immune reconstitution, Graft Enhancement, Immunologic, Immunocompromized Host

Infusion of escalating doses of CD45RA-depleted donor-derived allogeneic peripheral blood mononuclear cells

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

Inclusion Criteria: recipient of allogeneic hematopoietic stem cell graft from haploidentical or matched unrelated donor TCR alpha/beta depletion of the hematopoietic stem cell graft CMV-seropositive donor stable hematopoietic engraftment Exclusion Criteria: active graft-versus-host disease grade 2-4 any systemic immune suppressive therapy except calcineurin inhibitor monotherapy uncontrolled sepsis

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.

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.