Contributions
Abstract: PB1415
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
Patients with R/R AML, or R/R higher risk MDS have a poor prognosis with a 5-year survival of <10%, or median overall survival of 0.8-3.0 years, respectively. Novel chimeric antigen receptor (CAR) T cell products have had limited clinical success in patients with myeloid disorders due to absence of clear targets and a hostile microenvironment. Complete remission with or without hematologic recovery was achieved in 20%>50% of patients treated with non-engineered, allogeneic, haplo-matched NK cells after lymphodepletion; and minimal cytokine release syndrome and neurotoxicity were observed. The cytolytic activity of NK cells is due to the balance of activating and inhibitory signaling; key among the activating receptors is NKG2D, which recognizes multiple ligands upregulated in tumor tissues. NKX101 is composed of CAR NK cells engineered to express a chimeric receptor that fuses the extracellular ligand-binding domain of NKG2D to co-stimulatory (OX40) and signaling (CD3ζ) domains, to enhance its intrinsic antitumor activity. NKX101 also expresses a membrane-bound form of interleukin-15 that serves as an autocrine growth factor to increase NK cell persistence. Preclinical characterization has demonstrated that NKX101 achieves a 4- to 8-fold greater cytotoxicity, superior intrinsic longevity, and enhanced antitumor activity in AML xenograft models relative to nonengineered NK cells.
Aims
A Phase 1 study to investigate NKX101 in subjects with R/R AML or higher risk MDS.
Methods
This multicenter, open-label, Phase 1 study of NKX101 will be conducted in 2 parts: Part 1 to determine the recommended Phase 2 dose (RP2D) of NKX101 utilizing a modified “3+3” enrollment schema. The study will enroll subjects with either R/R primary or secondary AML or R/R higher risk (intermediate-, high-, and very high-risk) MDS. Building on existing clinical data with nonengineered haplomatched NK cells (referenced above), NKX101 manufactured from NK cells obtained from haplomatched, related donors (H) will be used in Part 1. Part 2 (dose expansion) will evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX101 from unrelated, HLA-mismatched donors with separate expansion cohorts for patients with AML or MDS. The starting dose of NKX101 is 1×108 CAR NK cells where NKX101 will be administered on Days 0, 7, and 14 of a 28‑day cycle following standard fludarabine/cyclophosphamide lymphodepletion. Three dose levels are planned. Additional dosing schedules may be considered in the future. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. AML patients will be assessed for efficacy using updated ELN criteria including measurable residual disease assessment, and MDS using modified IWG criteria. Exploratory endpoints are correlation of various degrees of HLA and KIR ligand match/mismatch between donor and recipient with primary and secondary safety, PK, and efficacy measures.
Results
The trial is in progress.
Conclusion
NKX101 is a novel fourth generation allogeneic CAR NK being evaluated in a Phase 1 trial with R/R AML or higher risk MDS patients at multiple centers (NCT04623944).
Keyword(s): AML, CAR-T, MDS, NK cell
Abstract: PB1415
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
Patients with R/R AML, or R/R higher risk MDS have a poor prognosis with a 5-year survival of <10%, or median overall survival of 0.8-3.0 years, respectively. Novel chimeric antigen receptor (CAR) T cell products have had limited clinical success in patients with myeloid disorders due to absence of clear targets and a hostile microenvironment. Complete remission with or without hematologic recovery was achieved in 20%>50% of patients treated with non-engineered, allogeneic, haplo-matched NK cells after lymphodepletion; and minimal cytokine release syndrome and neurotoxicity were observed. The cytolytic activity of NK cells is due to the balance of activating and inhibitory signaling; key among the activating receptors is NKG2D, which recognizes multiple ligands upregulated in tumor tissues. NKX101 is composed of CAR NK cells engineered to express a chimeric receptor that fuses the extracellular ligand-binding domain of NKG2D to co-stimulatory (OX40) and signaling (CD3ζ) domains, to enhance its intrinsic antitumor activity. NKX101 also expresses a membrane-bound form of interleukin-15 that serves as an autocrine growth factor to increase NK cell persistence. Preclinical characterization has demonstrated that NKX101 achieves a 4- to 8-fold greater cytotoxicity, superior intrinsic longevity, and enhanced antitumor activity in AML xenograft models relative to nonengineered NK cells.
Aims
A Phase 1 study to investigate NKX101 in subjects with R/R AML or higher risk MDS.
Methods
This multicenter, open-label, Phase 1 study of NKX101 will be conducted in 2 parts: Part 1 to determine the recommended Phase 2 dose (RP2D) of NKX101 utilizing a modified “3+3” enrollment schema. The study will enroll subjects with either R/R primary or secondary AML or R/R higher risk (intermediate-, high-, and very high-risk) MDS. Building on existing clinical data with nonengineered haplomatched NK cells (referenced above), NKX101 manufactured from NK cells obtained from haplomatched, related donors (H) will be used in Part 1. Part 2 (dose expansion) will evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX101 from unrelated, HLA-mismatched donors with separate expansion cohorts for patients with AML or MDS. The starting dose of NKX101 is 1×108 CAR NK cells where NKX101 will be administered on Days 0, 7, and 14 of a 28‑day cycle following standard fludarabine/cyclophosphamide lymphodepletion. Three dose levels are planned. Additional dosing schedules may be considered in the future. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. AML patients will be assessed for efficacy using updated ELN criteria including measurable residual disease assessment, and MDS using modified IWG criteria. Exploratory endpoints are correlation of various degrees of HLA and KIR ligand match/mismatch between donor and recipient with primary and secondary safety, PK, and efficacy measures.
Results
The trial is in progress.
Conclusion
NKX101 is a novel fourth generation allogeneic CAR NK being evaluated in a Phase 1 trial with R/R AML or higher risk MDS patients at multiple centers (NCT04623944).
Keyword(s): AML, CAR-T, MDS, NK cell