Trial in Progress: AB-101, an Allogeneic, Non-Engineered, Cord Blood-Derived Natural Killer (NK) Cell Therapy, As Monotherapy or in Combination with Rituximab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Abstract

Background: Natural Killer (NK) cells are known to eliminate tumors directly or via antibody-dependent cellular cytotoxicity (ADCC) which is dependent on the maturation, activation and FcγRIIIA (CD16) phenotype of NK cells. Many cancer patients have low NK cell number and dysfunctional innate immunity, which has been correlated with outcomes to monoclonal antibody (mAb) therapy. AB-101 is an allogeneic, non-genetically modified cord blood-derived NK cell therapy, developed to potentially enhance patients' innate anti-tumor activity in combination with approved oncology products with known ADCC mechanism of action. AB-101 has been optimized for combination with mAbs through the novel AlloNK™ proprietary large scale manufacturing process utilizing donor cord blood units. The cord blood unit is selected for key attributes, including an immunoglobulin-like receptor B (KIR-B) haplotype and the natural high-affinity variant of CD16 (158V/V polymorphism). The AlloNK™ process results in an activated and mature NK cell product with increased cell surface expression of CD16, NKG2D, NKp30/44/46, and DNAM-1, without any requirement for genetic engineering. Additionally, the process generates sufficient NK cells to treat hundreds to thousands of patients from a single cord blood unit and produces a consistently active NK cell product, with little donor-to-donor variability. The combination of AB-101 and rituximab has demonstrated strong cytotoxic activity in preclinical studies; the combination led to improved survival over rituximab or NK cells alone in xenograft mouse models. As a cryopreserved, "off-the-shelf", and infusion-ready product, AB-101 is being evaluated for the treatment of hematologic malignancies in combination with standard of care antibody therapies. Study Design, Treatment and Methods: AB-101-01 is a first in human, Phase 1/2, multi-center, open-label study to evaluate the safety and anti-tumor activity of AB-101 as monotherapy and in combination with rituximab in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) of B-cell origin or CLL. This study has 3 parts: Phase 1, 1b, and 2. Phase 1 will evaluate 2 dose levels as monotherapy or in combination with rituximab using the 3+3 dose escalation method. Phase 1b will enroll up to 45 patients in combination with rituximab to determine the recommended phase 2 dose (RP2D). Phase 2 will enroll an additional 15 patients at the RP2D. AB-101 will be given at 1 or 4 billion cells per dose. All enrolled patients will receive at least 1 treatment cycle of 4 doses of AB-101, administered once weekly. Prior to receiving the first dose of AB-101, patients will receive 3 consecutive days of lymphodepleting chemotherapy consisting of fludarabine (30 mg/m2/day) and cyclophosphamide (250 or 500 mg/m2/day). After each AB-101 infusion, patients will receive interleukin-2 (IL-2) at 1×106 IU/m2/dose or 6×106 IU/dose to potentiate NK cell activation and persistence. If given, 375 mg/m2 of rituximab is dosed on the second day of lymphodepletion and with the second and fourth dose of AB-101. Patients who have a complete or partial response or maintain stable disease with the first cycle of the combination may receive 3 additional cycles such that cycle 2 is given with lymphodepletion and cycles 3 and 4 do not include lymphodepletion. Eligible patients must have a diagnosis of B-cell NHL or CLL and must have received at least 2 prior lines of therapy, including an anti-CD20 antibody therapy. Treatment with prior CD19 CAR T-cell therapy is permitted. Patients must be at least 18 years of age, have ECOG PS of 0 or 1, and have measurable disease per Lugano 2014 at the time of enrollment. The primary objectives of each phase are as follows: in Phase 1, the evaluation of the safety of 1 and 4 billion cells/dose of AB-101 as monotherapy or in combination with rituximab through the incidence of AEs and DLTs; in Phase 1b, determination of the RP2D based on safety and antitumor response to AB-101 with rituximab; and in Phase 2, further characterization of the efficacy profile. The study is currently enrolling at 10 U.S. centers. (ClinicalTrials.gov Identifier: NCT04673617)