Natural Killer Cell Therapies for Hematologic Malignancies

The "Natural Killer Cell Therapies for Hematologic Malignancies" study is an umbrella repository for data pertaining to multiple related clinical trials that aim to assess NK cell therapies as part of treatment strategies for a range of hematologic malignancies. Here, data from two trials, NCT03068819 and NCT02782546, are presented.Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLI) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), IL-15, and IL-18 to generate memory-like (ML) NK cells with enhanced anti-leukemia responses. We treated nine pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells on a phase I trial. Patients received fludarabine, cytarabine, and filgrastim followed two weeks later by infusion of DLI and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical, matched-related and matched-unrelated donors. Following infusion, donor-derived ML NK cells expanded and maintained ML multidimensional mass cytometry phenotype for over 3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered IFN-gamma production. Following DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for over 3 months with one patient in remission for greater than two years. No significant toxicity was experienced. This study demonstrates that in a compatible immune environment post-HCT, donor ML NK cells robustly expand and persist with potent anti-leukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://www.clinicaltrials.gov/study/NCT03068819.A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced anti-tumor function following stimulation with IL-12, IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on Day 7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in the clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well-tolerated and 87% of patients achieved a composite complete response at Day 28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for two months post-HCT with prolific expansion (1104-fold) over 1-2 weeks. Multidimensional mass cytometry and CITE-seq identified donor ML NK cells as distinct from conventional NK cells and persisting for over two months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patient and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML, with ML NK cells demonstrating enhanced in vivo persistence and functionality, overcoming barriers in the field.]]>
Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)Recipient Inclusion Criteria:Relapsed AML after HLA-matched or HLA-mismatched related or unrelated allogeneic hematopoietic cell transplant (per IWG definition of relapse)For pilot pediatric/young adult patient cohort: ≥1 and <18 years of age, and for phase 2 adult patient cohort: ≥18 years of ageAvailable original donor (same donor as used for the initial stem cell transplant) that is willing and eligible for non-mobilized collectionPatients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.Karnofsky performance status > 60%Adequate organ function: total bilirubin < 2 mg/dL; AST(SGOT)/ALT(SGPT) < 3.0 x IULN; creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 by Cockcroft-Gault Formula; oxygen saturation ≥90% on room airNot currently requiring systemic corticosteroid therapy (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) or any other immune suppressive medicationsWomen of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study including throughout the initial evaluation period (100 days after CIML NK cell infusion).Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).Recipient Exclusion Criteria:Acute or chronic GVHD with ongoing active systemic treatment. Circulating blast count >30,000/μL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed). Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B, or Hepatitis C infection.Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.New or progressive pulmonary infiltrates concerning for new or uncontrolled infectious process.Known hypersensitivity to one or more of the study agentsReceived any investigational drugs within the 14 days prior to CIML NK cell infusion datePregnant and/or breastfeedingDonor Inclusion Criteria:At least 2 years of ageWeight at least 15 kgSame donor as used for the allo-HCTIn general good health, and medically able to tolerate leukapheresis Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative)For donors < 18 years, eligible to undergo standard of care leukapheresis for DLIDonor Exclusion Criteria:Active hepatitis, positive for HTLV, or HIV on donor viral screen PregnantA Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)Recipient Inclusion Criteria:Refractory AML without complete remission (CR) after 2 or more cycles of induction therapy (primary induction failure), or AML relapsed after obtaining a CR and failed one or more cycles of re-induction therapy. Standard dose 10-day decitabine (20 mg/m2 daily IV x 10 days) or 7- day azacitidine (75-100 mg/m2 daily SC/IV x 7 days) will be considered as one cycle of induction therapy.At least 18 years of ageDeemed to be not otherwise eligible for a myeloablative hematopoietic cell transplant. High risk characteristics for a myeloablative transplant include age > 60 years and a HCT comorbidity index > 3.Available HLA-haploidentical donor that meets the criteria.Patients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.Karnofsky performance status > 60%.Adequate organ function: total bilirubin < 2 mg/dl; AST(SGOT)/ALT(SGPT) < 3.0 x IULN; creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 by Cockcroft-Gault Formula; oxygen saturation ≥90% on room air and adjusted DLCO of at least 40%; ejection fraction ≥40%Able to be off of corticosteroids (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) and any other immune suppressive medications beginning on Day -3Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study including throughout the initial evaluation period (100 days after CIML NK cell infusion). Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Recipient Exclusion Criteria:Relapsed after allogeneic transplantation. Circulating blast count >30,000/μL by morphology or flow cytometry (cyto-reductive therapies including leukapheresis or hydroxyurea are allowed).Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.Presence of donor specific antibodies (DSA) with Mean Fluorescence Intensity (MFI) of ≥5000 as assessed by the single antigen bead assay, < 6 weeks prior to starting transplant conditioningUncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.New or progressive pulmonary infiltrates. Progressive pulmonary infiltrate is defined as an increase of 20% or greater from prior radiologic exam. Radiologic assessment methods may be CT or PA/L x-ray imaging. Infiltrates attributed to infection must be stable or improving after 1 week of appropriate therapy, or 4 weeks for presumed or proven fungal infections to be eligible.Known hypersensitivity to one or more of the study agentsReceived any investigational drugs within the 14 days prior to the first day of transplant conditioningPregnant and/or breastfeedingDonor Inclusion Criteria:Related donor (parents, sibling, offspring, or offspring of sibling) At least 18 years of age HLA-haploidentical donor/recipient match by molecular typing at the HLA-A, HLA-B and HLA-DRB1 loci.In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study. Ability to understand and willingness to sign an IRB approved written informed consent document Donor Exclusion Criteria:Positive for hepatitis, HTLV, or HIV infectionPregnant and/or breastfeeding]]>