Abstract
Infection and disease relapse are the two major complications occurring after haplo-mismatched stem cell transplantation (SCT). Accelerating immune reconstitution would imply broader applicability of SCT by providing a transplant opportunity to the large number of patients who cannot find an HLA-matched related or unrelated donor. We have previously reported that photodynamic therapy (PDT) using TH9402 could selectively deplete donor alloreactive cell populations while preserving lymphocytes for immune responses. We present results of an ongoing Phase I clinical trial of haplo-mismatched allogeneic stem cell transplant (SCT) supplemented with DLIs PDT depleted of host-reactive T cells. Thirteen patients with high-risk hematologic malignancies (7 AML relapsed or refractory, 1 AML in CR3, 1 refractory ALL, 2 MDS, 1 NHL relapsing after autologous SCT, 1 refractory CLL) entered the trial. Eleven pts are evaluable for acute GVHD and reconstitution. Patients (7 M, 4 F) underwent transplantation with donor cells mismatched at 3 HLA Ags: 5 patients; 2Ags: 5 pts, and DR only: 1 pt). Donor mononuclear cells (MNCs) were incubated with recipient MNCs for 4 days, exposed to ATIR™ treatment (TH9402 PDT), stored frozen, and administered on day 33±6 after transplant at 5 graded DLI dose levels: 1×104 to 8×105 CD3+ cells/kg. Anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs by approximately 1.5 logs, and flow cytometry showed greater than 90% elimination of activated T cells (CD4+CD25+ and CD8+CD25+) by ATIR. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection. Median age at SCT was 56 years (range: 21–60). Eight patients were in partial remission or had progressive disease, and 3 patients were in complete remission at the time of SCT. Conditioning regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (40 mg/m2/day for 5 days) followed by infusion of CD3 depleted HSC grafts. No GVHD prophylaxis was administered. Evaluable patients showed durable hematologic engraftment: median time to >0.5×109 granulocytes/L was 11 days (8–20), and to >20×109 platelets/L without transfusion, 12 days (9–137) and all achieved complete donor chimerism. No patient developed acute GVHD (grade II–IV), while 3 patients developed signs of chronic GVHD. Four of the first 6 pts developed infectious complications in the first 6 months, and all resolved rapidly with appropriate therapy, except for EBV-PTLD in the first patient (1×104 CD3). Five patients died: 1 of relapsed CLL and 4 of infections (all after day+310), and all had received DLI containing 1.3 ×105 CD3+ cells (2 pts) or less. No other patient relapsed. The first 6 pts developed 10 infectious episodes (4 lethal), while none of the 5 pts receiving the highest DLI doses of CD3+ cells/kg developed any infection (median follow-up: 318 days). The overall disease-free-survival and survival are 57% at 1 year (median follow-up: 10.5 mo). Our results indicate that the post-transplant infusion of a ATIR-PDT treated DLI is feasible, does not induce acute GVHD, and suggests a clinical benefit for patients receiving the highest DLI doses to accelerate T cell reconstitution. This PDT strategy represents an appealing alternative for older patients and those at high risk for GVHD.
Reconstitution of T cell immunity against EBV in the immunocompromised host by adoptive transfer of peptide-stimulated T cells after allogeneic stem cell transplantation