Preliminary data from novel DLI strategies show a lower risk of GvHD

With the increased use of haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment of patients with donor-lymphocyte infusions (DLI) after transplant has experienced a revival. DLI derived from the transplant donor serve many purposes as it helps with engraftment and, due to its graft-versus­-leukemia effect, can be used to prevent or treat relapse, thereby prolonging leukemia-free survival. However, DLI come with a higher risk of graft-versus-host disease (GvHD)-related toxicities and mortality.¹ Novel allogeneic cell selection strategies can be used to induce an immunologic response to tumor cells while reducing GvHD and nonrelapse mortality (NRM) risk after allo-HSCT.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, there were two exciting phase I studies exploring some of these new and improved DLI approaches. Monzr M Al Malki, from the City of Hope Comprehensive Cancer Center, Duarte, US, presented the preliminary results of NEXI-001, an adoptive cellular therapy product containing leukemia-specific CD8+ T cells, while Raynier Devillier from the Institut Paoli-Calmettes, Marseille, FR, provided initial results of a study using prophylactic donor-derived IL-2 activated NK cell infusion.^2,3 The GvHD Hub is happy to provide a summary below.

Generating leukemia-targeted T cells²

NEXI-001 is a cell therapy product designed to precisely recognize several antigens specific for leukemia. This product is manufactured in 14 days from donor-derived CD8+ T cells by artificial immune modulation (AIM). The AIM nanoparticles act like synthetic dendritic cells and contain a cocktail of tumor-associated antigens consisting of several epitopes for each antigen. Thousands of AIM nanoparticles bind to the donor’s CD8+ T cells, inducing expansion to a multiantigen T-cell product containing cells at various differentiation stages. Maintaining this diverse composition is essential since it improves the product’s self-renewal, proliferation, and effector function.

NEXI-001 was used in patients with acute myeloid leukemia who relapsed after allo-HSCT (NCT04284228). Patients with high-risk mutations and/or cytogenetics received NEXI-001 as part of a dose-escalation study. Two dose levels were selected: 100 million cells or 200 million cells. The selected dose will be explored in a dose-expansion cohort.

By the time of this report, a total of 7 patients were enrolled and dosed. The production process yielded sufficient CD8+ cells with an antigen specificity of around 34%, and all patients received bridging therapy with fludarabine and cyclophosphamide before NEXI-001 infusion. With a median follow-up of 4 (1–7) months, the second cohort with 200 million cells is still on-going. Moreover, antigen-specific T cells were detected at Day 8 and expanded and persisted for up to 2 months in peripheral blood and bone marrow. Most reported adverse events (AEs) were Grade 1–2, with no GvHD, cytokine release syndrome, neurotoxicity, or infusion-related reactions. Therefore, the pharmacokinetics and the safety profile of NEXI-001 are promising based on currently available data.

Interestingly, the investigators reported an improved reconstitution of CD4+ and CD8+ lymphocyte compartments after NEXI-001 infusion (starting at Day 3 after infusion), compared with what is usually seen after lymphodepletion (1 to 3 months).

Efficacy data are too preliminary to be reported, but the on-going study aims to demonstrate if the immune responses detected with NEXI-001 will correlate positively with clinical responses.

Exploring alternatives to T cells: What about NK cells?³

NK cells represent a promising alternative to T cells in the context of DLI post-allo-HSCT because they do not depend on antigen presentation to be activated. As donor NK cells do not recognize foreign major histocompatibility complex (MHC) molecules from the patient's healthy cells, the risk of GvHD is reduced while a potent antitumor effect is maintained or even enhanced in the allogeneic transplant context. Furthermore, impaired NK cell recovery after allo-HSCT is associated with a higher risk of acute GvHD and relapse. Altogether, these data support the hypothesis of a potential benefit of donor-derived activated NK cell infusion after allo-HSCT.

Initial phase I results presented by Raynier Devillier explored using prophylactic donor-derived IL-2 activated NK cell infusion after allo-HSCT from a matched sibling donor (NCT01853358).

Before infusion, the donor's NK cells were cultured for a week with IL-2 1000 IU/mL, which significantly increased the expression of activating receptors and led to a higher antitumor activity in vitro. The investigators aimed to reach a target dose of 1–5 × 10⁶ cells/kg, but it was challenging: the higher level could not be achieved in 5 out of 10 cases.

A total of 16 patients with different underlying hematologic malignancies received activated NK cell infusions at Day +60 and Day +90 after allo-HSCT. Interestingly, there were no acute GvHD events, while four patients experienced chronic GvHD (one mild, two moderate, and one severe). All patients recovered from their chronic GvHD, three of them after treatment with steroids. Currently, none of these patients is on immunosuppressive treatment. Four other patients relapsed, and one patient died from nonrelapse complications. To date, 13 out of 16 patients are alive and in complete response, leading to a remarkable 2-year progression-free survival of 75% and a 2-year overall survival rate of 88%.

Conclusions

New modified DLI strategies after allo-HSCT seem to be safe and might decouple the benefits of the graft-versus-tumor effect from the GvHD toxicities. Both alternatives discussed need to be further explored in more extensive clinical trials to assess their therapeutic, preemptive, or prophylactic efficacy in disease relapse.