Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor

Abstract

Background: NK cell-based immunotherapy to prevent relapse after allogeneic transplantation is an appealing strategy because NK cells can provide strong antitumor effect without inducing graft-versus-host disease (GVHD). Thus, we designed a phase-I clinical trial evaluating the safety of a prophylactic donor-derived ex vivo IL-2 activated NK cell (IL-2 NK) infusion after allo-HSCT for patients with hematologic malignancies. Methods: Donor NK cells were purified and cultured ex vivo with IL-2 before infusion, at three dose levels. To identify the maximum tolerated dose was the main objective. In addition, we performed phenotypical and functional characterization of the NK cell therapy product, and longitudinal immune monitoring of NK cell phenotype in patients. Results: Compared to unstimulated NK cells, IL-2 NK cells expressed higher levels of activating receptors and exhibited increased degranulation and cytokine production in vitro. We treated 16 patients without observing any dose-limiting toxicity. At the last follow up, 11 out of 16 treated patients were alive in complete remission of hematologic malignancies without GVHD features and immunosuppressive treatment. Conclusions: Prophylactic donor-derived IL-2 NK cells after allo-HSCT is safe with low incidence of GVHD. Promising survivals and IL-2 NK cell activated phenotype may support a potential clinical efficacy of this strategy.

Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

“… 33 By contrast, the therapeutic manipulation of NK cells appears to be a safe approach, as none of the toxic effects associated with T cell therapies have been reported for NK cell-based therapies. 3 , 34 Our data confirmed a good tolerability profile for tetraspecific ANKETs, as no off-target cytokine release or cytotoxicity was observed. However, even if the promotion of NK activity appears to be a safe approach, the toxicity linked to IL-2 therapy is a matter of concern.…”

Adoptive cellular therapy after hematopoietic stem cell transplantation

“…In a subgroup of active AML or MDS patients, CR rate post haplo-SCT with NK cell therapy was 77% (23/30). 122 Other clinical studies also showed safety and efficacy of NK cell therapy after transplantation, [123][124][125][126] including for pediatric solid tumors 127 (Table 2).…”

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

“…The other phase I trial tested prophylactic IL-2 activated donorderived NK cell infusions 60-120 days after matched sibling allo-HCT in 16 patients with hematological diseases (AML, n = 6). The safety of this strategy was demonstrated, and promising efficacy was indicated (137). Meanwhile, Jaiswal et al observed that a well-designed CD56-enriched DLI infusion after PT-Cybased haplo-HCT prompted the good reconstitution of mature NK cells with a reduced incidence of aGVHD (121).…”