Depletion of Naïve T Cells From Peripheral Blood Stem Cell Grafts for Gvhd Prevention

Graft-versus-host disease (GVHD) frequently causes morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). In HLA-identical HCT, GVHD results from donor T cell recognition of minor histocompatibility (H) antigens on recipient tissues. Complete T cell depletion (TCD) of donor hematopoietic cell products is more effective than pharmacologic immunosuppression for preventing GVHD, but is complicated by delayed immune reconstitution and consequent life-threatening infections. Approaches to HCT that preferentially deplete T cells responsible for GVHD and preserve pathogen-specific T cells may improve outcomes.

Mature CD3⁺CD8⁺ and CD3⁺CD4⁺ T cells can be classified into CD45RA⁺CD62L⁺ naïve (T_N) and CD45RO⁺ memory (T_M) subsets, the latter of which includes effector memory (T_EM) and central memory (T_CM) T cells. Murine studies in MHC-matched and –mismatched models demonstrated that transplanting T_N cells causes severe GVHD, purified T_CM causes mild GVHD, and T_EM do not cause GVHD. In vitro studies have similarly demonstrated that human donor CD8⁺ T cells specific for recipient minor H antigens are found predominantly within the T_N cell subset. In sum, these data suggest that selective T_Ncell depletion may alter the incidence or severity of GVHD in human HCT.

We developed an effective process for engineering human peripheral blood stem cell (PBSC) grafts that depletes CD45RA⁺ T_N and retains CD34⁺ stem cells and functional CD45RO⁺ T_M specific for diverse opportunistic pathogens. We initiated a clinical trial to evaluate selective depletion of T_N cells from allogeneic PBSC for the prevention of GVHD in patients with acute leukemia.  Each of the first 22 patients has engrafted (median day 12), regimen-related toxicity has been acceptable, T-cell numbers recover faster than reported for TCD HCT (median 412 CD3⁺ T cells/μl on day 28), and there is no increase in the rate of relapse, opportunistic infections, or EBV reactivation compared to patients treated with T cell replete PBSC grafts. Early onset gastrointestinal symptoms that are compatible with mild acute GVHD occur frequently, but rapidly respond to therapy, and most patients have successfully tapered immunosuppression. T cell responses to pathogens recover early after HCT.  At a median of 14 months follow-up, overall and disease free survival are 80% and 75% respectively, and the frequency and severity of chronic GVHD is substantially reduced compared to recipients of T cell replete PBSC grafts.