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

Abstract

Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.

Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients

“…Ex vivo TCD is still the method of choice for minimizing T-cell mediated alloreactivity without the need for prolonged immunosuppression and yet low rates of acute and chronic GVHD. In addition, T-cell-depleted approaches might be the ideal platform for further applications of adoptive immunotherapy such as donor lymphocyte infusions [ 26 ], virus-specific T-cells, or lately allogeneic CAR T-cells. The haploidentical family donor is usually easily available for these adoptive approaches.…”

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

“…MMUD is still the best alternative option for patients without related HLA-matched donors during CR1 to intermediate-risk AML ( 97 ). However, although haploidentical ASCT is an alternative ASCT with debatable LFS outcomes ( 98 , 99 ), recent results pertaining to myeloablative conditioning (MAC) were at least, either equal or better than MMUD ASCT ( 100 , 101 ), that led to a prospective investigation of MMUD versus haploidentical ASCT (NCT03655145). Notably, in CR1, MAC regimen is associated with a greater risk for infection, particularly bacterial infection, before day 100, compared with reduced-intensity of non-myeloablative conditioning (RIC/NMA) ( 102 ).…”

Inflammation-induced tissue damage mimicking GvHD in human skin models as test-platform for immunotherapeutics

“…Furthermore, recent and highly promising developments in the field of biomarkers may allow early detection and treatment of clinically relevant GvHD (Major-Monfried et al, 2018;Ahmed et al, 2015). Ex vivo graft manipulation techniques such as selective allodepletion prevented or reduced the likelihood of high-grade GvHD in HLA-mismatched allotransplantation, allowing to reduce immunosuppression, thereby enhancing graft-versus-leukemia effects (Roy et al, 2019(Roy et al, , 2020. Thus, tests predicting severe GvHD after ex vivo selection or manipulation of allogeneic immune cells could be of significant value for patient safety.…”