Allodepleted T‐cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft‐versus‐host disease (GVHD) in the absence of GVHD prophylaxis

Abstract

Summary Graft‐versus‐host disease (GVHD) is a major cause of transplant‐related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T‐cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose‐finding study, 19 adults (median age: 54 years) with high‐risk haematological malignancies were treated with T‐cell‐depleted human leucocyte antigen‐haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104–5 × 106 CD3+ cells/kg (median 31 days post‐transplant). No patient received post‐transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long‐term follow ‐up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3–2 × 106 CD3+ cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse‐related mortality was 33% and overall survival was 67% in these patients.

ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia

“…By comparison, in a meta-analysis of haploidentical HSCT plus PTCY, the 100-day rate of Grade 3/4 aGvHD ranged from 0 to 25% [43]. There, 2-year rates of moderate/severe cGvHD ranged from 0 to 36% [43], whereas only one patient with TCD-haplo + ATIR101 experienced moderate/severe cGvHD, in line with Phase 1 data [34], demonstrating that ex vivo photodepletion successfully removes GvHDcausing cells.…”

“…Grade 3/4 acute GvHD (aGvHD) was not observed at doses up to 5.0 × 10 6 CD3 + cells/kg. At lower doses of 0.3-2.0 × 10 6 cells/kg, there were no serious infections at 1 year and a transplant-related mortality of 0% with 67% stable survival after 8 years [34]. Consequently, safety, feasibility, and efficacy of ATIR101 at a dose of 2.0 × 10 6 CD3 + cells/kg after TCD-haplo were evaluated in this single-arm, pivotal, and multicenter Phase 2 study (CR-AIR-007).…”

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

“…Subsequent activation of TH9402 with visible light leads is then selectively toxic to and eliminates alloreactive T cells via an oxidative damage mechanism (115). Early results from a clinical trial in which patients received the photodynamically allodepleted T-cell product subsequent to a CD34 + selected graft appear promising (116).…”

Donor-cell leukemia with novel genetic features 2 years after sex-mismatched T cell-depleted haploidentical stem cell transplantation

“…In the current case, the lack of lymphocytes in the CD34-selected haploidentical stem cell allograft may have indeed hampered the immune surveillance of rising genetic instability. Nowadays, CD34-selected haploidentical stem cell sources which are more likely to be followed by adoptive transfer of selected or manipulated lymphocytes or T-replete procedures such us post-transplant cyclophosphamide are applied [11].…”