Adoptive Transfer of Haploidentical NK Cells and N-803

NCT03899480 | Completed Phase 1 FDA Drug

• 1 other identifier: IDIM-2018-26587
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

This is a pilot therapeutic study of related donor HLA-haploidentical NK-cell based therapy to determine if the treatment is safe and well-tolerated and if there is any measureable impact on virus reservoirs.

Conditions

Hiv; HIV Infections; Immune Deficiency

Keywords

Suppressive Antiretroviral Therapy (ART)

Outcome Measures

Primary Outcomes (21)

• Adverse Events

  Toxicity and adverse events will be classified according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events v2.0. Scale ranges from grade 0 to 4 with a grade of 0 indicating normal signs and symptoms and a grade of 4 indicating potentially life-threatening signs and symptoms. Grade 2, 3, and 4 adverse events will be considered when determining the safety and tolerability of treatment.

  throughout trial participation: 100 days post infusion

• CBC; White Blood Cell Count

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. White blood cell count will be evaluated by principle investigator. WBC outside of established clinical reference range (4.5-11.0 k/ul) may indicate adverse treatment reaction. Total occurrence of abnormal CBC results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CBC; Red Blood Cell Count

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Red blood cell count will be evaluated by principle investigator. RBC outside established clinical reference range (2.5-5.5 mil/ul) may indicate adverse treatment reaction. Total occurrence of abnormal CBC results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 day post infusion

• CBC; Hemoglobin

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Hemoglobin will be evaluated by principle investigator. Hemoglobin outside established clinical reference range (14-17 g/dl) may indicate adverse treatment reaction. Total occurrence of abnormal hemoglobin results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CBC; Hematocrit

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion. Hematocrit will be evaluated by principle investigator. Hematocrit outside established clinical reference range (42-52%) may indicate adverse treatment reaction. Total occurrence of abnormal hematocrit results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CBC; Mean Corpuscular Volume

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. MCV will be evaluated by principle investigator. MCV outside established clinical reference range (84-96 fl.) may indicate adverse treatment reaction. Total occurrence of abnormal MCV results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CBC; Mean Corpuscular Hemoglobin

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. MCH will be evaluated by principle investigator. MCH outside established clinical reference range (28-34 pg) may indicate adverse treatment reaction. Total occurrence of abnormal MCH results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CBC; Mean Corpuscular Hemoglobin Concentration

  Complete blood count will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. MCHC will be evaluated by principle investigator. MCHC outside established clinical reference range (33-36 g/dl) may indicate adverse treatment reaction. Total occurrence of abnormal MCHC results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Sodium

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Sodium concentration will be evaluated by principle investigator. Sodium concentration outside established clinical reference range (136-145 mmol/l) may indicate adverse treatment reaction. Total occurrence of abnormal sodium concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Potassium

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Potassium concentration will be evaluated by principle investigator. Potassium concentration outside established clinical reference range (3.5-5.1 mmol/l) may indicate adverse treatment reaction. Total occurrence of abnormal potassium concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Chloride

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Chloride concentration will be evaluated by principle investigator. Chloride concentration outside established clinical reference range (98-107 mmol/l) may indicate adverse treatment reaction. Total occurrence of abnormal chloride concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Glucose

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Glucose concentration will be evaluated by principle investigator. Glucose concentration outside established clinical reference range (70-99 mg/dl) may indicate adverse treatment reaction. Total occurrence of abnormal glucose concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Calcium

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Calcium concentration will be evaluated by principle investigator. Calcium concentration outside established clinical reference range (8.2-10.2 mg/dl) may indicate adverse treatment reaction. Total occurrence of abnormal calcium concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Blood Urea Nitrogen

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. BUN concentration will be evaluated by principle investigator. BUN concentration outside established clinical reference range (6-25 mg/dl) may indicate adverse treatment reaction. Total occurrence of abnormal BUN concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Creatinine

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Creatinine concentration will be evaluated by principle investigator. Creatinine concentration outside established clinical reference range (0.8-1.3 mg/dl) may indicate adverse treatment reaction. Total occurrence of abnormal creatinine concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Alkaline Phosphatase

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Alkaline phosphatase concentration will be evaluated by principle investigator. Alkaline phosphatase concentration outside established clinical reference range (26-137 u/l) may indicate adverse treatment reaction. Total occurrence of abnormal alkaline phosphatase concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Alanine Transaminase

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Alanine transaminase concentration will be evaluated by principle investigator. Alanine transaminase concentration outside established clinical reference range (15-65 u/l) may indicate adverse treatment reaction. Total occurrence of abnormal alanine transaminase concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Aspartate Transaminase

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Aspartate transaminase concentration will be evaluated by principle investigator. Aspartate transaminase concentration outside established clinical reference range (0-37 u/l) may indicate adverse treatment reaction. Total occurrence of abnormal aspartate transaminase concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Total Bilirubin

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Total bilirubin concentration will be evaluated by principle investigator. Total bilirubin concentration outside established clinical reference range (\<1.1 mg/dl) may indicate adverse treatment reaction. Total occurrence of abnormal total bilirubin concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Albumin

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Serum albumin will be evaluated by principle investigator. Serum albumin concentration outside established clinical reference range (3.2-4.7 g/dl) may indicate adverse treatment reaction. Total occurrence of abnormal serum albumin concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

• CMP; Total Protein

  Comprehensive metabolic panel will be performed at days 2, 3, 10, 21 post infusion to aid in the continuous assessment of safety and tolerability throughout the study. Total protein will be evaluated by principle investigator. Total protein concentration outside established clinical reference range (6.4-8.2 g/dl) may indicate adverse treatment reaction. Total occurrence of abnormal total protein concentration results will be used to determine treatment safety and tolerability.

  2, 3, 10, and 21 days post infusion

Secondary Outcomes (1)

• Decrease in HIV reservoirs

  100 days post infusion

Study Arms (1)

Haploidentical Natural Killer Cells

EXPERIMENTAL

Day -7 the subject will undergo inguinal lymph node biopsy \& colonoscopy to obtain ileal \& rectal biopsies. Blood samples will be obtained. PBMCs will be obtained to sort into CD4 subsets \& measure frequencies of HIV RNA \& DNA. On Day -1, the donor will undergo apheresis \& donor cells will be obtained \& incubated overnight. On Day 0 subjects will be infused with N-803 activated NK cells. Subjects will receive 1st dose of N-803 4 hrs after the infusion. Plasma will be obtained at 2, 4 \& 12 hrs after. Subjects will return on Days 2, 4, 7, 10, \& 14 for blood draw. Subjects will return Days 21 \& 42 for blood work \& to receive 2 additional doses of N-803, for a total of 3 doses. Subjects will be monitored for toxicity assessment by targeted physical exam \& laboratory evaluations on Days 2, 4, 7, 10, 21, \& 42. On day 49, we will perform lymph node biopsy \& colonoscopy to obtain ileal \& rectal tissues. The patient will then be followed until day 100 post infusion.

Biological: Haploidentical Natural Killer (NK) Cells

Interventions

Haploidentical Natural Killer (NK) Cells BIOLOGICAL

infusion with N-803 activated NK cells

Haploidentical Natural Killer Cells

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age-18-65
• Stable ART for at least 12 months.
• Screening plasma HIV RNA levels below level of quantification (\<40 to \<50 copies RNA/mL depending on the assay).
• Screening CD4 count ≥500 cells/µl
• Laboratory tests (Complete Blood Count, Comprehensive Metabolic Panel, Mg, Phosphorus, international normalized ratio/partial thromboplastin time (INR/PTT), Thyroid stimulating hormone (TSH)/T4,) performed within 14 days of infusion of donor NK cells. All laboratory results (unless otherwise specified) must be Grade 1 or normal based on the DAIDS Adverse Event Grading Scale (Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events v2.0)
• Adequate kidney function defined by estimated Glomerular Filtration Rate (CrCl) \> 60 ml/min or ml/min/1.73 m2 (≤ grade 2 per DAIDS) and creatinine ≤ 1.5 x ULN
• Pulmonary Function Testing (PFT) must show FEV1 and DLCOcorr \> 50% of predicted if subjects have symptomatic or prior known impairment.
• Normal transthoracic echocardiogram
• Ability to be off prednisone and other immunosuppressive drugs for at least 14 days before infusion of cells
• Women of child bearing potential and men with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy
• Voluntary written consent provided by the subject

You may not qualify if:

• Any condition that precludes leukapheresis, lymph node biopsy or colonoscopy with biopsy
• Active infection other than HIV currently requiring systemic antimicrobial therapy
• History of deep vein thrombosis
• Active significant, tissue invasive fungal infection requiring systemic antifungal therapy (dermatologic conditions requiring only topical therapy are allowed).
• Chronic active hepatitis B or C (defined as antibody positive and DNA+ or HepBsAG+).
• Breastfeeding
• Intended modification of antiretroviral therapy in the next 24 weeks
• NYHA (New York Heart Association) Class III or IV heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunction
• Symptomatic congestive heart failure, unstable angina pectoris, or Myocardial infarction within 6 months prior to screening
• Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval greater than 500 milliseconds)
• On-going chronic systemic corticosteroid use or other immunosuppressive therapy (a history of mild asthma not requiring therapy is eligible and inhaled corticosteroids is allowed. Topical steroids are allowed.)
• Psychiatric illness/social situations that would limit compliance with study requirements
• Previous diagnosis of an autoimmune disease (e.g. rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sclerosis, vasculitis)
• Use of any anticoagulants within the previous 4 weeks.
• Other illness that in the opinion of the investigator would exclude the patient from participating in this study

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• Miller JS, Rhein J, Davis ZB, Cooley S, McKenna D, Anderson J, Escandon K, Wieking G, Reichel J, Thorkelson A, Jorstad S, Safrit JT, Soon-Shiong P, Beilman GJ, Chipman JG, Schacker TW. Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection. J Infect Dis. 2024 May 15;229(5):1256-1265. doi: 10.1093/infdis/jiad578.

  PMID: 38207119 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes

Interventions

Cell Count

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cell Physiological Phenomena

Study Officials

• Timothy Schacker, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Non-controlled intervention groups

Study Record Dates

• First Submitted: March 14, 2019
• First Posted: April 2, 2019
• Study Start: May 1, 2019
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: April 23, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)