A Phase 1 Trial of CIML NK Cell Infusion for Myeloid Disease Relapse after Haploidentical Hematopoietic Cell Transplantation

This research study is studying cytokine induced memory-like natural killer (CIML NK) cells
combined with IL-2 in adult patients (18 years of age or older) with Acute Myeloid Leukemia
(AML), Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) who relapse
after haploidentical hematopoietic cell transplantation (haplo-HCT) or HLA matched stem
cells. This study will also study CIML NK cell infusion combined with IL-2 in pediatric
patients (12 years of age or older) with AML, MDS, JMML who relapse after stem cell
transplantation using HLA-matched related donor or related donor haploidentical stem cells.

1. Inclusion Criteria:

1.1 Relapse or post-transplant persistence of AML, MDS (including JMML) or MPN (CMML,
myelofibrosis or MDS/MPN). Disease relapse or persistence will be defined as any
measurable disease by morphology, flow-cytometry, validated tests for minimal residual
disease or disease-defining mutations in the bone marrow, or non-immune privileged
extramedullary sites.

1.2 Persistence of disease within 4 weeks before planned NK cell infusion and at least
2 weeks after completion of immune suppression taper as long as it is > 2 months after
stem cell transplantation for both adult and pediatric patients. If 2 weeks after
completion of the immune suppression taper is still within 2 months of the most recent
stem cell transplant, then chemotherapy with Fludarabine/Cyclophosphamide would need
to start no earlier than at least 2 months after the transplant. For adults, disease
persistence after a second transplant is allowed as long as the most recent transplant
was a haploidentical or HLA matched stem cell transplant. In the pediatric cohort,
disease persistence or recurrence after a second transplant is allowed as long as the
most recent transplant was a haploidentical or matched related donor SCT.

1.3 Available original donor (same donor as used for the most recent haploidentical or
HLA matched stem cell transplant for adults, or for the most recent matched related
donor or related haploidentical donor for pediatrics) that is willing and eligible for
non-mobilized collection.

1.4 Age ≥12 years.

1.5 ECOG performance status ≤2. For For patients in the pediatric cohort, this
corresponds to a Lansky (patients <16 years) or Karnofsky (≥16years) performance
status of ≥50.

1.6 T cell chimerism ≥20% donor-derived within the 4 weeks prior to cell infusion.

1.7 Patient with ≤80% bone marrow involvement within 4 weeks prior to cell infusion.
Medications like hydroxyurea, decitabine or cytarabine are allowed to control rising
blasts between study enrollment and cell infusion.

1.8 No systemic corticosteroid therapy for GVHD (≤ 5mg of prednisone or equivalent
dose of systemic steroids for non-GVHD, non-autoimmune indications are allowed) for at
least 4 weeks prior to cell infusion. Patients on systemic GVHD prophylaxis
medications such as tacrolimus or sirolimus need to be off these medications for at
least 4 weeks prior to cell infusion.

1.9 No other systemic medications/treatments (e.g. ECP) for GVHD for at least 4 weeks
prior to cell infusion.

1.10 Ability of the patient or legal guardian to understand and the willingness to
sign a written informed consent document.

1.11 Adequate organ function within 2 weeks of NK cell infusion as defined below:

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then <3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- Serum creatinine ≤2.0mg/dL

- O2 saturation: ≥90% on room air

- LVEF >40%. If there is no clinical evidence of a change in cardiovascular
function from the time of pre-transplantation ECHO, then there is no need to
repeat it. Otherwise, an ECHO will need to be repeated within 2 weeks of NK cell
infusion.

1.12 Negative pregnancy test for women of childbearing potential only.

1.13 The effects of CIML NK cells and IL-2 on the developing human fetus are unknown.
For this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 4 months after the last IL-2 dose administration.

2. Exclusion Criteria:

2.1 Extramedullary relapse involving immuno-privileged sites (e.g. CNS, testes, eyes).
Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma) are
acceptable.

2.2 Participants who have had investigational agents within 4 weeks prior to cell infusion
(6 weeks for nitrosoureas or mitomycin C), or immunotherapy within 8 weeks prior, or those
who have not recovered from adverse events due to agents administered more than 4 weeks
prior or standard chemotherapy administered more than 14 days ago. Use of hydroxyurea,
hypomethylating agents, low-dose cytarabine or venetoclax to control counts within 4 weeks
prior to cell infusion is permitted with study PI approval but would need to be stopped 1
day prior to administration of Fludarabine and Cyclophosphamide preceding the NK cell
infusion (provided that there are no ongoing AEs attributed to these agents that would
preclude start of lymphodepletion in the view of the investigator). Patients on standard of
care FLT-3, IDH1, and IDH2 inhibitors can stay on this treatment. Therapy with BCR-ABL
inhibitors or bcl-2 inhibitors must be stopped 2 weeks before NK cell infusion and may be
resumed after the end of the DLT period.

2.3 Prior history of Donor Lymphocyte Infusion (DLI) within 8 weeks of CIML NK infusion.
DLI that was given before this time period and that did not result in any GVHD requiring
systemic treatment is not an exclusion criterion.

2.4 Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring
systemic treatment.

2.5 Solid organ transplant recipient. Prior allogeneic HLA matched or mismatched stem cell
transplant is allowed in the pediatric cohort. Prior HLA matched related donor or HLA
matched unrelated donor stem cell transplant is allowed in the adult cohort.

2.6 History of allergic reactions attributed to compounds of similar chemical or biologic
composition to IL-2 or other agents used in study.

2.7 Autoimmune disease: Patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with
a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
Wegener's Granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g.
Guillain-Barre Syndrome and Myasthenia Gravis). Patients with Hashimoto's thyroiditis are
eligible to go on study.

2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with study
requirements.

2.9 Patients who develop a critical illness prior to NK cell infusion that would
contraindicate the administration of Fludarabine and Cyclophosphamide conditioning.
Patients who recover from such illness may still be eligible, but this must be reviewed
with the study PI. A repeat bone marrow examination may be required depending on the timing
of recovery. Patients who become critically ill on the planned day of NK cell infusion are
excluded if the NK cell infusion cannot be given within 48 hours of the planned day 0.

2.10 Pregnant women are excluded from this study because of the unknown teratogenic risk of
CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient effects by
Flu/Cy chemotherapy regimen. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with CIML NK cells and IL-2,
breastfeeding should be discontinued if the mother is treated on this study.

2.11 HIV-positive participants are ineligible because of the potential for pharmacokinetic
interactions with anti-retroviral agents used in this study. In addition, these
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

2.12 Individuals with active uncontrolled hepatitis B or C, HIV, or HTLV-1 are ineligible
as they are at high risk of lethal treatment-related hepatotoxicity after HSCT.

2.13 Individuals with a history of a different malignancy are ineligible except for the
following circumstances: 1. History of other malignancy and have had complete remission of
disease for at least 2 years; 2. Diagnosed and treated within the past 2 years for:
nonmetastatic melanoma, surgically resected (not needing systemic chemotherapy) squamous
cell carcinoma of skin and nonmetastatic prostate cancer not needing systemic chemotherapy.