Immune Reconstitution in Recipients of Photodepleted HLA-Identical Sibling Donor Stem Cell Transplantations: T Cell Subset Frequencies Predict Outcome

Abstract

We evaluated an ex-vivo photodepletion technique to selectively deplete graft-versus-host disease (GVHD) alloreacting T cells given to 24 HLA-identical sibling stem cell transplant (SCT) recipients. Donor lymphocytes were activated by 72 hr exposure to irradiated in-vitro expanded recipient T lymphocytes and pulsed with TH9402 photosensitizer. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The photodepletion product showed an inverted CD4+/CD8+ ratio with greatest depletion occurring in the CD4+naïve and central memory populations. In contrast, the CD8+ naive and effector cells were relatively conserved, reflecting the differential extrusion of TH9402 by T cell subsets. CMV reactive T cells were reduced in the photodepletion product and in recipient blood 100 days after SCT when compared with contemporaneous HLA-identical sibling donor T cell depleted SCT recipients. Although PD SCT recipients experienced similar absolute lymphocyte counts during the first 100 days after SCT, they achieved 100% donor T cell chimerism more rapidly and had higher CD8+ naive T cell counts early after SCT. SCT recipients of photodepleted products with the lowest CD4 central memory content had the highest risk of developing chronic GVHD (p = 0.04), and a poorer survival (p = 0.03). While the persistence of CD8+ naive T cells may have contributed to important anti-leukemia responses resulting in a relatively low relapse rate, our findings emphasize the role of donor memory T cells and CD4 cells in establishing immune competence post SCT. Although photodepletion is associated with excellent outcomes in the haploidentical setting, the low frequency of alloactivations in HLA-matched pairs makes the PD approach used by our group for allodepletion in HLA-matched sibling transplantations an inefficient technique.

Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation

“…Seven patients received a T-cell-depleted graft (protocol 06-H-0248) and 13 received a selectively depleted graft (protocol 07-H-0136). 10 During conditioning, lymphocyte and monocyte counts fell rapidly whereas granulocytes showed a median 3-fold (range, 1.5-6.3) increase over 2 days (related to the dexamethasone administered during the radiation treatment) followed by a rapid decline to zero over the subsequent 5 days ( Figure 1A). All patients established donor myeloid chimerism by day 14, and all 20 patients achieved greater than 95% donor T-cell chimerism at a median of 30 days (range, 14-270 days).…”

Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant

“…[12][13][14][15][16] However, the contribution of mature donor lymphocytes infused at the time of transplantation has not been fully defined. 17 To explore the influence of immunological characteristics of the donor further, we studied donor lymphocyte counts in a series of patients undergoing HSCT to identify the potential contribution of donor regulatory and conventional T lymphocyte populations to immune recovery and transplant outcomes.…”

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

“…31,34 While photo depletion exhibited positive results in haploidentical transplant, 34,35 off-target depletion of CD4 + CM T cells in matched sibling transplants was associated with increased rate of infection and transplant-related mortality. 10 We have shown that adenosine specifically targets alloactivated T cells in mMLR and does not significantly deplete resting memory T cells. Importantly, using adenosine we achieved SD in both haploidentical and matched sibling mMLR (Figure 7).…”

“…Photodepletion with a TH9402-based dye failed to improve outcomes in HLA-matched sibling transplants but has shown promise in haploidentical transplants. [10][11][12] An effective, immune modulating strategy for SD which conserves Tregs and can be consistently and easily reproduced in clinical scale has not yet been achieved.…”