Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease
Phase: PHASE1
Conditions: Hiv, HIV Infections, AIDS
Sponsor: University of Minnesota

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV 
Disease 
 
Sponsored by: 
NIH 
 
DAIDS-ES Document Number: DAIDS-ESID 38604 (DARE IL-15) 
 
NIAID Funding Mechanism:    NIH 5UM1AI126611 
 
 
Principal Investigator/Protocol Chair: 
Timothy Schacker, MD 
 
Other Collaborators: 
Co-I: Steven Deeks, MD 
Co-I: Jeff Miller, MD 
Co-I: Zach Davis, PhD 
Co-I: Anne Eaton, PhD 
Co-I: Jon Karn, PhD 
Co-I: Jason Baker, MD 
Co-I: Joshua Rhein, MD 
 
Pharmaceutical Support Provided by: 
ImmunityBio., Inc. 
 
IND Sponsor:  
University of Minnesota 
 
IND Number: 
125191 
 
STUDY PHASE: 
1B 
 
Version Number: 
Version 4.4 
 
Day Month Year 
21 January 2022 
 
 
 
 

 
PROTOCOL VERSION HISTORY 
 
Version Number 
Date 
Significant Changes 
1.0 
10/17/2018 
Original document 
1.1 
01/07/2019 
Changes to background and other modifications requested by 
DAIDS 
1.2 
04/01/2019 
Changes per DAIDS CSRC comments 
1.3 
07/16/2019 
Changes per DAIDS CSRC May 20, 2019 comments 
1.4 
08/20/2019 
Added EKG evidence for ischemia to early stopping rules and more 
detail re: prolonged QTC interval per ProPEP April 1, 2019 
comments  
1.5 
10/01/2019 
Changes per DAIDS Full regulatory review from 9/20/2019 
1.6 
10/10/2019 
Added Nant Reporting Requirements 
1.7 
01/16/2020 
Removed UCSF as study site, added Hennepin Healthcare study site, 
replaced NantKwest with ImmunityBio 
1.8 
04/09/2020 
Per IRB stipulations, noted the study personnel performing study 
specific procedures.  
1.9 
08/28/2020 
Per FDA, added additional EKG testing at specified visits, clarified 
language re: safety reporting of all enrolled participants, (7.16) 
Personnel change for Biostatistician 
Added COVID-19 testing protocol (7.18) 
Indicated external monitor will conduct site initiation visit  
2.0 (formerly 1.10) 
10/16/2020 
Modified details about COVID-19 testings 
2.1 
11/10/2020 
Added Joshua Rhein as Co-I; revised instructions about drug 
administration (5.2.3) 
2.2 
11/19/2020 
Addressed comments from NIH: added instructions to match the ICF 
regarding isolating at home after PCR test and before injections and 
biopsies 
3.0 
1/6/2021 
Added rectal swabs and stool collection at baseline, day 7, day 28, 
day 49, post study drug procedures, and 90 days after 3rd dose 
follow-up visits; added windows for the follow-up visits 
4.0 
1/25/2021 
Removed community member from the Safety Monitoring 
Committee (SMC) in section 14.7 
4.1 
2/8/2021 
Changed the inclusion criteria to be on ART for at least 24 months 
rather than between 12 and 48 months; added the SARS-CoV-2 
vaccine in sections 4.3 and ll.4 
4.2 
4/9/2021 
Contraindications clarified in section 6.2; added a range of 
colonoscopy of 14-18 tissue biopsies in section 7.13; added 
collection of adjacent adipose tissue during the LN biopsy in section 
7.14; added storage and DNA and RNA in section 7.17; removed 
rectal swabs and modified the stool collection schedule; added 
details about the screening blood tests in section 8.1 

4.3 
11/29/2021 
Added a large volume blood draw if the participant is not eligible for 
leukapheresis in sections 4.3, 7.12, 8.2, 8.9 
4.4 
1/21/2022 
Modified details about COVID-19 testing, including an exception to 
COVID-19 screening for 90 days following a positive diagnosis. 
SIGNATURE PAGE 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision, as 
outlined in the protocol. It is understood that all information pertaining to the study will 
be held strictly confidential and that this confidentiality requirement applies to all study 
staff at this site. I will conduct the study in accordance with the provisions of this protocol 
and all applicable protocol-related documents. I agree to conduct this study in compliance 
with United States (US) Health and Human Service regulations (45 CFR 46); applicable 
U.S. Food and Drug Administration regulations; standards of the International 
Conference on Harmonization Guideline for Good Clinical Practice (E6); Institutional 
Review Board/Ethics Committee determinations; all applicable in-country, state, and 
local laws and regulations; and other applicable requirements (e.g., US National Institutes 
of Health, Division of AIDS) and institutional policies. 
 
Principal Investigator:   Timothy W. Schacker 
  
  Print/Type 
 
 
Signed: 
  Date: 1/21/2022 
Name/Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Table of Contents 
PROTOCOL VERSION HISTORY ........................................................................................ 2 
SIGNATURE PAGE .............................................................................................................. 3 
LIST OF ABBREVIATIONS ................................................................................................. 8 
KEY ROLES ........................................................................................................................ 11 
PROTOCOL SUMMARY ..................................................................................................... 13 
1. 
INTRODUCTION / BACKGROUND AND SCIENTIFIC RATIONALE ...................... 18 
1.1. 
Overview .......................................................................................................................... 18 
1.2. 
Study Rationale and Hypothesis ...................................................................................... 29 
1.3. 
Risk / Benefit Assessment ................................................................................................. 29 
2. 
STUDY OBJECTIVES ................................................................................................. 31 
2.1. 
Primary Objectives .......................................................................................................... 31 
2.2. 
Secondary Objectives ....................................................................................................... 31 
2.3. 
Exploratory Objectives ....................................................................................................... 31 
3. 
STUDY DESIGN .......................................................................................................... 31 
3.1. 
Study Overview ................................................................................................................ 31 
3.1.1. Rationale for Dose and Dosing Interval ........................................................................... 31 
3.2. 
Criteria for Evaluation ..................................................................................................... 32 
3.2.1. 
Primary Endpoint ............................................................................................................................. 32 
3.2.2. 
Secondary Endpoints ........................................................................................................................ 33 
3.2.3. 
Exploratory Endpoints ..................................................................................................................... 33 
4. 
STUDY POPULATION ................................................................................................ 33 
4.1. 
Study Population .............................................................................................................. 33 
4.2. 
Inclusion Criteria ............................................................................................................. 33 
4.3. 
Exclusion Criteria ............................................................................................................ 34 
5. 
STUDY TREATMENTS / AGENTS .............................................................................. 35 
5.1. 
Product Characteristics, Preparation and Storage .......................................................... 35 
5.2. 
N-803 Administration (General Guidelines) .................................................................... 36 
5.2.1. 
Formulation and Composition ......................................................................................................... 36 
5.2.2. 
Storage and Handling ....................................................................................................................... 36 
5.2.3. 
General Guidelines ............................................................................................................................ 36 
5.3. 
Individual Dose Delays ..................................................................................................... 39 

6. 
CONCOMITANT MEDICATIONS .............................................................................. 39 
6.1. 
Prohibited Medications ............................................................................................. 39 
6.2. 
Contraindicated Medications ..................................................................................... 40 
7. 
STUDY PROCEDURES ............................................................................................... 40 
7.1. 
Medication Review ........................................................................................................... 41 
7.2. 
Demographics and Medical History ................................................................................. 41 
7.3. 
Clinical Assessment .......................................................................................................... 41 
7.4. 
Physical Examination ....................................................................................................... 41 
7.5. 
Clinical Laboratory Measurements ................................................................................. 42 
7.6. 
HIV Clinical Laboratory Measures .................................................................................. 42 
7.7. 
Cryopreservation of Plasma ............................................................................................. 42 
7.8. 
Cryopreservation of PBMCs ............................................................................................ 42 
7.9. 
Collection of PAXgene Specimen ..................................................................................... 43 
7.10. 
Immunologic Measures .................................................................................................... 43 
7.11. 
Virologic Measures ........................................................................................................... 45 
7.12. 
Leukapheresis .................................................................................................................. 45 
7.13. 
Colonoscopy with Biopsy .................................................................................................. 46 
7.14. 
Inguinal Lymph Node Biopsy ........................................................................................... 46 
7.15. 
Pulmonary Function Test (PFT) ...................................................................................... 46 
7.16. 
EKG ................................................................................................................................. 46 
7.17. 
Sample Processing and Specimen Management ................................................................. 46 
7.18. 
COVID-19 Screening and Testing .................................................................................... 47 
8. 
STUDY SCHEDULE BY VISIT .................................................................................... 47 
8.1. 
Screening .......................................................................................................................... 51 
8.2. 
Baseline Procedures: Days -14 to -7 ................................................................................. 51 
8.3. 
Dose 1 (Day 0) ................................................................................................................... 52 
8.4. 
Dose 1 (Day 7) ................................................................................................................... 52 
8.5. 
Dose 2 (Day 21) ................................................................................................................. 53 
8.6. 
Dose 2 (Day 28) ................................................................................................................. 54 
8.7. 
Dose 3 (Day 42) ................................................................................................................. 54 
8.8. 
Dose 3 (Day 49) ................................................................................................................. 55 
8.9. 
Post Study Drug Procedures (Day 49 - 56) ....................................................................... 55 
8.10. 
Post Biopsy Follow Up (within 7 days of final LN biopsy) ............................................... 56 

8.11. 
Monthly for 3 Months (Day 77-81; Day 107-111; Day 137-141) ....................................... 56 
8.12. 
Early Discontinuation Visit .............................................................................................. 56 
8.13. 
Unscheduled Visit(s) ......................................................................................................... 57 
9. 
ADVERSE EVENT DOCUMENTATION and REPORTING ....................................... 57 
9.1. 
Definitions ........................................................................................................................ 57 
9.2. 
AE Severity ....................................................................................................................... 58 
9.3. 
AE Relationship to Study Drug ........................................................................................ 58 
9.4. 
Reporting Procedures ....................................................................................................... 58 
9.5. 
Summary of Reporting Guidelines and Timeframes ........................................................ 59 
9.6. 
Procedures for Documenting Pregnancy During the Trial .............................................. 61 
9.7. 
Reporting Requirements to Nant Drug Safety ................................................................. 61 
10. 
CLINICAL MANAGEMENT ISSUES ...................................................................... 62 
11. 
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS ....................... 64 
11.1. 
Early Removal .................................................................................................................. 64 
11.2. 
Withdrawal of Participants from the Study ..................................................................... 64 
11.3. 
Replacement of Participants ............................................................................................ 65 
11.4. 
Study Pause Criteria ........................................................................................................ 65 
12. 
PROTOCOL VIOLATIONS ...................................................................................... 65 
13. 
STATISTICAL METHODS AND CONSIDERATIONS ............................................ 66 
13.1. 
Data Sets Analyzed ........................................................................................................... 66 
13.2. 
Safety Analysis ................................................................................................................. 66 
13.3. 
Data Analysis Plan ........................................................................................................... 66 
13.4. 
Sample Size and Randomization ...................................................................................... 67 
14. 
DATA COLLECTION, RETENTION AND MONITORING ..................................... 67 
14.1. 
Data Collection Instruments ............................................................................................ 67 
14.2. 
Data Management Procedures ......................................................................................... 67 
14.3. 
Data Quality Control and Reporting ................................................................................ 67 
14.4. 
Archival of Data ............................................................................................................... 68 
14.5. 
Availability and Retention of Investigational Records ..................................................... 68 
14.6. 
Monitoring ....................................................................................................................... 68 
14.7. 
Safety Monitoring ............................................................................................................. 69 
15. 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 69 
15.1. 
Protocol Amendments ...................................................................................................... 70 

15.2. 
Institutional Review Boards and Independent Ethics Committees .................................. 70 
15.3. 
Informed Consent Form ................................................................................................... 71 
15.4. 
Subject Compensation ...................................................................................................... 71 
15.5. 
Publications ...................................................................................................................... 71 
15.6. 
Biohazard Containment ................................................................................................... 71 
15.7. 
Investigator Responsibilities ............................................................................................. 72 
16. 
REFERENCES ......................................................................................................... 72 
 
 
 
 

LIST OF ABBREVIATIONS 
ACC/AHA 
American College of Cardiology/American Heart Association 
ADCC  
Antibody-dependent cell-mediated cytotoxicity 
AE 
 
Adverse Event 
AIDS  
Acquired Immune Deficiency Syndrome 
ALT/SGPT 
Alanine Aminotransferase 
ART  
Antiretroviral Therapy 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST/SGOT 
Aspartate Aminotransferase 
BP 
 
Blood Pressure 
BUN  
Blood Urea Nitrogen 
CA 
 
Cell-associated 
CLIA  
Clinical Laboratory Improvement Amendments 
ConA  
Concanavalin A 
CD 
 
Cluster of Differentiation  
cDNA  
Complementary DNA 
CFR 
 
Code of Federal Regulations 
CMV  
Cytomegalovirus 
CNS 
 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CRF 
 
Case Report Form 
CRP 
 
C-reactive Protein 
CS 
 
Clinical Significance 
CSR 
 
Clinical Study Report 
CSRC  
DAIDS Clinical Science Review Committee 
CTL 
 
Cytotoxic T Cell 
CXCR5 
CXC chemokine receptor type 5 
DAIDS 
Division of Aids, NIH 
DARE  
Delaney AIDS Research Enterprise 
DNA  
Deoxyribonucleic Acid 
E/CIA  
HIV Enzyme or Chemiluminescence Immunoassay 
EDITS  
Envelope Detection by Induced Transcription-based Sequencing 
EKG  
Electrocardiogram 
FACS  
Fluorescence-activated cell sorting 
FDA  
Food and Drug Administration 
FDC 
 
Follicular Dendritic Cells 
GALT  
Gut Associated Lymphoid Tissue 
GCP 
 
Good Clinical Practice 
HCG  
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus 
HLA  
Human Leukocyte Antigen 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
Id2 
 
DNA-binding protein inhibitor 

IEC 
 
Independent Ethics Committee 
Ig 
 
Immunoglobulin 
IL-2 
 
Interleukin-2 
IL-15  
Interleukin-15  
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
ISM 
 
Independent Safety Monitor 
IUD 
 
Intrauterine device 
IV 
 
Intravenous 
Kg 
 
Kilogram 
KIRS  
Killer-cell Immunoglobulin Receptors 
LDMS  
Laboratory data management system 
LN 
 
Lymph node 
LT 
 
Lymphatic Tissues 
MHC-I 
Major Histocompatibility Complex Class 1 
mL 
 
Milliliter 
µg 
 
Microgram 
MO 
 
DAIDS Medical Officer 
MOLT  
Cell line 
mQVOA 
Quantitative Viral Outgrowth Assay 
MTD  
Maximum Tolerated Dose 
N-803  
IL-15 superagonist (Nant-803, formerly ALT-803) 
NCI 
 
National Cancer Institute 
Nef 
 
Negative Regulatory Factor 
NGS  
Next Generation Sequencing 
NHP  
Non-human Primate Model 
NIAID  
National Institute of Allergy and Infectious Diseases 
NIH 
 
National Institutes of Health 
NK 
 
Natural Killer 
PB  
 
Peripheral Blood 
PBMC  
Peripheral Blood Mononuclear Cell 
PCR 
 
Polymerase Chain Reaction 
PD-1  
Programmed Cell Death Protein 1 
PE 
 
Physical Exam 
PFT 
 
Pulmonary Function Test 
PI 
 
Principal Investigator 
PO 
 
DAIDS Program Officer 
PRD 
 
Participant Reminder Diary 
pVL 
 
Plasma Viral Load 
qPCR  
Quantitative polymerase chain reaction 
QT/QTc 
Heart-rate Corrected QT(QTc) Interval 
RNA  
Ribonucleic Acid 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SEM  
Standard error of the mean 
SIV 
 
Simian Immunodeficiency virus 

SMC  
Safety Monitoring Committee 
SQ 
 
Subcutaneous 
TB 
 
Tuberculosis 
TEM  
Effector T cell Memory Subset 
TFh 
 
T Follicular Helper cell 
TIA 
 
Transient Ischemic Attack 
TID 
 
Three times a Day 
TIGIT  
T-cell immunoreceptor with Ig and ITIM domains 
Treg 
 
Regulatory T cell 
TTM  
Transitional T cell Memory Subset 
UCSF  
University of California, San Francisco 
UMN  
University of Minnesota 
vRNA  
Viral RNA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

KEY ROLES 
Timothy Schacker, MD, Principal Investigator 
University of Minnesota 
420 Delaware Street SE 
Minneapolis, MN 55455 
612-624-9955 
Schac008@umn.edu 
 
Steven Deeks, M.D., Co-Investigator 
Managing Affairs at UCSF 
University of California San Francisco 
1001 Potrero Avenue 
San Francisco, CA 94110 
415-476-4082 ext. 404 
Steven.deeks@ucsf.edu 
 
Jeff Miller, MD, Co-Investigator 
Coordinating Immunologic Assays 
University of Minnesota 
425 East River Pkwy 
Minneapolis, MN 55455 
612-625-7409 
Mille011@umn.edu 
 
Zach Davis, PhD, Co-Investigator 
Laboratory Scientist Conducting Immunologic Assays 
University of Minnesota 
425 East River Pkwy 
Minneapolis, MN 55455 
612-626-4074 
zbdavis@umn.edu 
 
Anne Eaton, PhD, Co-Investigator 
Biostatistician 
University of Minnesota 
A460 Mayo Building MMC303 
420 Delaware St. SE 
Minneapolis, MN 55455   
612-624-4655   
eato0055@umn.edu  
 
Jon Karn, PhD, Co-Investigator 
Case Wester Scientist Conducting EDITS Assays 
Case Western Reserve University 
10900 Euclid Avenue LC4960 
Wood Bldg. W200 

Cleveland, OH 44106 
216-368-3915 
Jonathan.karn@case.edu 
 
Jason Baker, MD, MS, Co-Investigator 
Managing Clinical Affairs at Hennepin Healthcare 
Hennepin Healthcare 
701 Park Avenue, Mail Code G5 
Minneapolis, MN 55415 
612-873-2705 
 
ImmunityBio., Inc. 
NantKwest, Inc. 
Providing N-803 
9920 Jefferson Blvd 
Culver City, CA 90232 
1-844-696-5235 
contact@nantkwest 
 
Randall Tressler, M.D., Medical Officer 
HIV Research Branch/DAIDS/NIAID/NIH 
5601 Fishers Lane, 9E49 
Rockville, MD 20852 
240-627-3072 
randall.tressler@nih.gov 
 
Joshua Rhein, MD, Co-Investigator 
Managing Clinical Affairs at University of Minnesota 
420 Delaware ST SE 
MMC 250 
Minneapolis, MN 55455 
612-624-9996 
rhei0005@umn.edu 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
13 
PROTOCOL SUMMARY 
 
TITLE 
Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV 
Disease 
SPONSOR 
University of Minnesota 
PRINCIPLE 
INVESTIGATOR 
Timothy Schacker, MD 
FUNDING 
ORGANIZATION 
NIAID: NIH 5UM1AI126611 
NUMBER OF SITES 
University of Minnesota 
Hennepin Healthcare 
RATIONALE 
HIV-specific CD8+ T cells are the primary mechanism by which the 
virus is controlled. CD8+ T cells and other effector cells, including 
NK cells, are excluded from B-cell follicles. As a consequence, HIV 
replicates at higher titers in the follicles. This reservoir for the virus 
and may prove to be difficult to target with immune-based curative 
interventions but therapies that allow effector cells (i.e., CD8+ T cells 
or NK cells) to access this reservoir will likely be needed for many of 
the emerging curative approaches. 
The interleukin-15 (IL-15) superagonist N-803 (previously ALT-803) 
induces the expression of CXCR5 on CD8+ T cells, allowing them to 
access to B cell follicles. In a recent study by Webb et al, N-803 
administration to SIV infected macaques was associated with 
increased frequency of SIV specific CD8 T cells in B cell follicles in 
spatial proximity to SIV infected T follicular helper (TFh) cells.  
In an ongoing Phase 1 dose escalation study of N-803 in HIV-infected 
adults on effective ART, we have thus far found in peripheral blood: 
1. There is activation and proliferation of CD4 and CD8 T cells 
and NK cells. 
2. HIV transcription is induced at all doses tested. 
3. There was a significant reduction in the frequency of cells with 
an inducible provirus after 3 doses of drug that persisted up to 
6 months. 
Based on these findings, we hypothesize that the mechanism of 
reservoir reduction is proliferation and activation of HIV specific CD8 
T cells that migrate into follicles and clearance of virus producing 
cells. 
 
STUDY DESIGN 
A phase 1B single arm study of 10 HIV-infected adults on effective 
ART will be performed. This is a two-center, non-randomized, open 
label, and uncontrolled study. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
14 
All participants will undergo an extensive baseline evaluation 7-14 
days before the first dose that will include an excisional biopsy of a 
lymph node, colonic biopsies, and leukapheresis. Participants will 
then receive three doses of N-803 administered every 21 days. A 
second excisional biopsy will be performed between 7-14 days after 
the final dose. The study drug N-803 will be administered at 6 
mcg/kg, which is the maximum tolerated dose determined in a 
recently completed dose-escalation study. 
PRIMARY 
OBJECTIVE 
• To determine the impact of N-803 on the frequency and function 
of CD8+ T cells in B cell follicles. 
• To determine the safety of N-803 HIV+ ART suppressed 
individuals by assessment of adverse events experienced by 
participants during the conduct of the trial. 
SECONDARY 
OBJECTIVES 
• To determine the impact of IL-15 on the frequency, location, and 
phenotype of vRNA+ and vDNA+ cells in lymphoid tissues. 
EXPLORATORY 
OBJECTIVES 
 
 
 
 
 
 
 
 
• To determine the effect of N-803 on frequency of T follicular 
helper cells harboring intact HIV genomes 
• To determine the effect of N-803 on frequency and activation 
status of NK cells in tissue and blood 
• Impact of N-803 on Antibody-dependent cell-mediated 
cytotoxicity (ADCC) in tissues and blood. 
• Impact of N-803 on HIV specific cytotoxic T cell (CTL) in 
tissues and blood. 
• Impact of N-803 on detection of HIV RNA in plasma 
RATIONALE FOR 
TARGET 
POPULATION 
 
 
 
 
 
 
 
 
 
 
 
 
We carefully considered the ideal target population for this trial to 
maximize the impact of the study. 
The role of the B cell follicle as a potential sanctuary for HIV 
replication and persistence has been demonstrated in untreated SIV-
infected macaques, particularly those with low-level viremia (“elite” 
controllers). Data in humans are more limited, but Banga and 
colleagues found replication-competent HIV to be highly enriched in 
the PD-1 expressing TFh cells that reside in the germinal centers of 
the B cell follicle. These inflammatory centers are more readily 
apparent during early ART. 
To enhance our capacity to characterize the impact of IL-15 on 
follicular integrity and the size of the reservoir we will enroll 
individuals who started therapy during chronic infection (and hence 
likely have a relatively high reservoir size). 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
15 
NUMBER OF 
PARTICIPANTS 
Ten HIV-infected adults on short-term effective ART will be studied. 
SUBJECT 
SELECTION 
CRITERIA 
Key Inclusion Criteria: 
1. Male or female, age ≥ 18 and ≤ 65 years 
2. HIV-1 infection (see section 4.2) 
3. On continuous antiretroviral therapy for at least 24 months 
without any interruptions of greater than 14 consecutive 
days, without plans to modify ART during the study 
period 
4. Plasma HIV RNA levels < 20 copies/mL at screen and on 
at least one determination in past 12 months (isolated 
single values ≥ 20 but < 200 copies/mL will be allowed if 
they were preceded and followed by undetectable viral 
load determinations) 
5. Screening CD4+ T-cell count ≥ 350 cells/mm3  and nadir 
CD4+ T cell count of >200 per participant report 
Key Exclusion Criteria: 
1. Pregnant, breastfeeding, or unwilling to practice birth 
control during participation in the study 
2. Active or recent malignancy requiring systemic 
chemotherapy or surgery in the preceding 36 months or for 
whom such therapies are expected in the subsequent 12 
months; minor surgical removal of localized skin cancers 
(squamous cell carcinoma, basal cell carcinoma) are not 
exclusionary 
3. Chronic liver disease defined as Class B and C on the 
Child-Pugh scale 
4. Active and poorly controlled atherosclerotic cardiovascular 
disease (ASCVD), as defined by 2013 ACC/AHA 
guidelines, including a previous diagnosis of any of the 
following: (a) acute myocardial infarction, (b) acute 
coronary syndromes, (c) stable or unstable angina, (d)    
coronary or other arterial revascularization, (e) stroke, (f) 
transient ischemic attack (TIA), or (g) peripheral arterial 
disease presumed to be of atherosclerotic origin. 
5. History of potential immune-mediated medical conditions 
requiring concomitant treatment with immunomodulatory 
drugs, and/or exposure to any immunomodulatory drug in 
the 30 days prior to study enrollment  
6. Exposure to any experimental therapies within 90 days of 
study screening. Exposure to long acting injectable ART 
therapies is not exclusionary.  
7. Clinical vaccination administered within 14 days of screen 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
16 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
• N-803, provided by ImmunityBio., Inc. administered 
subcutaneously at a dose 6  mcg/kg on Days 0, 21, and 42 
(with a dosing window of up to 14 days post the planned 
dosing day) 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
 
Participants will be observed on study for up to six months. 
 
CONCOMITANT 
MEDICATIONS 
All participants should be maintained on a stable antiretroviral drug 
regimen through the end of the study. 
PRIMARY 
ENDPOINTS 
• Frequency of CD8+ T cells in follicles (and their phenotypes) 
before and after N-803 therapy will be measured using 
quantitative image analysis techniques we have developed in 
our lab (10, 11, 15, 39-41). Briefly we will stain cells with 
antibodies to CD8 and determine their frequency per unit area. 
We have used these techniques to account for changes in CD4 
T cell populations in the parafollicular T cell zone after 
antifibrotic therapy (42).  
• Safety of N-803 given at this dose and frequency in this 
population. Any participant who receives an injection of N-
803 will be followed for AEs. Clinical and laboratory adverse 
events will be recorded in the CRF and the study will have 
quarterly monitoring by the team of monitors in the University 
of Minnesota Clinical and Translational Science Institute 
Regulatory Core. This group monitors all FDA trials at the 
University of Minnesota and routinely monitors multi-site 
trials at different institutions. Every 14 days, the co-
investigators will review any and all clinical and laboratory 
adverse events to ensure compliance with the study pause 
criteria listed in section 11.4. 
 
SECONDARY 
ENDPOINTS 
• Frequency, location, and phenotype of vRNA+ and vDNA+ 
cells in lymphoid tissues. 
• Frequency of vRNA+ TFH cells in B cell follicles before and 
after N-803 therapy. 
• Amount of HIV RNA/DNA detected in follicles before and 
after N-803 therapy. 
EXPLORATORY 
ENDPOINTS 
• Changes in frequency and activation status of NK cells in 
tissue and blood 
• Impact of N-803 on ADCC 
• Impact of N-803 on HIV specific CTL in tissues and blood 
• Structure and integrity of the FDC network before and after N-
803 therapy 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
17 
 
SAFETY 
EVALUATIONS 
All participants will be followed for possible adverse events (AEs) 
throughout their involvement in the study. Routine blood work will be 
performed on a regular basis (see sections 7.5 and 8). AEs will be 
graded according to Corrected Version 2.1 (July 2017) of the 
NIH/NIAID Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events. 
PLANNED INTERIM 
ANALYSES  
A Safety Monitoring Committee (SMC) will be convened and will 
meet biannually to review all adverse events and the conduct of the 
study. Serious adverse events will be monitored by the committee on 
an ongoing basis throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
18 
1. INTRODUCTION / BACKGROUND AND SCIENTIFIC RATIONALE 
1.1. Overview 
N-803 (formally ALT-803) is an IL-15 receptor super-agonist (IL-15/IL-15Ra-Fc) that is in clinical trials 
for hematologic and other malignancies. It is a potential candidate for HIV reservoir reduction studies as 
it can activate CD4 T cells, reactivating virus from latency, but also expand and activate CD8 and NK 
cells providing an increased pool of potential effector cells. Important to this proposal it also has been 
shown in at least one model of a non-human primate model of SIV infection to increase the frequency of 
SIV specific CD8 T cells in B cell follicles of secondary lymphoid tissues (LT). N-803 was used in a 
Phase 1 trial for HIV infection at the University of Minnesota 
with Dr. Schacker as the PI. This trial in individuals who are 
HIV-infected was a dose-escalation trial to establish the safety 
and tolerability of the drug in this population. There are 3 
formulations of IL-15 that are in clinical trials for treatment of 
various solid and hematologic malignancies (Fig 1). The first 
is a formulation from NCI that is just the IL-15 molecule, the 
second is the IL-15 molecule that is fused to the IL-15 
receptor, which is in clinical trials at Novartis, and third is the ImmunityBio., Inc. molecule that is an IL-
15/IL-15Ra-Fc superagonist complex that contains a mutation that increases avidity of the molecule for 
IL-2Rbg on NK cells and also includes the IgG1Fc domain (1-3). These modifications in N-803 increase 
the half-life and stability of the drug and also provide better penetration of the drug into lymphatic tissues 
(LT) (4) where > 99% of the virus reservoir resides (5). All of the data presented here were generated 
using N-803. 
 
N-803 is ideally suited to be part of an HIV cure strategy for several reasons. First, we have shown in our 
dose escalation study, described below, that even at the lowest doses studied, N-803 can induce HIV 
transcription. Secondly, N-803 is associated with increased frequency of activated NK and CD8 cells (6) 
to clear virus infected cells. In addition, in the non-human primate model (NHP) of SIV infection, N-803 
is associated with an increased frequency of SIV-specific CD8-T cells in B cell follicles where virus 
infected TFh reside(7). Thus, we have identified a single intervention with potential to both induce virus 
from latency and to clear clear virus infected cells. In this study, we focus on the effect of N-803 on B 
cell follicle structure and function and on the ability of the drug to reduce the reservoir of infected cells in 
this specific virus reservoir. 
 
 
N-803 induces HIV transcription 
As mentioned above, we have completed an IRB and FDA approved Phase 1 clinical trial (IND 125191) 
to determine the safety and tolerability of N-803 in HIV infected people where Dr. Schacker was the 
Principal Investigator. The study was a dose-escalation trial to establish the maximum tolerated dose 
(MTD) of N-803 in HIV infected ART suppressed individuals. Two individuals were studied at 0.3 
mcg/kg. A total of 3 individuals were studied at each subsequent dose level with the first dose level: 1, 3, 
and 6 mcg/kg. The protocol design allowed an increase to 10 mcg/kg as the final dose tested however the 
study was concluded after the 6 mcg/kg dose cohort because of the increased frequency of myalgia’s and 
other flu-like symptoms at the higher doses tested.  The protocol was initially designed for drug to be 
administered intravenously however while we were completing the 0.3 mcg/kg dose level it was learned 
that subcutaneous (SQ) administration of N-803 provided better penetration into lymph nodes and was 
 
Fig 1: IL-15 drugs in clinical trials.  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
19 
associated with fewer systemic symptoms of fever, myalgia. The 1, 3, and 6 mcg/kg doses of N-803 were 
administered SQ. 
 
In addition to the primary safety endpoints, additional virologic and immunologic data was obtained to 
determine the immunologic activity of N-803 in these participants and if there was an impact on HIV 
reservoirs. We first noted that measures of plasma HIV-RNA became intermittently detectable after doses 
of N-803. This observation was not consistent nor was it dose dependent. However, Dr. Karn of Case 
Western Reserve University, a co-investigator on these studies, has recently developed a novel Next 
Generation Sequencing (NGS)-based protocol, called EDITS (Envelope Detection by Induced 
Transcription-based Sequencing), to measure inducible cell-associated HIV RNA (8). Sequences of 
envelope are detected using a nested PCR on 1.25 x106 resting memory cells from aviremic HIV-1-
infected participants before and after ConA stimulation. Samples from different patients are bar-coded, 
pooled, and sequenced simultaneously which saves both time and sequencing costs, and allows accurate 
comparisons since input cDNA levels are effectively normalized. All EDITS experiments include control 
reactions set up without the addition of reverse transcriptase, as well as no template controls. In addition, 
this assay is quantitative because latently infected cells carry, on average, only one provirus (9) and 
therefore the frequency of inducible RNAs is proportional to the numbers of inducible cells in each of the 
wells. Comparing the reads obtained in the EDITS assay after maximal activation of cells by treatment 
with the mitogenic lectin ConA to a standard curve obtained by sorting known numbers of productively 
infected cells (Fig 2), provides an accurate measurement of the number of latently infected cells in any 
patient sample. Using this method, we are able to accurately detect 20% changes in the pool of cells with 
inducible HIV RNA. 
 
 
The EDITS assay was performed on PB samples collected at baseline and again at 7 days after receiving 
a dose of N-803 from all 15 participants. Another sample was obtained at least 6 months after the last 
dose of N-803. Prior to Con A stimulation (Fig 3A) we measured a significant increase in HIV 
transcription after the first 2 doses but after dose 3 there were fewer transcription events. At the 6-month 
time-point the frequency of cells transcribing HIV was back to baseline. With ConA stimulation, (Fig 
3B) the population of inducible cells was largest at baseline (before N-803) and trended lower after each 
subsequent dose and remained stable at the 6-month time-point. The 6 mcg/kg dose gave the most 
consistent increase in transcription and is the reason we are using 6 mcg/kg in this trial. Note, the interval 
between doses was 2 weeks for the 6 mcg/kg dose and 1 of the participants receiving 3.0 mcg/kg because 
 
 
Fig 2. Edits assay to measure 
inducible cell-associated HIV 
RNA.  
Fig. 3: Mean frequency and SEM of transcription events in PBMC from 8 
participants receiving N-803 before (A) and after stimulating PBMCs with ConA 
(B). 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
20 
of the longer duration of the rash and adenopathy at the higher dose. In Figure 3 A and B we combine the 
data for simplicity in presentation of data to justify the 6 mcg/kg dose. 
 
N-803 induces CD4, CD8, and NK cell activation and proliferation 
We are interested in studying the impact of N-803 on B cell follicle function for several reasons. The first 
is that the lymphoid tissue (LT) compartment is where the primary reservoir resides (5, 10-16). While 
many of the vRNA+ cells are located in the parafollicular T cell zone (TZ), a significant proportion of 
these cells are in the B cell follicle in the T follicular helper cells (Tfh). Importantly, effector cells are 
excluded from the B cell follicle (7) but at least one study in NHP showed that animals treated with N-
803 had an increased frequency of SIV specific CD8 T cells in the follicles. N-803 has been shown to 
activate CD4 and CD8 T cells. In vitro, Sekaly and colleagues showed that IL-15 increases CD8 T cell 
proliferation by up-regulating the expression of Id2, a transcriptional adaptor that is critical for inducing 
the proliferation and differentiation of CD8 memory T cells (17, 18). IL-15 induces proliferation of all 
CD8 T cell memory subsets and the differentiation and activation of the transitional (TTM) and effector 
(TEM) memory subsets (18). 
 
N-803 has been shown to activate NK cells which is important in HIV infection. There is an association 
between possession of specific killer-cell immunoglobulin-like receptors (KIRs) on NK cells and control 
of HIV infection (19-22). HIV selectively modulates MHC-I molecules on the infected cell surface 
which, in turn, impairs NK cell killing. The HIV protein Nef down-regulates HLA-A and –B, but not 
HLA-C or –E (23, 24) which reduces the susceptibility of infected cells to recognition by most virus-
specific T cells. The retention of HLA-C and –E impairs the response by NK cells that express the 
inhibitory KIRs KIR2DL (KIR2DL1/2/3) and CD94/NKG2A, which are the receptors for HLA-C and –E 
(respectively) (25, 26). However, activation of NK cells through cytokine stimulation can lower the 
activation threshold and overcome this inhibitory receptor dampening to induce NK mediated target cell 
killing and cytokine secretion (27). While there are many cytokines and combinations of cytokines that 
will activate NK cells (e.g., IL-2 & IL-12)(27, 28), IL-15 is particularly appealing as it is necessary for 
NK cell homeostasis (29-31) and will not cause expansion of regulatory T cells (Tregs) that can suppress 
NK cell responses like other cytokines might (e.g., IL-1) (32, 33). 
 
N-803 may also restore CD8 T cell responses and cause activation and proliferation of both CD4 T and 
CD8 Tcells. In vitro, Sekaly and colleagues showed that IL-15 increases CD8 T cell proliferation by up-
regulating the expression of Id2, a transcriptional adaptor that is critical for inducing the proliferation and 
differentiation of CD8 memory T cells (17, 18). IL-15 induces proliferation of all CD8 T cell memory 
subsets and the differentiation and activation of the transitional (TTM) and effector (TEM) memory 
subsets (18). 
 
In SIV+ Rhesus macaques, N-803 therapy is associated with significant reductions in plasma viremia. In 
Rhesus macaques infected with SIVmac239 for > 1 year, who were given N-803 at 0.1 mg/kg weekly for 
3 weeks, there was a rapid decline in plasma viremia to undetectable 1 week after the first dose (Fig 4) 
that correlated with rapid increases of CD8 T cell and NK cell numbers suggesting that NK cells and 
CD8 T cells may have been responsible for the rapid reduction in plasma viremia (34).  
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
21 
 
Fig 4: N-803 reduces viral loads in the absence of ARVs. The effect is temporally associated with expansion of the CD8 
T cell and NK cell population, each arrow represents a dose of N-803. The x-axis represents days. 
 
Side Effect Profile and adverse events associated with N-803 in patients with cancer 
To date a total of 250 patients in 20 cancer related clinical trials have received multiple doses of N-803. 
The dosing range was 0.1 mcg/kg – 20 mcg/kg and included both IV and SQ routes of administration. 
These trials included patients with pancreatic cancer, refractory multiple myeloma, non-Hodgkin’s 
lymphoma, bladder cancer, metastatic non-small cell lung cancer, CEA expressing cancer, Merkel Cell 
carcinoma, hematologic malignancies, and ovarian cancer. Of those 20 trials, 7 have completed sufficient 
accrual to report preliminary efficacy data. Most of these trials were N-803 in combination with other 
interventions (e.g., checkpoint inhibitors, rituximab, etc). All of the trials reporting efficacy data were 
dose-escalation trials, typically starting at very low doses and there is no data reported about dose-effect. 
The reported data are in Table 1. 
 
Table 1: Efficacy data for N-803 in cancer trials that has been reported to date 
NCT# 
Tumor Type 
N 
CR 
PR 
SD 
DP 
01946789 
Solid Tumors 
26 
0 
0 
0 
 
0255967 
Pancreatic  
7 
0 
1 
1 
 
02138734 
Bladder* 
9 
100 
 
 
 
02099539 
Refractory Myeloma 
19 
 
 
 
15 
02384954 
Non-Hodgkin’s Lymphoma 
21 
7 
3 
8 
3 
01885897 
Relapsing hematologic malignancy 
33 
1 
5 
 
 
02523469 
Non-small cell lung cancer 
23 
6 (reported as 
overall 
response rate) 
 
 
CR=complete response, PR=partial response, SD=stable disease, and DP=disease progression 
* Bladder study data show % response, not number of subjects. Due to nature of the study 
and the types of cancer seen in subjects as part of this study, there is no such thing as a CR. 
9/9 subjects had either a CR or a lack of recurrence/progression 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
22 
A total of 3 of the studies reported data on the effect of N-803 on CD8 T cells and NK cells (no data 
reported on CD4 T cells). In each of the 3 trials CD8 T cell numbers in PBMC modestly expanded and 
NK cells were significantly increased. 
 
In Table 2 we present the clinical AEs that were observed in the trial for people with solid tumors (NCT 
01946789). The dose escalation scheme was similar to our dose-escalation trial in people with HIV 
infection and representative of the other AEs reported in the other cancer trials. There has been a total of 
37 serious AEs reported in the cancer trials. Of those, 9 were associated with IV infusion, 24 with 
subcutaneous injection, and 4 by intravesical instillation (for bladder cancer). In Table 3 we present 
adverse events encountered in a healthy volunteer study conducted by the pharmaceutical company.  
Note, we do not have attribution data to know if these adverse events were felt to be associated with N-
803. 
 
Table 2: Clinical Adverse Events Associated with N-803 in patients with cancer, note that this table shows the highest grade 
value AE observed among all reported incidents for a particular AE within each dose cohort. 
Intravenous N-803 
Highest AE Grade/Dose Cohort 
Adverse Event 
# IV Subjects 
Affected, Total 
(N=11) 
# IV Subjects Affected, 3 
& 6 µg/kg 
(N=6) 
0.3-0.5 
µg/kg 
1 µg/kg 
3 µg/kg 
6 µg/kg 
Fatigue 
6 (55%) 
3 (50%) 
1 
2 
1 
1 
Nausea 
6 (55%) 
3 (50%) 
2 
1 
1 
1 
Vomiting 
4 (36%) 
2 (33%) 
1 
2 
1 
- 
Chills 
4 (36%) 
1 (17%) 
1 
1 
- 
2 
Fever 
3 (27%) 
2 (33%) 
1 
- 
1 
2 
Table 2 continued 
Subcutaneous N-803 
Highest AE Grade/Dose Cohort 
Adverse Event 
# SubQ Subjects 
Affected, Total 
(N=13) 
# SubQ Subjects 
Affected, 15 & 20 µg/kg 
(N=7) 
6 µg/kg 
10 µg/kg 
15 µg/kg 
20 µg/kg 
Injection site reaction 
11 (85%) 
7 (100%) 
2 
2 
2 
1 
Fatigue 
7 (54%) 
4 (57%) 
- 
2 
2 
2 
Hypoalbuminemia 
6 (46%) 
4 (57%) 
2 
2 
2 
2 
Anemia 
5 (38%) 
4 (57%) 
- 
2 
3 
2 
Fever 
5 (38%) 
2 (29%) 
1 
2 
2 
2 
Lymphocyte count 
decreased 
4 (31%) 
3 (43%) 
- 
3 
4 
2 
Limb Edema 
3 (23%) 
3 (43%) 
- 
- 
1 
1 
Anorexia 
3 (23%) 
2 (29%) 
- 
2 
2 
2 
Arthralgia 
3 (23%) 
2 (29%) 
- 
2 
1 
- 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
23 
Vomiting 
3 (23%) 
2 (29%) 
- 
2 
1 
- 
 
 
Table 3: Incidence of Treatment-Emergent Adverse Events by Study Period, MedDRA System Organ Class, and Preferred 
Term (Occurring in >1 Subject) in Healthy Volunteers– note that all incidences of AEs reported in this table are graded ≤2 
 
Study Period 1 
10 μg/kg 
Study Period 2 
20 μg/kg 
System Organ Class 
   Preferred Term 
N-803 
1.0 mg/mL 
n = 10 
N-803 
2.0 mg/mL 
n = 10 
N-803 
1.0 mg/mL 
n = 7 
N-803 
2.0 mg/mL 
n = 7 
Subjects with at least 1 AE 
10 (100%) 
10 (100%) 
7 (100%) 
7 (100%) 
Blood and lymphatic system disorders 
2 (20%) 
2 (20%) 
1 (14%) 
1 (14%) 
 
Lymphadenopathy 
2 (20%) 
2 (20%) 
1 (14%) 
1 (14%) 
Gastrointestinal disorders 
3 (30%) 
8 (80%) 
6 (86%) 
4 (57%) 
 
Abdominal pain lower 
3 (30%) 
7 (70%) 
5 (71%) 
3 (43%) 
 
Vomiting 
0 
0 
0 
3 (43%) 
General disorders and administration site conditions 
10 (100%) 
10 (100%) 
7 (100%) 
7 (100%) 
 
Axillary pain 
2 (20%) 
1 (10%) 
0 
1 (14%) 
 
Chest pain 
0 
0 
2 (29%) 
1 (14%) 
 
Chills 
8 (80%) 
8 (80%) 
6 (86%) 
7 (100%) 
 
Fatigue 
2 (20%) 
0 
 
 
 
Feeling of body temperature change 
3 (30%) 
7 (70%) 
2 (29%) 
4 (57%) 
 
Injection site reaction 
10 (100%) 
10 (100%) 
7 (100%) 
7 (100%) 
 
Malaise 
0 
3 (30%) 
0 
1 (14%) 
 
Pyrexia 
4 (40%) 
4 (40%) 
6 (86%) 
5 (71%) 
Musculoskeletal and connective tissue disorders 
4 (40%) 
4 (40%) 
3 (43%) 
5 (71%) 
 
Back pain 
1 (10%) 
0 
0 
4 (57%) 
 
Myalgia 
3 (30%) 
4 (40%) 
3 (43%) 
2 (29%) 
Nervous system disorders 
6 (60%) 
6 (60%) 
4 (57%) 
6 (86%) 
 
Dizziness 
0 
0 
1 (14%) 
2 (29%) 
 
Headache 
6 (60%) 
6 (60%) 
4 (57%) 
6 (86%) 
Respiratory, thoracic and mediastinal disorders 
2 (20%) 
2 (20%) 
4 (57%) 
1 (14%) 
 
Cough 
2 (20%) 
1 (10%) 
3 (43%) 
1 (14%) 
Skin and subcutaneous tissue disorders 
3 (30%) 
1 (10%) 
1 (14%) 
2 (29%) 
 
Night sweats 
2 (20%) 
1 (10%) 
1 (14%) 
2 (29%) 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
24 
Pharmacokinetic Profile in Cancer Studies 
Pharmacokinetic data were obtained pre-dose and at 30 minutes, 2, 4, 8 and 24 hours after N-803 dosing 
in the solid tumor trial discussed above (NCT01946789) where participants received either IV or SQ 
dosing. PK data were obtained from 2 participants in each dose cohort according to the study protocol 
(Fig 5). The Tmax occurred consistently at 30 minutes after IV administration. By contrast, SQ N-803 
exhibited a very gradual increase in serum concentration, with maximal serum levels >100-fold less than 
the average peak after IV N-803. In 4 of 8 SQ subjects, the serum concentration peaked at 4 to 8 hours, 
but in the remaining 4 subjects, the highest concentration measured occurred at 24 hours, the last time 
point tested. Therefore, it is possible that the Tmax occurred either at or after 24 hours in these 4 subjects. 
 
 
Fig 5: Panel A ALT-803 (AKA N-803) IV dose levels for subjects 1 – 10 are as follows: 1 = 0.3 µg/kg; 2 = 0.5 µg/kg; 3 and 4 = 1 µg/kg; 6 and 7 
= 3 µg/kg; 9 and 10 = 6 µg/kg. (4.2-2) ALT-803 (AKA N-803) Panel B SQ dose levels for subjects 12 – 23 are as follows: 12 and 13 = 6µg/kg; 
15 and 16 = 10 µg/kg; 18 and 19 = 15 µg/kg; 22 and 23 = 20 µg/kg. 
 
Side-effect profile and adverse events associated with N-803 in HIV infected people 
Clinically the drug has been relatively well-tolerated. All participants dosed SQ experience an injection 
site reaction that resolves in 7-10 days. All of the HIV + patients dosed at 1 mcg/kg or higher have 
experienced lymphadenopathy in the draining LN and the one participant dosed at 3 mcg/kg experienced 
bilateral inguinal and axillary adenopathy. The adenopathy resolves in 7-10 days. There is a risk of QTc 
prolongation. Note: Two individuals had a grade 1 prolonged QTc interval prior to receiving study drug 
that persisted through follow-up. One individual experienced grade 1 prolonged QTc interval that 
persisted through follow-up. One individual experienced grade 1 and 2 prolonged QTc intervals that 
resolved. At this point in time, there is no clear connection between the administration of N-803 and 
these minor abnormalities.(See Table 6 below). 
 
In Table 4 below we present the AE data for clinical and laboratory abnormalities. The primary clinical 
AE was an injection site reaction that was dose-dependent and persisted for a longer period of time but 
which resolved in 5-7 days. These were all considered to be Grade 3 AEs by DAIDS grading criteria. 
 
In Table 5 we present measures of serum creatinine and the eGFR collected during the dose escalation 
trial in HIV infected individuals. These values are reported as many HIV infected people on ARTs, who 
are otherwise doing clinically well and would be qualified for studies of IL-15, often have baseline 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
25 
abnormalities in renal function that would qualify as a grade 1 or 2 abnormality using the DAIDS adverse 
event criteria. 
 
 
Table 4: Adverse events data for clinical and laboratory abnormalities for N-803  
(Note: For each dosing arm, the instances documented for each AE are shown by grade (G1, G2, and G3). The overall 
prevalence of the AE among the participants for each dosing arm is represented in the column of # Affected) 
Clinical AEs 
 
0.3 mcg/kg 
IV N-803 
(N = 2) 
1 mcg/kg  
Subcutaneous N-803  
(N = 6) 
3 mcg/kg  
Subcutaneous N-803 
(N = 3) 
6 mcg/kg  
Subcutaneous N-803 
(N = 5) 
Adverse 
Event 
G1 G2 
# 
G1 
G2 
G3 
#Affected 
G1 
G2 
G3 
#Affected 
G1 
G2 
 G3 
#Affected 
Injection 
Site 
Erythema 
- 
- 
- 
11 
11 
9 
6 
(100%) 
7 
6 
5 
3 
(100%) 
9 
7 
9 
5 
(100%) 
Injection 
Site 
Induration 
- 
- 
- 
3 
- 
1 
4 (67%) 
3 
3 
2 
3 
(100%) 
4 
3 
5 
4 (80%) 
Injection 
Site Pruritis 
- 
- 
- 
5 
- 
- 
3 (50%) 
6 
- 
- 
2 (67%) 
9 
- 
- 
5 
(100%) 
Injection 
Site Pain 
- 
- 
- 
3 
- 
- 
2 (33%) 
3 
- 
- 
1 (33%) 
11 
- 
- 
5 
(100%) 
Injection 
Site 
Swelling 
- 
- 
- 
2 
4 
2 
3 (50%) 
2 
2 
- 
2 (67%) 
1 
- 
1 
1 (20%) 
Injection 
Site 
Tenderness 
- 
- 
- 
3 
- 
- 
2 (33%) 
2 
- 
- 
1 (33%) 
- 
- 
- 
- 
Pain1 
- 
- 
- 
8 
- 
- 
5 (83%) 
7 
- 
- 
2 (67%) 
5 
1 
- 
4 (80%) 
Fatigue 
- 
- 
- 
3 
- 
- 
2 (33%) 
1 
- 
- 
1 (33%) 
2 
- 
- 
2 (40%) 
Myalgia 
- 
- 
- 
2 
1 
- 
2 (33%) 
3 
- 
- 
1 (33%) 
3 
- 
- 
2 (40%) 
Nausea 
- 
- 
- 
3 
- 
- 
3 (50%) 
1 
- 
- 
1 (33%) 
3 
- 
- 
1 (20%) 
Chills 
- 
- 
- 
- 
- 
- 
- 
2 
- 
- 
2 (67%) 
1 
- 
- 
1 (20%) 
Fever 
- 
- 
- 
- 
- 
- 
- 
- 
2 
- 
1 (33%) 
3 
- 
- 
3 (60%) 
Headache 
- 
- 
- 
1 
- 
- 
1 (17%) 
- 
- 
- 
- 
2 
- 
- 
2 (40%) 
Arthralgia 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
5 
- 
- 
2 (40%) 
Bruising 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
1 
- 
1 (20%) 
Diarrhea 
- 
- 
- 
1 
1 
- 
1 (17%) 
- 
- 
- 
- 
- 
- 
- 
- 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
26 
Rash 
- 
- 
- 
- 
- 
- 
- 
1 
- 
- 
1 (30%) 
- 
- 
- 
- 
Syncope 
- 
- 
- 
- 
1 
- 
1 (17%) 
- 
- 
- 
- 
- 
- 
- 
- 
Prolonged 
QTc 
Interval 
2 
1 
1 
(50%
) 
6 
3 
- 
3 (50%) 
- 
- 
- 
- 
- 
- 
- 
- 
Vertigo 
- 
- 
- 
1 
2 
- 
1 (17%) 
- 
- 
- 
- 
- 
- 
- 
- 
Other AE 
not 
identified2 
- 
- 
- 
6 
- 
- 
3 (50%) 
8 
2 
- 
3 
(100%) 
4 
4 
- 
4 (80%) 
1. 
Pain includes inguinal lymph node pain, lymph node tenderness, chest pain, sore throat, shoulder pain, abdominal pain, sinus pain, midback 
pain, knee pain, and tenderness at biopsy site 
2. 
“Other AE not identified” includes events not covered in the DAIDS AE grading such as nasal congestion, cough, pimple, vesicles at injection 
site, flaky skin at injection site, greater than 20% decrease in FEV1, mitral valve insufficiency diagnosed 5 months after the last dose of N-803, 
dizziness, and sneezing 
Laboratory AEs 
 
0.3 mcg/kg  
IV N-803 
(N = 2) 
1 mcg/kg  
Subcutaneous N-803  
(N = 6) 
3 mcg/kg  
Subcutaneous N-803 
(N = 3) 
6 mcg/kg  
Subcutaneous N-803 
(N = 5) 
Adverse 
Event 
G1 
G2 
# 
G1 
G2 
G3 
#Affected 
G1 
G2 
G3 
#Affected 
G1 
G2 
 G3 
#Affected 
Albumin, 
Low 
- 
- 
- 
2 
- 
- 
1 (17%) 
2 
- 
- 
1 (33%) 
- 
- 
- 
- 
AST, High 
1 
- 
1 
(50% 
- 
- 
- 
- 
1 
- 
- 
1 (33%) 
- 
- 
- 
- 
Calcium, 
Low 
2 
- 
1 
(50% 
3 
- 
- 
2 (33%) 
- 
- 
- 
- 
2 
- 
- 
2 (40%) 
Creatinine, 
High 
2 
- 
1 
(50%
) 
- 
- 
- 
- 
- 
- 
- 
- 
1 
- 
- 
1 (20%) 
eGFR, Low 
- 
- 
- 
- 
6 
- 
3 (50%) 
- 
- 
- 
- 
- 
- 
2 
2 (40%) 
Glucose, 
High 
2 
- 
1 
(50%
) 
6 
- 
- 
5 (83%) 
- 
- 
- 
- 
2 
1 
- 
1 (20%) 
Glucose, 
Low 
- 
- 
- 
1 
- 
- 
1 (17%) 
- 
- 
- 
- 
- 
1 
- 
1 (20%) 
Increased 
Bilirubin 
- 
- 
- 
1 
- 
2 
1 (17%) 
- 
- 
- 
- 
- 
- 
- 
- 
Potassium, 
Low 
- 
- 
- 
2 
- 
- 
1 (17%) 
- 
- 
- 
- 
- 
- 
- 
- 
Absolute 
Neutrophil, 
Low 
 
- 
 
- 
 
- 
1 
- 
- 
1 (17%) 
 
- 
 
- 
 
- 
 
- 
 
 
- 
 
- 
 
- 
 
- 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
27 
Hemoglobin
, Low 
- 
- 
- 
3 
1 
- 
2 (33%) 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Table 5: Measures of serum creatinine (SCr) and the eGFR during the dose escalation trial 
 
 
 
Dose 1 
Dose 2 
Dose 3 
FU1 
  
  
Screen Day 0 Day 1 
Day 4 
Day 0 Day 1 Day 4 Day 0 Day 1 
Day 4 
 
0.3 mcg/kg 
(IV) 
  
  
  
  
  
  
  
  
  
  
  
2349 SCr 
1.25 
1.19 
1.3 
1.38 
1.28 
1.3 
1.23 
1.28 
1.42 
  
1.18 
  
eGFR 
59 
62 
56 
52 
57 
56 
60 
57 
51 
  
63 
2354 SCr 
1.28 
1.27 
1.14 
1.23 
1.05 
1.14 
1.03 
1.24 
1.15 
1.05 
1.09 
  
eGFR 
67 
67 
76 
70 
84 
76 
86 
69 
76 
84 
80 
1 mcg/kg 
(SQ) 
  
  
  
  
  
  
  
  
  
  
  
2356 
SCr 
1.07 
1.03 
1.13 
1.17 
1.14 
1.11 
1.05 
1.14 
1.05 
1.07 
1.03 
  
eGFR 
74 
77 
69 
66 
68 
71 
75 
68 
75 
74 
77 
2383 
SCr 
0.84 
0.87 
0.86 
0.76 
  
  
  
  
  
  
  
  
eGFR 
>90 
>90 
>90 
>90 
  
  
  
  
  
  
  
2403 
SCr 
0.85 
0.91 
0.82 
0.96 
0.9 
0.95 
1.02 
0.85 
0.89 
0.92 
0.82 
  
eGFR 
>90 
88 
>90 
83 
89 
84 
77 
>90 
>90 
88 
>90 
2413 
SCr 
0.95 
0.83 
0.93 
1 
  
  
  
  
  
  
  
  
eGFR 
>90 
>90 
>90 
89 
  
  
  
  
  
  
  
2470 
SCr 
0.67 
0.76 
0.86 
0.69 
0.86 
0.84 
0.72 
  
  
  
  
  
eGFR 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
  
  
  
  
2530 
SCr 
1.14 
1.15 
1.05 
1.1 
0.94 
0.99 
1.06 
1.02 
1.07 
1.06 
1.19 
  
eGFR 
73 
72 
80 
76 
>90 
86 
79 
83 
78 
79 
69 
3 mcg/kg 
(SQ) 
  
  
  
  
  
  
  
  
  
  
  
2543 
SCr 
0.96 
0.93 
0.91 
1.02 
1.01 
0.92 
  
0.91 
0.85 
1.05 
1.02 
  
eGFR 
>90 
>90 
>90 
87 
88 
>90 
  
>90 
>90 
84 
87 
2124 
SCr 
1.05 
0.79 
0.9 
0.9 
1.08 
0.86 
1.1 
1.06 
0.9 
0.89 
0.9 
  
eGFR 
70 
>90 
84 
84 
68 
88 
66 
69 
83 
85 
84 
2045 
SCr 
0.91 
0.96 
0.91 
1.05 
0.99 
0.87 
1.05 
0.97 
0.92 
1.03 
0.92 
  
eGFR 
76 
72 
76 
65 
70 
80 
65 
71 
75 
66 
75 
6 mcg/kg 
(SQ) 
  
  
  
  
  
  
  
  
  
  
  
2189 
SCr 
1.27 
1.24 
1.28 
1.24 
1.4 
1.34 
1.18 
  
  
  
1.19 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
28 
  
eGFR 
60 
62 
60 
62 
54 
57 
65 
  
  
  
65 
2531 
SCr 
0.97 
0.9 
1.02 
1.13 
  
  
  
  
  
  
  
  
eGFR 
>90 
>90 
>90 
>90 
  
  
  
  
  
  
  
2415 
SCr 
1.14 
0.99 
1.04 
1.08 
1.04 
1.14 
1.1 
1.11 
1.18 
1.26 
1.11 
  
eGFR 
68 
80 
76 
72 
76 
68 
71 
70 
65 
61 
70 
2484 
SCr 
0.76 
0.82 
0.9 
0.81 
0.75 
0.84 
0.81 
0.71 
0.76 
0.71 
0.71 
  
eGFR 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
>90 
2603 
SCr 
0.91 
0.86 
0.85 
0.96 
0.88 
0.86 
0.82 
0.82 
0.95 
0.97 
0.99  
  
eGFR 
>90 
>90 
>90 
85 
>90 
>90 
>90 
>90 
86 
84 
 82 
1. Measure made 1 week after the last dose received 
 
In Table 6 we present the QTc measures made during the dose-escalation study. A total of 4 individuals 
experienced a QTc > 450 ms; 1 at 0.3 mcg/kg IV and 3 at 1.0 mcg/kg. Among these 4 individuals there were 15 
EKGs with a QTc > 450 ms. Of those, 10 were a grade 1 and 5 were a grade 2 AE.  
 
Table 6: Measures of QTc (ms) from the dose escalation study.  
Values that are considered adverse events are marked with the grades of G1 or G2 per DAIDS criteria. 
 
Screen 
Dose 1  
Dose 2 
Dose 3 
 
 
 
 
 
 
0.3 mcg/kg 
IV 
 
Predose 
+ 6 
hours 
Predose 
+ 6 
hours 
Predose 
+ 6 
hours 
 
 
 
 
 
 
 
2349 413 ms 
433 ms 407 ms 403 ms 422 ms 
413 ms 
416 ms  
 
 
 
 
 
2354 454 ms 
(G1) 
436 ms 422 ms 420 ms 431 ms 
479 ms 
(G2) 
468 ms 
(G1) 
 
 
 
 
 
 
 
Screen 
Dose 1 
Dose 2 
Dose 3 
1 mcg/kg 
SQ 
 
Predose 
 + 6 
hours 
 + 24 
hours 
Day 3 
Day 4 
Day 7 
Predose 
 + 6 
hours 
Day 4 
Day 7 Predose 
 + 6 
hours 
2383 423 ms 
465 ms 
(G1) 
463 ms 
(G1) 
475 ms 
(G2) 
464 ms 
(G1) 
423 ms 
455 ms 
(G1) 
 
 
 
 
 
 
2356 410 ms 
403 ms 428 ms 426 ms 428 ms 
413 ms 
 
441 ms 414 ms 
 
 
439 ms 
392 ms 
2413 407 ms 
415 ms 412 ms 420 ms 406 ms 
417 ms 
423 ms 
 
 
 
 
 
 
2470 405 ms 
406 ms 440 ms 423 ms 435 ms 
417 ms 
 
452 ms 
(G1) 
459 
ms 
(G1) 
 
 
 
 
2403 415 ms 
447 ms 462 ms 
(G1) 
420 ms 450 ms 
(G1) 
446 ms 
477 ms 
(G2) 
428 ms 420 ms 455 ms 
(G1) 
 
482 ms 
(G2) 
434 ms  
3 mcg/kg 
SQ 
 
2543 408 ms 
407 ms 394 ms 385 ms 406 ms 
427 ms 
425 ms 
406 ms 386 ms 
 
420 
ms 
402 ms 
399 ms 
2124 373 ms 
392 ms 397 ms 386 ms 403 ms 
382 ms 
 
405 ms 403 ms 
 
 
384 ms 
388 ms 
2045 413 ms 
420 ms 424 ms 411 ms 
433 
426 
 
425 ms 435 ms 426 ms 
 
429 ms 
430 ms 
6 mcg/kg 
SQ 
 
2189 426 ms 
418 ms 420 ms 415 ms 439 ms 
439 ms 
426 ms 
436 ms 441 ms 
 
 
 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
29 
2531 379 ms 
388 ms 402 ms 381 ms 389 ms 
392 ms 
 
 
 
 
 
 
 
2415 403 ms 
407 ms 417 ms 397 ms 413 ms 
429 ms 
 
428 ms 397 ms 
 
 
426 ms 
421 ms  
2484 409 ms 
421 ms 431 ms 430 ms 445 ms 
434 ms 
 
411 ms 446 ms 
 
 
426 ms 
412 ms  
2603 414 ms 
421 ms 414 ms 423 ms 419 ms 
426 ms 
 
434 ms 420 ms 
 
 
435 ms 
426 ms  
 
 
The current dose-escalation study has been put on pause 5 times. Two of those were for protocol 
changes to switch the route of administration from intravenous to subcutaneous (SQ) and to modify 
language in the consent for the addition of lymph node biopsies and colonoscopy procedures. Three of 
the pauses were for adverse events. The first was for a participant receiving 1 mcg/kg SQ who 
experienced an injection site reaction that was a grade 3 which resolved within 5-7 days. We modified 
the protocol to state” “In the case of injection site erythema or redness or injection site induration or 
swelling (Grades 1-3), ALT-803 will be held until the injection site reaction resolves by at least 50%. In 
cases where injection site reaction occurs, photographs may be taken to document the reaction and 
assess resolution”. We also changed the protocol to state that a grade 3 injection site reaction does not 
count toward any stopping rules. The second adverse event requiring a pause was a change in the FEV1 
of >20% in one participant. In the original protocol, the baseline FEV1 was collected at screening which 
could have been several weeks prior to the initiation of dosing. We did not have any PFT measures 
collected just prior to the administration of the drug to be able to determine if the change was related to 
the drug. We amended the protocol to add PFT screening within 4 hours before the drug is given and 
again 12 and 24 (+/-4) hours after each dose. The third pause was due to a change in the eGFR for a 
participant at the 6.0 mcg/kg dose that qualified as a grade 3 toxicity. This individual had a baseline 
eGFR of 64 ml/min that was a grade 2 toxicity (< 90 to 60 ml/min) which was allowed in the protocol. 
His eGFR decreased to 59 ml/min which was determined by the SMC to be most likely related to 
dehydration. It returned to baseline; per protocol, he did not receive further doses of study drug. 
 
Each time the study was paused due to an AE, the SMC was consulted, and the FDA and IRB were 
notified. Protocol changes were made in consultation with the FDA and approved by our IRB. 
 
1.2. Study Rationale and Hypothesis 
As discussed above, N-803 has demonstrated ability to reactivate HIV from latency and can activate T 
cells and NK cells to clear those cells, thus reducing the reservoir. However, a concern is that CD8 T 
cells may be excluded from the B cell follicles, where a significant part of the reservoir resides. Webb, et 
al, has shown that in SIV infected monkeys CD8 T cells in follicles increase in frequency when N-803 is 
administered. We hypothesize that in HIV infected humans treated with N-803 that CD8 T cells will 
increase in B cell follicles and that there will be a further reduction in the frequency of cells with an 
inducible provirus. 
 
1.3. Risk / Benefit Assessment 
There is no expected direct benefit for the study participant. The primary benefit is the gain in 
knowledge regarding a potentially effective intervention that may in future studies allow for a durable 
control of HIV in absence of therapy (a remission). There are several risks involved with this study. N-
803 is an unlicensed molecule, and the available safety data on this molecule are based on trials with 
very small numbers of participants. The adverse events, directly attributable to the study drug, 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
30 
experienced by HIV infected people are an injection site reaction and lymphadenopathy that typically 
clears in 7-10 days. As seen in the cancer and HIV trials, other adverse events that may be related to the 
administration of N-803 include fatigue, myalgia, arthralgia, fever, chills, and injection site pain. Other 
potential risks include drug interactions which are discussed in section 6. Other clinical management 
issues that may pose a risk to the participant are discussed in section 10. Other risks involved with 
participation in this study include: 
 
1) (Medical history and information from medical record) Discussion of HIV serostatus, collection 
of medical history, and physical exam can cause embarrassment and discomfort. Research 
coordinators are trained to be sensitive to stigma and embarrassment that participants may feel, and 
provide support. Anticipation of a medical procedure may cause stress or anxiety. All data collection 
and storage of PHI will be compliant with HIPAA and techniques for Good Clinical Practice (GCP) 
in research. 
 
2) (Blood draws and leukapheresis) Risk to study participants associated with blood draw procedures 
will be minimal. There is potential for bruising, bleeding, infection and mild discomfort from the 
venipuncture. To minimize this discomfort, there is required training and certification for research 
technicians, and they routinely use the smallest gauge butterfly (21 gauge) needle compatible with 
the protocol and prevention of hemolysis. Rarely, participants experience faintness (near-syncope or 
syncope) at the time of phlebotomy. The risks of leukapheresis include the risks associated with 
blood draws listed above, as well as fatigue, headache, nausea, vomiting, and hypotension and air 
embolism. Other risks of leukapheresis include allergic reaction, damage to red blood cells, and loss 
of platelets. Very rare risks include heart attack, stroke, and death. Due to citrate anticoagulation, 
participants may experience temporary numbness or tingling of the fingertips or around the mouth, 
cramping, chills, or anxiety.  
 
3) (Lymph node biopsy procedure) Lymph node (LN) biopsies will be performed at the University of 
Minnesota by surgical faculty that have collaborated with Dr. Schacker’s projects for over 15 years. 
Risks from LN biopsy include bleeding, bruising, infection, pain, development of a seroma, and 
scarring. Thus far they have performed over 635 LN biopsies on HIV+ patients for related studies 
without any significant adverse events. If complications do develop, at least one surgeon will be 
available to provide immediate and appropriate follow up care. Participants from both study sites 
will undergo the LN biopsies at the UMN study site. 
 
4) (Colonoscopies) Colonoscopies will be performed within clinical procedure suites at the U of 
Minnesota by physician faculty in Gastroenterology, Alexander Khoruts, MD. Conscious sedation 
will be used during colonoscopies consistent with standard of care for clinical protocols, and 
participants will be monitored by nursing within clinical research units following the procedure. 
Risks from colonoscopy include discomfort, cramping, anxiety, dizziness after sedation, and 
bleeding. Colonoscopy is also associated with risk of colonic perforation, estimated to occur in 
approximately 1/3000 procedures. They have performed over 473 colonoscopies in MN in 
similar protocols with no significant adverse events. Participants from both study sites will undergo 
colonoscopies with biopsy at the UMN study site.  
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
31 
2. STUDY OBJECTIVES 
2.1. Primary Objectives 
• To determine the impact of N-803 on the frequency and function of CD8+ T cells in B cell follicles. 
• To determine the safety of N-803 in HIV+ ART suppressed individuals by assessment of adverse events 
experienced by participants during the conduct of the trial 
 
2.2. Secondary Objectives 
• To determine the impact of IL-15 on the frequency, location, and phenotype of  vRNA+ and vDNA+ 
cells in lymphoid tissues (inguinal lymph node, ileal, and rectal tissues) 
 
2.3. Exploratory Objectives 
• To determine the impact of IL-15 on frequency of T follicular helper cells harboring intact HIV 
genomes 
• To determine the effect of IL-15 on frequency and activation status of NK cells in tissue and blood 
• Impact of N-803 on ADCC in tissues and blood 
• Impact of N-803 on HIV specific CTL in tissues and blood 
• Impact of N-803 on detection of HIV RNA in plasma 
 
3. STUDY DESIGN 
3.1. Study Overview 
This is a Phase 1B, single arm, two-center, non-randomized, open label, uncontrolled study to 
determine how administration of N-803 affects B cell follicle structure and function and the impact on 
measures of virus in the follicles. The two sites will be the University of Minnesota and Hennepin 
Healthcare. There will be a total of 10 participants. Participants will be generally healthy HIV infected 
men or women suppressed on ART >24 months, who have undetectable plasma viremia, and CD4 ≥ 
350 cells/µl. The study drug N-803 will be administered at 6 mcg/kg, which is the maximum tolerated 
dose determined in a recently completed dose-escalation trial. At screening participants will have an 
EKG, medical history obtained, and blood drawn to assess if they meet entry criteria. At least 7 days 
(up to 14) prior to the first dose of drug, an inguinal lymph node will be obtained by excisional biopsy, 
colon and ileal tissue will be obtained via colonic biopsy, and a large volume of PBMCs obtained by 
leukapheresis. These procedures will occur at least 7 days prior to the first dose of N-803 to ensure that 
N-803 induced lymphadenopathy will not impair wound healing. Each participant will receive 3 doses 
of N-803, each dose separated by at least 3 weeks and not more than 5 weeks (see 5.3). Blood will be 
obtained at regular intervals to monitor for drug toxicity and changes in plasma viral load and CD4 cell 
count. At least 7 days after the last dose (and not more than 14 days) a second set of tissue biopsies will 
be obtained. The participant will return for a healing assessment within the following 7 days. The 
participant will be seen at monthly intervals for an additional 3 months to obtain peripheral blood to 
monitor for long-term toxicity, including development of antibodies for IL-15. 
 
3.1.1. Rationale for Dose and Dosing Interval 
In our dose escalation study with N-803 in HIV infected persons, we started with a dose of 0.3 mcg/kg 
IV with plans to increase to 1, 3, 6, and 10 mcg/kg IV. As we completed the 0.3 mcg/kg cohort it was 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
32 
reported that giving the drug subcutaneously (SQ) had 2 benefits. First the frequency of the cytokine 
related symptoms of fevers, rigor, and hypotension virtually resolved and second, the drug concentrated 
primarily into lymphatic tissues. This is the rationale for dosing the drug SQ. For this protocol where we 
study the impact that N-803 will have on effector cell function in B cell follicles, we will use 6 mcg/kg. 
This is the maximum tolerated dose from our recently completed dose-escalation trial. 
 
In this protocol we will administer the drug every 21 days. We have chosen this dosing interval because 
in cancer trials, there has been a consistent observation that shorter dosing intervals are associated with 
decreased proliferation of NK cells and an exhausted phenotype (35) which likely explains the loss of 
antiviral effect with N-803 in a macaque trial when the dosing interval was shorter (34). Those 
investigators found the antiviral effect was restored when there was a longer period of time between 
dosing intervals. An exhausted phenotype is not a novel concept and has been described with T cells (36, 
37) but also in experimental models of prolonged NK cell activation with prolonged exposure to 
ionomycin where reduced cytolytic function and cytokine production was observed (38). 
In studies in humans with cancer using N-803 at weekly intervals there was a diminished proliferative 
capacity of NK and CD8 T cells after repeated weekly dosing, and we saw this in our study (Fig 6) 
 
 
Fig 6 The percentage of NK cells that were Ki67+ 24 hours after each 
dose of N-803. There was a decrease after the first dose. These data are 
based on the 3 individuals receiving 3 mcg/kg. 
 
3.2. Criteria for Evaluation 
For purposes of efficacy, only those participants who have received all 3 doses of N-803 and have 
tissue available from both the first and second procedure timepoints will be considered evaluable. Any 
participant who does not have tissue from both timepoints, and/or has not received all 3 doses of N-803 
will be replaced.  
3.2.1. Primary Endpoint  
• Frequency of CD8+ T cells in follicles (and their phenotypes) before and after N-803 therapy will be 
measured using quantitative image analysis techniques we have developed in our lab (10, 11, 15, 39-
41). Briefly we will stain cells with antibodies to CD8 and determine their frequency per unit area. 
We have used these techniques to account for changes in CD4 T cell populations in the parafollicular 
T cell zone after antifibrotic therapy (42).  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
33 
• Safety of N-803 given at this dose and frequency in this population. Any participant who receives an 
injection of N-803 will be followed for AEs. Clinical and laboratory adverse events will be recorded 
in the CRF and the study will have quarterly monitoring by the team of monitors in the University of 
Minnesota Clinical and Translational Science Institute Regulatory Core. This group monitors all 
FDA trials at the University of Minnesota and routinely monitors multi-site trials at different 
institutions. Every 14 days, the co-investigators will review any and all clinical and laboratory 
adverse events to ensure compliance with the study pause criteria listed in section 11.4. 
3.2.2. Secondary Endpoints 
• Frequency, location, and phenotype of vRNA+ and vDNA+ cells in lymphoid tissues. 
• Frequency of vRNA+ TFH cells in B cell follicles before and after N-803 therapy. 
• Amount of HIV RNA/DNA detected in follicles before and after N-803 therapy. 
3.2.3. Exploratory Endpoints 
• Changes in frequency and activation status of NK cells in tissue and blood 
• Impact of N-803 on ADCC in tissues and blood 
• Impact of N-803 on HIV specific CTL in tissues and blood 
• Structure and integrity of the FDC network before and after N-803 therapy 
 
4. STUDY POPULATION 
4.1. Study Population 
Participants will be HIV infected and on ART >24 months, have undetectable plasma viremia, and CD4 
≥ 350 cells/µl.  
 
4.2. Inclusion Criteria 
1) Male or female, age ≥ 18 and ≤ 65 years 
2) HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence 
immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot 
or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 
antigen or plasma HIV-1 RNA viral load. 
3) On continuous antiretroviral therapy for over 24 months without any interruptions of greater than 14 
consecutive days, without plans to modify ART during the study period. 
4) Screening plasma HIV RNA levels < 20 copies/mL and on at least 1 determination in past 12 months 
(isolated single values ³ 20 but < 200 copies/mL will be allowed if they were preceded and followed by 
undetectable viral load determinations) 
5) Screening CD4+ T cell count ³ 350 cells/mm3 and nadir CD4+ T cell count of >200 per participant 
report, if able to recall.  
6) Ability to be off prednisone and other immunosuppressive drugs for at least 14 days before screen. 
Inhaled, nasal spray, intraarticular injections, and topical steroids are acceptable. 
7) Acceptable blood pressure and heart rate parameters within normal limits (systolic = 88-140mmHg; 
diastolic = 50-<90mmHg; heart rate = 46-100 bpm). Treatment with antihypertensive medication is 
allowed. However, if someone is on a beta-blocker this must be switched to another class of medication 
as there is a theoretical risk for bradycardia if the participant were to experience cytokine release 
syndrome symptoms (which has not happened with this drug delivered SQ). 
8) Sexually active females of child bearing potential and males with partners of child bearing potential 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
34 
must agree to use effective contraception during study participation and for 1 month following the final 
study visit (4 months after final dose of study drug)  
a) Acceptable birth control is defined as the following:  
i) For female participants of childbearing potential, two of the following forms of contraception 
are required, one of which must be a barrier method:  
(1) Condoms (male or female) with or without a spermicidal agent 
(2) Diaphragm or cervical cap with spermicide 
(3) Intrauterine device (IUD) with published data showing that expected failure rate is < 1% per 
year 
(4) Tubal ligation 
(5) Hormone-based contraceptive such as oral birth control pills 
9) Laboratory tests performed within 14 days of study enrollment must be a grade 0 or 1 as defined by the 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, with the following exceptions: 
● Platelet counts (≥ 150,000/mm3) 
● Hemoglobin > 12.5 g/dL for men and > 11.5 g/dL for women. It is not acceptable for patients to 
be transfused to meet this requirement. The use of Epogen is permitted. 
● Estimated Cr Cl (eGFR) > 50  
10) Voluntary written consent provided by the participant 
 
 
4.3. Exclusion Criteria 
1) Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or 
for whom such therapies are expected in the subsequent 12 months; minor surgical removal of localized 
skin cancers (squamous cell carcinoma, basal cell carcinoma) are not exclusionary 
2) Chronic liver disease defined as Class B and C on the Child-Pugh chronic liver disease scale. 
3) Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 
ACC/AHA guidelines, including a previous diagnosis of any of the following: (a) acute myocardial 
infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial 
revascularization, (e) stroke, (f) transient ischemic attack (TIA), or (g) peripheral arterial disease 
presumed to be of atherosclerotic origin. 
4) History of potential immune-mediated medical conditions requiring concomitant treatment with 
immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 30 days prior to 
screen (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more 
than 10 days, IL-2, interferon, methotrexate, cancer chemotherapy). NOTE: use of inhaled, nasal 
steroid or topical steroid lotions and creams is not exclusionary. Prior exposure to N-803 is not 
exclusionary if prior exposure occurred at least 6 months before screen. 
5) Exposure to any experimental therapies within 90 days of study screen. Exposure to long acting 
injectable ART therapies is not exclusionary. 
6) Latent TB infection or active TB disease prior to completing a standard regimen of anti-TB therapy that 
is defined as meeting PPD criteria for TB exposure or a positive quantiferon gold test collected at 
screening. 
7) Active fungal infection requiring systemic antifungal therapy 
8) Active herpes outbreak or varicella-zoster virus infection requiring episodic treatment  
9) Chronic active hepatitis B or C. For Hepatitis B this will be defined as HBs antigen + and for Hepatitis 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
35 
C this will be defined as Hepatitis C antibody positive and Hepatitis C PCR+. 
10) History and/or presence of any clinically significant disease or disorder, such as cardiovascular, 
pulmonary, renal, hepatic, neurological, gastrointestinal and psychiatric/mental disease/disorder, which, 
in the opinion of the site Principle Investigator may either put the subject at risk because of 
participation in the study, influence the results of the study or the subject’s ability to participate in the 
study.  
11) Any degree of baseline QT/QTc interval prolongation (QTc interval > 450 msec in men and > 470 
msec in women.) 
12) Any ischemic changes seen in the stress treadmill test administered per the discretion of the PI in order 
to assess any other EKG abnormalities as discussed in section 7.17 
13) History or evidence of uncontrollable CNS disease such as dementia, demyelinating disease, 
Parkinson’s, or a CNS degenerative disease that, in the opinion of the site Principle Investigator, may 
either put the subject at risk because of participation in the study, influence the results of the study or 
the subject’s ability to participate in the study. 
14) Prior organ allograft or allogeneic transplantation  
15) Planning or current pregnancy or breastfeeding 
16) Any clinically indicated vaccination (other than influenza or SARS-CoV-2) administered within 14 
days of screen 
 
5. STUDY TREATMENTS / AGENTS 
5.1. Product Characteristics, Preparation and Storage 
N-803 is an investigational drug supplied to investigators by the ImmunityBio., Inc. in Culver City, CA. 
It will be sent to and maintained by Investigational Drug Services (IDS) using established procedures. 
Sufficient study drug will be available for this protocol to treat all of the projected enrolled patients. The 
Principal Investigator will be responsible for the maintenance of records of receipt and disposition of 
study drug including dates, quantities administered and availability, and patient assignment. At the end of 
the study, ImmunityBio’s representatives will perform a full accountability of all study drugs. All unused 
study drug vials will be returned to ImmunityBio. All partially used or empty study drug vials will be 
destroyed at the study sites according to the established procedures. 
 
Investigator agrees not to supply or administer N-803 to any person except those named as Co-
Investigators on Form FDA 1572 or to individuals participating in this study, respectively. 
 
Study drug will be stored at the trial site in a secured area at 2°C to 8°C with limited access and 
protection from excess light and heat.  
 
The research pharmacy at the University of Minnesota offers in-house investigational drug services and 
dispensing of research drugs. The research pharmacist and credentialed pharmacy technician charged 
with dispensing research-related drugs receive protocol-specific training and are compliant with State 
Board of Pharmacy requirements, FDA Guidelines and Good Clinical Practices. Pharmacy documents, 
including study drug accountability logs, study drug ordering and shipping logs, and regulatory 
documents are maintained by the pharmacy technician.  
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
36 
Assessment of adherence. N-803 will be administered by subcutaneous injection in a research unit at the 
University of Minnesota for all study participants. Participants will be advised to remain adherent to their 
antiretroviral drugs during the conduct of this study. 
 
5.2. N-803 Administration (General Guidelines) 
5.2.1. Formulation and Composition 
The biological drug product, N-803, is formulated in a phosphate buffered saline (PBS) solution. The 
solution appears as a clear and colorless liquid. The drug substance is produced by a recombinant 
mammalian cell line and is manufactured using protein-free media. Study medication is provided in a 2 
mL single-dose/single-use vial containing 0.6 mL of N-803 (extractable volume is 0.5 mL) at a 
concentration of 2 mg/mL. The vialed quantitative composition of N-803 is listed in Table 7. 
 
Table 7: Quantitative Composition of N-803 
Component 
Concentration 
Amount / Vial 
N-803 
2 mg/mL 
1.2 mg 
Phosphate Buffered Saline (PBS) 
QS 
0.6 mL 
PBS Formulation: Sodium Chloride (USP) 8.18 g/L; Sodium Phosphate Dibasic 
(USP) 1.43 g/L; Potassium Phosphate Monobasic (NF) 1.36 g/L pH 7.4. 
 
5.2.2. Storage and Handling 
Vials are packaged in cartons and shipped to the clinical site. Study medication must be 
maintained at a temperature between 2˚C and 8˚C. The drug will be maintained in the 
Investigational Drug Service at each institution using the manufacturers guidelines for 
storage. The individual dose for administration to each participant will be prepared in 
syringes by the investigational pharmacist using protocols provided by the manufacturer 
and then delivered to the Clinical Research Unit at each institution. The product expires 
24 hours after it is drawn in to the syringe. The syringe is labelled with the date and time 
of its expiration, and is then stored in a refrigerator until its appropriate use or 
expiration.  
5.2.3. General Guidelines 
N-803 injections will occur in a research facility at the University of Minnesota. Each dose will be 
separated by at least 21 days but not more than 35 days (see section 5.3). Study drug will be provided 
free of charge to the study participants. The dosing interval of 21 days is to avoid the “cytokine 
exhaustion syndrome” that has been described using this compound in cancer trials. When the interval 
is too short (e.g., 7 days) the T cells and NK cells do not have the same magnitude of response to N-803 
and there is less activation (as measured by CD69) or proliferation (as measured by Ki67). This 
phenomenon has been characterized in the mouse model (35) and is avoided when the interval is at 
least 14-21 days between dose. We have chosen 21 days as that is the current practice in most of the 
cancer trials going forward. 
 
The study drug N-803 will be administered at 6 mcg/kg, which is the maximum tolerated dose 
determined in a recently completed dose-escalation trial. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
37 
 
N-803 dosing is calculated using a weight obtained on the day of each dose administration. For 
participants > 100 kilograms weight, the N-803 dose is calculated using a weight capped at 100 kg. The 
weight will be re-checked prior to each injection with the dose re-calculated if ≥ 10% change from the 
weight used for the baseline calculation. The calculated amount of N-803 will be drawn into a syringe 
for subcutaneous injection. The current IDS stock concentration is 2 mg/ml. Doses will be drawn 
directly into the syringe for injection.   
 
Injections are given in the abdominal area. The injection site should be rotated per institutional 
guidelines and each injection site separated by at least 1 inch. 
 
Required post N-803 monitoring: Participants will be observed for a minimum of 2 hours after each 
dose of N-803 for immediate adverse events. Vital signs (heart rate, blood pressure, respiration, 
temperature, and oxygen saturation) will be documented prior to the N-803 injection and then at 30, 60 
and 120 minutes with a ± 20 minute window for each time point. If systolic blood pressure drops to less 
than 90, and or diastolic drops to less than 50, obtain vital signs every 5 minutes for 30 minutes. Then 
obtain vital signs every 15 minutes and proceed with frequent vital signs as directed by the PI and/or 
Co-I. 
 
Administration of additional glucocorticoids is discouraged during the N-803 treatment period as the 
use of systemic steroid medications may result in loss of therapeutic effects of the study drug (see 
section 6.1).  
 
Pre and post-therapy intervention guidelines. The intervention guidelines described in the section 
below can be modified by the individual study center as medically necessary or as appropriately 
without requiring a protocol amendment or being considered a protocol deviation. In general, these 
guidelines are intended to address AEs graded 3 or greater (see Note 1 in table). 
 
Condition  
Agents  
Dose  
Route  
When  
Fever/chills  
Acetaminophen  
up to 650 mg  
or  
10 to 15 mg/kg 
recipient weight  
Orally  
Prior to each dose & 
repeat 4 hours after 
dosing.  
Repeat every 4 hours if 
fever present  
AND 
Indomethacin 
25 mg daily 
dose  
or  
50 mg when 
participant 
experienced a 
fever > 39.0°C 
in a previous 
dose  
Orally  
Prior to each dose & 
repeat it  
4-6 hours after dosing  
If persistent fever > 
39.0°C, repeat 50 mg 
every 8 hours (if 
adequate renal function) 
with acetaminophen 
every 6 hours.  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
38 
Condition  
Agents  
Dose  
Route  
When  
Allergies  
Diphenhydramine  
25 mg  
or  
up to 0.5 to 1 
mg/kg recipient 
weight  
Orally or IV  Prior to each dose and 
Repeat 4-6 hours after 
dosing.  
Antihistamine, such as 
diphenhydramine or 
cetirizine, should be 
taken for one day before 
and one to two days after 
dosing.  
In combination with one of the following:  
Ranitidine  
300 mg  
Orally  
Cimetidine  
300 mg  
Orally  
Famotidine  
20 mg  
Orally  
Hypotension  
Normal saline 
(0.9%)  
2 mL/kg/hr (up 
to 100 
mL/hr)***  
Continuous 
IV  
Begin 30 min prior to 
and for 6 hours after each 
dose  
Nausea/  
Vomiting/  
Ondansetron  
0.2 mg/kg (up 
to 8 mg)  
IV  
30 min prior to each dose  
OR other 5-HT3 antagonists at the discretion of the Investigator.  
Pain  
Hydromorphone  
0.5 mg  
IV  
30 min prior to each dose  
OR other opioid medications at the discretion of the Investigator 
***In the last 2 hours, if BP does drops slightly, it is recommended to increase the normal saline 
rate to 250 mL/hr (given no evidence of fluid overload) and give over 2 hours until pressure is 90 
mm systolic or more stable. Alternatively, if this has occurred previously, a higher rate of fluid 
administration from the start of the dosing protocol (i.e. 200 mL/hr over 6 hours) can be used as 
long as there are no signs of fluid overload (i.e. crackles in the lungs or peripheral edema or > 10% 
weight gain).  
Note 1: Acetaminophen and diphenhydramine will be administered approximately 30 minutes prior 
to each dose to every participant on every dosing day. Participants will also be instructed to take 
another dose of acetaminophen and diphenhydramine 4 hours after the study drug is given. These 
medications will be provided by the study at no cost to the participant. 
Note 2: Non-steroidal anti-inflammatory medication including acetaminophen, ibuprofen, or 
naproxen may be given per physician discretion following the recommended dosing thresholds:  
Acetaminophen: not to exceed 3000 mg (3 grams) in 24 hours  
Ibuprofen: not to exceed 2400 mg in 24 hours  
Naproxen: not to exceed 1100 mg in 24 hours  
Note 3: The use of systemic steroid medications may result in loss of therapeutic effects of the study 
drug and should be avoided; however, in the event of a life-threatening inflammatory reaction to N-
803, the IV administration of dexamethasone or other steroid-based medication is warranted.  
 
Based on current experience, localized skin reactions are common with subcutaneous administration. If 
a reaction occurs and the reaction area surrounding the N-803 injection site is > 6 cm or symptomatic 
(painful and/or itchy), it may be treated with topical 0.05% clobetasol propionate, 0.1% triamcinolone, 
or 1% hydrocortisone cream. Diphenhydramine may be administered pre- (25-50 mg TID orally) and 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
39 
post-dosing (25-50 mg TID orally x 2 days) of N-803 at the discretion of the treating physician. 
Diphenhydramine should be eliminated if not tolerated. Generally, the reaction associated with an N-
803 starts small at the site of the injection and spreads outwardly sometimes covering a large area of the 
abdomen. It generally resolves within 7-9 days of treatment. 
 
5.3. Individual Dose Delays 
N-803 administration may be delayed by up to 14 days (resulting in a maximum 35 day period between 
doses) if on the day of the planned dosing for any of the following situations: 
• the participant has a fever (defined as a temperature of > 100.4°F (38°C)) 
• treatment related side effects have not resolved to grade 1 or better  
• if in the opinion of the treating physician, a delay would be of benefit  
 
However, if dosing is delayed for one of these reasons the participant will be evaluated at the end of 7 
days and if the issue has resolved the subject will receive the dose as soon as possible. If the participant 
does not receive the dose within the drug administration window (up to 14 days post the planned dosing 
day), they will be discontinued and replaced. 
 
6. CONCOMITANT MEDICATIONS 
All participants should be maintained on the same medications throughout the entire study period, as 
medically feasible.  
 
Participants must provide their own antiretroviral drugs. No restrictions will be placed on the antiretroviral 
drug combinations. If medically feasible, study participants will be encouraged to remain on their entry 
antiretroviral regimen through the entire study period. If a participant’s ART regimen does change, refer to 
section 11.3 for the guideline concerning discontinuation.   
 
Participation in the study will not interfere in any manner with the subject’s standard of care.  
 
Prohibited and contraindicated medications are defined below. There are no precautionary medications. 
6.1. 
Prohibited Medications 
1. Glucocorticoids: 
• These have been shown to reduce cytokine-induced side effects including fever, renal 
insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of 
these agents with N-803 may reduce the biologic effectiveness of N-803. Therefore, 
administration of glucocorticoids is prohibited during N-803 treatment period.  
• They should be avoided except in the event of a severe toxicity or unrelated condition 
requiring steroid and their use will be an indication to stop N-803.  
• Inhaled, nasal spray, and topical steroids are acceptable. 
2. Chemotherapies and interferon: 
• Hypersensitivity reactions have been reported in patients receiving combination regimens 
containing sequential high dose IL-2 and antineoplastic agents, specifically, dacarbazine, 
cisplatin, tamoxifen and interferon-a. These reactions consisted of erythema, pruritus, 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
40 
and hypotension and occurred within hours of administration of chemotherapy. 
Concomitant chemotherapies and interferon-a with N-803 are prohibited.  
3. IL-2 and interferon: 
• Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, 
and severe rhabdomyolysis appear to be increased in patients receiving IL-2 and 
interferon-α concomitantly. Exacerbation or the initial presentation of a number of 
autoimmune and inflammatory disorders has been observed following concomitantly use 
of interferon-α and IL-2, including crescentic IgA glomerulonephritis, oculo-bulbar 
myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-
Johnson syndrome. Therefore, concomitant interferon-α treatment with N-803 is 
prohibited.  
 
6.2. 
Contraindicated Medications 
All of the potential drug interactions with cytokine therapy listed below might occur with N-803 
treatment. Contraindicated medications will be generally avoided when possible, but will be allowed in 
situations deemed low clinical risk per the discretion of study investigators.  Medication dosing, 
frequency (intermittent for symptom alleviation vs continuous), and indication will be considered in these 
decisions 
1. Psychotropic drugs: 
• Central nervous function may be affected. Therefore, interactions could occur following 
concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, 
sedatives). Intermittent use of oxycontin (5 mg tablets) is permitted for procedure related 
pain or if required for trauma. Analgesics purchased over the counter are permitted. The 
sleep aides Ambien and Lunesta are permitted. SSRI/SNRIs are considered low risk, and if 
used in standard doses are allowed.  Other psychotropic medications that are not currently 
associated with sedating or cognitive side effects and are not being used to treat symptoms 
related to psychosis or alterations in thought processing are also allowed. 
2. Kidney and liver 
• Kidney and liver function may be impaired during the treatment. Use of concomitant 
nephrotoxic (e.g., aminoglycosides), myelotoxic (e.g., cytotoxic chemotherapy, which are 
excluded anyhow), cardiotoxic (e.g., doxorubicin, which is excluded anyhow) or hepatotoxic 
(e.g., methotrexate, asparaginase, which are excluded anyhow) medications may further 
increase toxicity to the kidney or liver. These medications should be generally minimized 
during N-803 regimen treatment period. 
3. Beta-blockers  
• may potentiate the hypotension seen with cytokine therapy. Therefore, administration of 
these medications should be avoided during the N-803 portion of the treatment period. Use 
during a time that there is a least 72 hours gap away from hypotension and from N-803, then 
these may be used on the judgment of the treating physician.  
 
7. STUDY PROCEDURES 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
41 
Blood collection will occur at indicated visits and will be timed to stay within Red Cross Guidelines (less 
than 500 mL every 8 weeks). 
7.1. Medication Review 
All concomitant medications taken within 30 days prior to screening and entry and a complete history of 
ART, HIV-1 related vaccines, and immune-based therapies will be documented at the Screening visit.  
 
At each subsequent visit, all additions or discontinuations of prescription medications should be recorded. 
Actual or estimated start and stop dates should be recorded. 
 
7.2. Demographics and Medical History 
Demographic information (date of birth, sex, race and ethnicity) will be recorded at Screening. 
 
At Screening, the medical history must include all diagnoses within the past 30 days and, regardless of 
when the diagnosis was made, a complete history of chronic conditions, malignancies, and AIDS-defining 
conditions. Self-reported or documented nadir CD4+ T cell count should be recorded. 
  
Any allergies to any medications or their formulations should also be recorded. 
 
7.3. Clinical Assessment 
Signs and Symptoms 
At screen and baseline visits, all grades of signs and symptoms that occurred 30 days prior to the visit 
must be recorded.  
 
At all subsequent visits, all grades of signs and symptoms that occurred since the previous visit must be 
recorded as part of an Adverse Event (AE) assessment. Duration (start and stop dates and times), 
severity/grade, outcome, treatment and relation to study drug will be recorded on the case report form 
(CRF). Criteria for participant management, dose interruptions, modifications, and discontinuation of 
treatment will be mandated only for toxicities attributable to the study medication(s).  
 
Diagnoses 
All clinical events and new diagnoses or changes in diagnoses should be recorded.  
 
7.4. Physical Examination 
Complete Physical Exam 
A complete physical examination should be conducted at screening. It is to include at minimum an 
examination of the skin, head, mouth, and neck, auscultation of the chest, cardiac and abdominal exam, 
and examination of the lower extremities for edema. The complete physical exam will also include resting 
vital signs (temperature, pulse, respiratory rate, and blood pressure), height and weight.  
 
Targeted Physical Exam or Assessment 
A targeted physical examination should be conducted by and MD or advanced practice provider at each 
dosing visit. Targeted physical assessments can be conducted by an RN at all other visits except screen 
and dosing days. It is to include resting vital signs (temperature, pulse, respiratory rate, blood pressure) 
and weight, and is to be driven by any new signs or symptoms that the participant has experienced since 
the last visit.  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
42 
 
7.5. Clinical Laboratory Measurements 
All clinical laboratory evaluations will be conducted in Clinical Laboratory Improvement Amendments 
(CLIA) certified laboratories. 
  
Hematology 
Complete blood count with differential (CBCD) will be obtained at the indicated visits. 
 
Chemistry 
Basic metabolic chemistry panel (CBASIC) and hepatic panel (BHEPAT) will be obtained at the indicated 
visits. This will include serum sodium, potassium, chloride, CO2, anion gap, random glucose, blood urea 
nitrogen (BUN), creatinine, eGFR, aspartate aminotransferase (AST/SGOT), alanine aminotransferase 
(ALT/SGPT), alkaline phosphatase, total bilirubin, direct bilirubin, albumin, and total protein.   
 
Pregnancy Testing 
A serum or urine β-human chorionic gonadotropin HCG test (urine test must have a sensitivity of 25 
mIU/mL) will be obtained from female participants with reproductive potential at screening, prior to each 
dosing visit, and anytime during the study when pregnancy is suspected.  
 
Hepatitis B Testing 
Hepatitis B antibodies will be measured, and, if positive, a Hepatitis B antigen test will be obtained at 
Screen.  
 
Hepatitis C Testing 
Hepatitis C antibodies will be measured and, if positive, a Hepatitis C PCR will be obtained at Screen. 
 
Tuberculosis Testing 
A quantiferon gold test will be ordered at screening. If the test is positive and the potential participant has 
no prior history of TB treatment they will be referred to their primary provider for further testing. If they 
do have a history of prior treatment they will be considered eligible for the study. 
 
7.6. HIV Clinical Laboratory Measures 
Blood will be obtained and sent to a CLIA-certified laboratory for real-time determination of absolute 
CD4+ and CD8+ T cell counts, percentages, and CD4/CD8 ratio and plasma HIV-1 RNA quantification 
(viral load) at the indicated visits. All efforts should be made to have collection of blood for T cell counts 
occur between 8am and 11am, in order to account for diurnal variation in CD4+ T cell count.  
 
7.7. Cryopreservation of Plasma 
Plasma will be collected and stored at the indicated visits per the appropriate laboratory standards of 
procedure. 
 
7.8. Cryopreservation of PBMCs 
PBMCs will be collected and stored at the indicated visits per the appropriate laboratory standards of 
procedure. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
43 
7.9. Collection of PAXgene Specimen 
Whole blood will be collected in PAXgene tubes at the indicated visits. Blood will be collected in the 
following upright tubes - PAXgene Blood RNA Tube (16x200 mm / 2.5 mL). The tubes must be filled 
completely. Specimens will be shipped overnight on wet ice or stored at -80 freezer until ready to ship. 
 
7.10. 
Immunologic Measures 
T cell and NK immunogenicity. T cell immunogenicity will be measured via several different assays. T cell 
activation, proliferation, and function: Routine flow cytometric analysis of sorted T cells (CD4 and CD8) 
will be completed to assess markers of proliferation and activation. Briefly, purified PBMCs and LN cell 
suspensions from baseline and after the last dose of N-803 will be thawed, and stimulated with various 
HIV peptides. Cells will be incubated for 6 hours in the presence of Brefeldin A at 37°C. Antibody panels 
using some or all of the following surface molecules will be used to assess the quantity, phenotype, and 
function of responding CD4 and CD8 T cells: Aqua Blue, CD3, CD4, CD8, CD27, CD45RO, CD57, 
CCR7, PD-1, ICOS, CD150, CXCR5, and CCR6. These panels will allow discrimination of differentiated 
CD8 and CD4 memory and TFH phenotypes. In panels using fewer surface markers we will also assess 
function by fixing and staining for the following intracellular functional markers: IFNgamma, IL-2, TNF, 
MIP-1alpha, and IL-21. Following identification of small live lymphocytes and T cells, a gate will be set 
for each respective phenotype using combinations that provided optimal separation (central memory, 
effector memory, peripheral TFH, germinal center TFH). Boolean gate platform will be used to create the 
full array of possible functional combinations for each phenotype. 
 
NK activation, proliferation, function and exhaustion (Miller Laboratory, UMN): To assess blood and LT 
NK cell functional activity, flow cytometric analysis for NK cell degranulation (CD107a) and type-II 
interferon production will be performed on NK cells isolated from all tissue compartments using K562 
cells (a human leukemia cell line) as targets. In addition, we will evaluate the killing of HIV-infected 
targets by staining for activated caspase-3 and -7 (CellEvent Caspase-3/7 Green Flow Cytometry Assay 
Kit, ThermoFisher). Primary CD4s will be isolated and in vitro infected from patient samples with a 
variety of primary HIV strains obtained from the NIH AIDS Reagent Program as previously described 
(43). HIV-infected CD4+ T cells are then enriched by taking the negative fraction from a CD4 positive 
selection to remove all uninfected cells. NK and HIV-infected cells are then cultured at an effector to 
target ratio of 5:1. As shown in (Fig 7) resting autologous NK cells degranulate 3-fold greater against 
HIV-infected T cells than uninfected CD4’s. This suggests that NK cells can recognize HIV-infected 
CD4+ T cells presumably through upregulation of NKG2D ligands ULBP1/2, as shown previously (44). 
The ability of NK cells from N-803 treated participants to mediate ADCC will also be evaluated. NK cells 
isolated from participant PBMC will be exposed to the CD20 expressing B-cell line, Raji, in the presence 
and absence of the anti-CD20 monoclonal antibody, Rituxin. Rituxin bound Raji cells are a potent inducer 
of ADCC through Rituxin’s Fc portion bound to CD16. ADCC will be evaluated by NK cell expression of 
CD107a after exposure to targets. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
44 
 
Fig 7: Functional response of primary NK cells to autologous HIV-infected T cells. Purified primary NK cells and CD4+ T cells 
were isolated from the same healthy donor using magnetic columns. NK cells were co-cultured (E:T ratio of 5:1 for 4 hours) with 
autologous CD4+ T cells or CD4+ T cells in vitro infected with HIV. Cells were then stained for CD56 and CD107a and analyzed 
by flow cytometry to determine the NK cell response to HIV-infected CD4+ T cells or uninfected controls. 
 
To measure the possibility of NK cell exhaustion after N-803 treatment, we will compare NK cells 
isolated from PBMC prior to and 7 days after each N-803 dose for the following analyses validated in our 
lab: 1) NK cell degranulation measured after 4 hour exposure to K562 cells; 2) NK cell proliferation by 
measure of CellTrace dye dilution after cytokine activation; 3) NK cell expression of transcription factors 
T-bet and Eomesodermin by intracellular flow; 4) NK cell expression of checkpoints PD-1 and TIGIT 
expression; 5) NK cell metabolic exhaustion by measure of intracellular CPT1a expression. CPT1a is a 
key component of FAO machinery, shown by us to be downregulated in functionally exhausted NK cells 
induced by repeated exposure of IL-15. We will also look for IL-15 receptor components (IL-15Ra, b, 
and g) to look for modulation after N-803 therapy as well as indirect activation of monocytes and 
macrophages.  
 
We will also explore if the newly described “adaptive NK cells” are stimulated by N-803 and if they play 
a role in reservoir reduction. Adpative NK cells lack the HLA-E specific inhibitory receptor, NKG2A, but 
posess the activating receptor NKG2C (45). These cells also lack the CD16 adaptor molecule, FcεR1γ, but 
retain CD3ζ for potent signaling. While the mechanism is still not well understood, this population 
appears to be induced or expanded in the context of past CMV infection and is enhanced with CMV 
reactivation as often happens in immunosuppressed people. We have shown that “adaptive” NK cells have 
increased function over conventional NK cells (46) and that these cells have a hypomethymation signature 
similar to CD8 T cells, are distinct from conventional NK cells and exhibit properties of immune memory. 
One striking difference between adaptive NK cell and T cell responses are that adaptive NK cells have 
enhanced responses to targets different from the antigens that induced their initial development (47). 
While the proportion of adaptive NK cells needed to erradicate disease is not known, we hypothesize that 
N-803 will enhance the function of this unique subset and we will explore if this is important for reservoir 
reduction. NK cell phenotype will be assessed for CD56, NKG2C, NKG2A, CD16, FcεR1γ and CD3ζ by 
flow cytometry in participant samples before and at various timepoints during the course of N-803 therapy 
to determine if N-803 induces expansion of the “adaptive” NK cell subset. Considering the enhanced 
function of “adaptive” NK cells and the importance of CD16 expressing NK cells in mediating ADCC, it 
is important to understand how these subsets respond to N-803 stimulation as significant loss of these 
populations may negatively impact responses to HIV infected cells. Conversely, expansion or functional 
enhancement of these NK cell subsets would positively affect surveillance of infected cells. Polyclonal 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
45 
NK cells (mixed conventional and adaptive from CMV+ donors) degranulate and produce type-II 
interferon in response to the HIV-infected T cell lines (HIVIIIB and ACH-2) compared to their uninfected 
counterparts (H9 and CEM CD4). Thus, endogenous NK cells or healthy donor NK cells alone may be 
good enough to eradicate HIV reservoir infected cells. However, it is possible that other signals will be 
needed. 
 
7.11. 
Virologic Measures 
We will apply a broad range of virologic assays to the samples collected to measure changes to the virus 
reservoir, by compartment. Our focus is on the B cell follicle, especially infected T follicular helper cells 
(TFh). 
 
EDITS assay (Karn Laboratory, Case Western Reserve University): Dr. Karn has recently developed a 
novel Next Generation Sequencing (NGS)-based protocol, called EDITS (Envelope Detection by Induced 
Transcription-based Sequencing), to measure inducible cell-associated HIV RNA (8). This assay is 
extremely sensitive and will allow us to both determine the extent of proviral reactivation in response to 
N-803 in vivo and its impact on the overall latent reservoir in the peripheral circulation and lymphatic 
tissues. Samples from PB, LN, and GALT will be analyzed with and without ConA stimulation and the 
number of cell equivalents that are transcribing HIV will be determined. Sequences of envelope are 
detected using a nested PCR on 1.25 x106 resting memory cells from participants before and after ConA 
stimulation. Samples from different participants are bar-coded, pooled, and sequenced simultaneously 
which saves both time and sequencing costs, and allows accurate comparisons since input cDNA levels 
are effectively normalized. All EDITS experiments include control reactions set up without the addition of 
reverse transcriptase, as well as no template controls. In addition, this assay is quantitative because 
latently infected cells carry, on average, only one provirus (9) and therefore the frequency of inducible 
RNAs is proportional to the numbers of inducible cells in each of the wells. Comparing the reads obtained 
in the EDITS assay after maximal activation of cells by treatment with the mitogenic lectin ConA to a 
standard curve obtained by sorting known numbers of productively infected cells provides an accurate 
measurement of the number of latently infected cells in any participant sample. Using this method, we are 
able to accurately detect 20% changes in the pool of cells with inducible HIV RNA. 
 
Ultrasensitive qPCR diagnostics will be used to quantify HIV RNA to single-copy levels.  
Cell-associated (CA) total RNA (48) and integrated DNA (49) will be quantified using qPCR assays 
where nucleic acid input is normalized to cell number. These or similar techniques will be used to identify 
HIV viral reservoir in adipose tissue. 
 
7.12. 
Leukapheresis 
Leukapheresis will be performed at Day -14 to -7 before first dose and between 7-14 days after the last 
dose. The UMN group has several IRB approved protocols that include leukapheresis. The collection will 
be performed by the University of Minnesota Medical Center - Fairview Transfusion Service staff 
following standard clinic policies and procedures. Leukapheresis will occur in the apheresis center and 
will require an apheresis consult visit. Leukapheresis is not a study-specific procedure.  If the participant 
is not eligible for leukapheresis based on the apheresis consultation appointment, an ultrasound-guided 
large volume (60 mL) blood draw be scheduled at the CRU instead.  
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
46 
7.13. 
Colonoscopy with Biopsy 
Colonoscopy with ileal and rectal biopsy will be performed at Day -14 to -7 before the first dose and 
between 7-14 days after the last dose for all participants. The procedure will be done in the Endoscopy 
Unit of the University of Minnesota Medical Center by a senior faculty Gastroenterologist, Alexander 
Khoruts, MD, under conscious sedation. Subjects will complete the required bowel regimen the night prior 
to their scheduled procedure. For the procedure, the participant will lie on their left side and the 
colonoscope will be inserted and guided through the colon. After 14-18 small tissue biopsies of the ileum 
and rectum are obtained, the colonoscope will be removed. To date we have safely performed this 
procedure on > 100 HIV infected participants in clinical trials at UMN. 
 
7.14. 
Inguinal Lymph Node Biopsy 
Inguinal LN biopsy will be performed at Day -14 to -7 before the first dose and between 7-14 days after 
the last dose on all participants from both study sites. The procedure will be performed by a general 
surgeon in an outpatient setting using standard surgical procedures under local anesthesia at the University 
of Minnesota study site. Ultrasound will be used to identify the appropriate lymph nodes. The surgeon will 
clean and sterilize the inguinal area, inject a local anesthetic and make a small (5 cm) incision over the 
lymph node. The lymph node and adjacent adipose tissue will be removed and the incision closed. 
Participants will be observed for 4 hours post-surgery for any side effects. If none are observed, 
participants will be allowed to leave. We have safely collected > 300 lymph nodes using this procedure 
with only minor adverse events (incisional pain and 2 minor infections requiring oral antibiotics). 
 
7.15. 
Pulmonary Function Test (PFT) 
A pulmonary function test will be done at Day -14 to -7 before the first dose and between 7-14 days after 
the last dose. A PFT is a non-invasive breathing test that shows how well the lungs are working. The test 
measures lung volume, capacity, rate of flow, and gas exchange. They will be performed in the research 
unit by trained staff. If there is a significant abnormality or concern, the subject will be referred back to 
their primary care physician. 
 
7.16. 
EKG 
A standard 12 lead EKG will be obtained at screening, before study drug is administered on Days 0, 21, 
and 42, and one week post each drug administration on Days 7, 28, and 49. Minor abnormalities or 
inconclusive results can be evaluated with a standard treadmill stress test or a stress echocardiogram 
evaluation at the discretion of the PI. Ischemic changes identified by stress treadmill test will be 
exclusionary. If no significant abnormalities are detected the individual can participate. If there is a 
significant abnormality or concern, the subject will be referred back to their primary care physician. 
 
7.17. 
Sample Processing and Specimen Management 
Samples obtained from participants at UMN will be managed using established protocols in the Schacker 
Laboratory. Blood, LN, and gut samples are transported on ice to the Schacker Lab shortly after the blood 
draw or tissue harvest. Processing and storage for preservation of live cells, DNA and RNA or FFPE 
tissues occurs as soon as the samples arrive in the lab. Samples preserved for preservation of live cells are 
maintained in liquid nitrogen in a freezer facility at the Microbiology Research Facility that is monitored 
by a programmable scanning alarm system wired into the university’s telephone system. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
47 
7.18. 
COVID-19 Screening and Testing 
During the COVID-19 pandemic, we will screen for COVID-19 symptoms before the patients arrive for 
visits and get a Polymerase chain reaction (PCR) 2-4 -days prior to any injections or procedures (with 
noted exceptions below). Participants will be asked to isolate at home after their PCR test and prior to 
injections and biopsy visits. 
 
If COVID-19 is diagnosed at any time during the study, the patient will be instructed to isolate according 
to current recommendations provided by the Centers Disease Control and Prevention (CDC). Any missed 
study visits resulting from COVID-19 isolation will be rescheduled, and complete recovery from COVID-
19 will be documented before proceeding with study procedures. We will continue to follow guidelines 
established by M Health Fairview around clinic visits and endoscopy regarding testing after COVID-19. It 
has been observed throughout the pandemic that persons with prior COVID-19 are protected from 
reinfection for at least 90 days, but may have persistent/recurrent positive PCR tests during that period 
despite resolution of infection. Based on these observations, participants with a prior documented 
history of COVID-19 will be excluded from PCR screening for COVID-19 for a period of 90 days 
from time of diagnosis. This is consistent with established local and national guidelines. We will 
continue screening for COVID-19 symptoms at all study visits. 
 
7.19. 
Stool Collection 
Stool will be collected at baseline, day 28, post study drug procedures, and 90 days after 3rd dose follow-
up visits.  Participants will be sent home with a collection kit at screening, day 21, day 49 and 60 days 
after 3rd dose follow-up visits; and asked to collect sample within 3 days of the next visit, and bring back 
on their next visit with the container provided. 
 
 
8. STUDY SCHEDULE BY VISIT 
Participants will be consented by the Principal Investigator or the research team before any procedures take 
place. All efforts will be made to have all visits occur between 8am and 11am, in order to account for diurnal 
variation in CD4+ T cell count and other assays and to allow for prompt specimen processing. 
 
Once a participant is identified as potentially eligible by phone screening and is to be scheduled for a 
screening visit, a unique identifier will be assigned. New participants will be assigned a unique number Once 
a unique ID is utilized, it cannot be reassigned to another subject. 
 
Participants who satisfy all inclusion/exclusion criteria will be enrolled into the study, which is summarized 
in the Schedule of Events below.  
As stated in section 5.3, N-803 administration may be delayed by up to 14 days (resulting in a maximum 35 
day period between doses). 
Scheduled evaluations, other than N-803 dose administration days or procedure days, during the course of 
the study may be performed +/-3 days from the targeted date.  
Baseline procedures are planned for Day -7, but can occur as earlier as Day -14. Final procedures are planned 
for Day 49, but can occur as late as Day 56.  
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
48 
 
Screening 
Period 
Baseline 
Procedures 
Dose 1  
Dose 2  
 
Dose 3 
 
Post Study 
Drug 
Procedures 
Post-
biopsy 
F/U 
1 Month 
F/U 
2 Month   
F/U 
3 Month 
F/U (final 
visit) 
Early 
Discontinuation 
 
Day -60 
to -14 
Day -14  
to -7 
Day 
0 
Day 
7 
Day 
21 
Day 
28 
Day 
42 
Day 
49 
Day 49-56 
7 days 
after 
LN 
biopsy 
Day 77-
81 
Day 
107-111 
Day 137-
141 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Exam or Assessment1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Medication Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBCD4 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Serum chem and 
hepatic panel4 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 T cell subset profile5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Plasma viral load5 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Quantiferon gold4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B ab/ag4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C ab/PCR4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC/plasma for 
storage 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
49 
 
Screening 
Period 
Baseline 
Procedures 
Dose 1  
Dose 2  
 
Dose 3 
 
Post Study 
Drug 
Procedures 
Post-
biopsy 
F/U 
1 Month 
F/U 
2 Month   
F/U 
3 Month 
F/U (final 
visit) 
Early 
Discontinuation 
 
Day -60 
to -14 
Day -14  
to -7 
Day 
0 
Day 
7 
Day 
21 
Day 
28 
Day 
42 
Day 
49 
Day 49-56 
7 days 
after 
LN 
biopsy 
Day 77-
81 
Day 
107-111 
Day 137-
141 
 
Serum or urine B-
HCG4 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
PAXgene tube 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
EKG6 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
LN biopsy7 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Colon biopsy8 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Leukapheresis9 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
PFTs10 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
N-803 dose11 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
COVID-19 Screen12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COVID-19 PCR test12 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Stool Collection 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
1. 
See section 7.4 
2. 
See section 7.1 
3. 
Vitals to include temperature, blood pressure, pulse, height, weight, and respiratory rate 
4. 
See section 7.5 
5. 
See section 7.6 
6. 
See section 7.16 
7. 
See section 7.14 
8. 
See section 7.13  
9. 
See section 7.12 
10. See section 7.15 
11. See section 5.2 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
50 
 
Screening 
Period 
Baseline 
Procedures 
Dose 1  
Dose 2  
 
Dose 3 
 
Post Study 
Drug 
Procedures 
Post-
biopsy 
F/U 
1 Month 
F/U 
2 Month   
F/U 
3 Month 
F/U (final 
visit) 
Early 
Discontinuation 
 
Day -60 
to -14 
Day -14  
to -7 
Day 
0 
Day 
7 
Day 
21 
Day 
28 
Day 
42 
Day 
49 
Day 49-56 
7 days 
after 
LN 
biopsy 
Day 77-
81 
Day 
107-111 
Day 137-
141 
 
12. COVID-19 PCR will not be performed for 90 days following COVID-19 diagnosis. See section 7.18 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
51 
 
 
8.1. Screening 
Participants will be consented by the investigator or qualified research study staff before any procedures 
take place. Participants will be screened for COVID-19 symptoms before coming in for their visit.  
 
The following procedures will be completed to confirm eligibility: 
• 
Medical history 
• 
Medication review 
• 
Complete physical exam 
• 
Vitals 
• 
EKG to measure QT interval (see section 7.17) 
• 
Screening blood tests (parameters considered in evaluating eligibility criteria in parentheses): 
o CBCD (WBC, hemoglobin, platelet count, ANC) 
o Hepatitis B surface antigen (if hepatitis B surface antibody positive) and Hepatitis C antibody 
o Quantiferon gold for TB 
o Serum or urine β-HCG (females of childbearing potential only) 
o Plasma HIV RNA 
o CD4+/CD8+ T cell counts 
o CBASIC, BHEPAT (sodium, potassium, bicarbonate, creatinine, eGFR, glucose, calcium, albumin, 
total bilirubin, alkaline phosphatase, ALT, AST) 
 
Screening evaluations should be completed within 60 days prior to administration of first N-803 dose. 
 
8.2. Baseline Procedures: Days -14 to -7 
 The following procedures will be performed between days -14 and -7 prior to administration of first N-
803 dose: 
• 
Targeted physical exam/assessment 
• 
Vitals 
• 
Medication review and AE assessment 
• 
PFTs 
• 
Leukapheresis or large-volume blood draw if the participant is ineligible for leukapheresis 
• 
Colonoscopy with biopsy  
• 
Inguinal LN biopsy  
• 
CD4+/CD8+ T cell counts 
• 
Plasma and PBMCs collected for research storage 
• 
PAXgene tube 
• 
Stool collection 
 
All procedures must be performed within the window, but not necessarily on the same visit day. During 
the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming in for 
their visit. In addition, a PCR test will be collected 2-4 days before any procedure takes place, except in 
cases when COVID-19 has been diagnosed in the last 90 days.  Participants will be asked to isolate at 
home after their PCR test and prior to biopsy visits. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
52 
In order for a participant to proceed with the administration of study drug, there must be tissue available 
from the baseline procedures.  If there is not tissue available, the participant will be replaced for 
purposes of efficacy (see section 3.2) 
 
8.3. Dose 1 (Day 0) 
The following procedures will be performed: 
• 
Targeted physical exam 
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Serum or urine β-HCG (females of childbearing potential only) 
o Plasma and PBMCs for research storage 
o PAXgene tube 
• 
N-803 injection: 6 mcg/kg SQ 
o Prior to receiving N-803 injection, participants will have the following pre-medication 
administered: 
 
§ 
Acetaminophen 650 mg PO and diphenhydramine 25 mg PO/IV approximately thirty 
minutes before.  
 
o Participants will have their N-803 injection and be required to stay for 2 hours for observation for 
toxicity. Vital signs (heart rate, blood pressure, respiration, temperature, and oxygen saturation) will 
be documented prior to each N-803 injection and then at 30, 60, and 120 minutes with a ± 20 
minute window for each time point. If they do not have signs of toxicity they will be sent home and 
instructed to call the on-call physician if symptoms occur while at home.  
o After they are discharged from observation, participants will be instructed to take acetaminophen 
650 mg PO and diphenhydramine 25 mg PO 4 hours after receiving the N-803 injection. These 
medications will be provided by the study at no cost to the participant. 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. In addition, a PCR test will be collected 2-4 days before any study drug is given, except 
in cases when COVID-19 has been diagnosed in the last 90 days. Participants will be asked to isolate at 
home after their PCR test and prior to injections. 
 
 
8.4. Dose 1 (Day 7) 
The following procedures will be performed: 
• 
Targeted physical assessment  
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
53 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Plasma and PBMCs for research storage 
o PAXgene tube 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming in 
for their visit. 
 
8.5. Dose 2 (Day 21) 
The following procedures will be performed: 
• 
Targeted physical exam 
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Serum or urine β-HCG (females of childbearing potential only) 
o Plasma and PBMCs for research storage 
o PAXgene tube 
• 
N-803 injection: 6 mcg/kg SQ 
o Prior to receiving N-803 injection, participants will have the following pre-medication 
administered: 
 
§ 
Acetaminophen 650 mg PO and diphenhydramine 25 mg PO/IV approximately thirty 
minutes before. 
 
o Participants will have their N-803 injection and be required to stay for 2 hours for observation for 
toxicity. Vital signs (heart rate, blood pressure, respiration, temperature, and oxygen saturation) will 
be documented prior to each N-803 injection and then at 30, 60, and 120 minutes with a ± 20 
minute window for each time point. If they do not have signs of toxicity they will be sent home and 
instructed to call the on-call physician if symptoms occur while at home.  
o After they are discharged from observation, participants will be instructed to take acetaminophen 
650 mg PO and diphenhydramine 25 mg PO 4 hours after receiving the N-803 injection. These 
medications will be provided by the study at no cost to the participant. 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. In addition, a PCR test will be collected 2-4 days before any study drug is given, except 
in cases when COVID-19 has been diagnosed in the last 90 days.  Participants will be asked to isolate at 
home after their PCR test and prior to injections. 
 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
54 
8.6. Dose 2 (Day 28) 
The following procedures will be performed: 
• 
Targeted physical assessment 
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Plasma and PBMCs for research storage 
o PAXgene tube 
• 
Stool collection 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming in 
for their visit. 
 
8.7. Dose 3 (Day 42) 
The following procedures will be performed: 
• 
Targeted physical exam 
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Serum or urine β-HCG (females of childbearing potential only) 
o Plasma and PBMCs for research storage 
o PAXgene tube 
• 
N-803 injection: 6 mcg/kg SQ 
o Prior to receiving N-803 injection, participants will have the following pre-medication 
administered: 
 
§ 
Acetaminophen 650 mg PO and diphenhydramine 25 mg PO/IV approximately thirty 
minutes before. 
 
o Participants will have their N-803 injection and be required to stay for 2 hours for observation for 
toxicity. Vital signs (heart rate, blood pressure, respiration, temperature, and oxygen saturation) will 
be documented prior to each N-803 injection and then at 30, 60, and 120 minutes with a ± 20 
minute window for each time point. If they do not have signs of toxicity they will be sent home and 
instructed to call the on-call physician if symptoms occur while at home.  
o After they are discharged from observation, participants will be instructed to take acetaminophen 
650 mg PO and diphenhydramine 25 mg PO 4 hours after receiving the N-803 injection. These 
medications will be provided by the study at no cost to the participant. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
55 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. In addition, a PCR test will be collected 2-4 days before any study drug is given, except 
in cases when COVID-19 has been diagnosed in the last 90 days. Participants will be asked to isolate at 
home after their PCR test and prior to injections. 
 
 
8.8.  Dose 3 (Day 49) 
The following procedures will be performed: 
• 
Targeted physical assessment 
• 
Vitals 
• 
Medication review and AE assessment 
• 
EKG 
• 
Blood collection: 
o CBCD 
o CBASIC, BHEPAT 
o CD4+/CD8+ T cell counts 
o Plasma HIV RNA 
o Plasma and PBMCs for research storage 
o PAXgene tube 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. 
 
8.9. Post Study Drug Procedures (Day 49 - 56) 
The following procedures will be performed as early as day 49 and up to day 56 (7-14 days post 
administration of final N-803 dose): 
• 
Targeted physical exam 
• 
Vitals 
• 
Medication review and AE assessment 
• 
PFTs 
• 
Leukapheresis or large-volume blood draw if the participant is ineligible for leukapheresis 
• 
 Colonoscopy with biopsy  
• 
Inguinal LN biopsy  
• 
CD4+/CD8+ T cell counts 
• 
CBCD 
• 
CBASIC, BHEPAT 
• 
Plasma HIV RNA 
• 
Plasma and PBMCs collected for research storage 
• 
PAXgene tube\ 
• 
Stool collection 
 
All procedures must be performed within the window, but not necessarily on the same visit day. During 
the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming in for 
their visit. In addition, a PCR test will be collected 2-4 days before any procedure is performed, except 
in cases when COVID-19 has been diagnosed in the last 90 days.  Participants will be asked to isolate at 
home after their PCR test and prior biopsy visits. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
56 
 
 
8.10. 
Post Biopsy Follow Up (within 7 days of final LN biopsy) 
The following procedures will be performed after the final LN biopsy: 
• 
Targeted physical exam/assessment 
• 
Vitals 
• 
Medication review and AE assessment 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. 
 
 
8.11. 
Monthly for 3 Months (Day 77-81; Day 107-111; Day 137-141) 
The following procedures will be performed at all 3 visits: 
• 
Vitals 
• 
Medication review and AE assessment 
• 
CBCD 
• 
CBASIC, BHEPAT 
• 
Plasma HIV RNA 
• 
CD4+/CD8+ T cell counts 
• 
Plasma and PBMCs for research storage 
• 
PAXgene tube 
 
In addition, the following procedures will be performed at the final/3 month (day 137-141) visit:  
• 
Stool collection 
 
The 90 days after 3rd dose F/U visit will serve as the final study visit. During the COVID-19 pandemic, 
participants will be screened for COVID-19 symptoms before coming in for their visit. 
 
8.12. 
Early Discontinuation Visit 
If a participant is discontinued per the list outlined in section 11.1, an early discontinuation visit should 
occur as soon as possible.  
The following procedures will be performed: 
• 
Targeted physical exam/assessment 
• 
Vitals 
• 
Medication review and AE assessment 
• 
CBCD 
• 
CBASIC, BHEPAT 
• 
CD4+/CD8+ T Cell counts 
• 
Plasma HIV RNA 
• 
Plasma and PBMCs for research storage 
• 
Serum or urine β-HCG (if indicated for females of childbearing potential only 
 
During the COVID-19 pandemic, participants will be screened for COVID-19 symptoms before coming 
in for their visit. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
57 
8.13. 
Unscheduled Visit(s) 
At the discretion of the PI, participants may be asked to return for a visit not directed by the protocol if 
they believe such a visit is needed for additional testing to address abnormal lab values or to assess a 
specific side effect or symptom during the course of the study. 
 
9. ADVERSE EVENT DOCUMENTATION and REPORTING 
 
9.1. Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 Part 312.32 
(21CFR312.32 (a)). 
 
• 
Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered related to study agents (N-803). 
 
• 
Suspected Adverse Reaction:  
Any adverse event for which there is a reasonable possibility that N-803 caused the adverse event. 
 
• 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction: An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. 
 
• 
Serious Adverse Event or Serious Suspected Adverse Reaction: An adverse event or suspected 
adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
• 
If either the IND sponsor or the investigator believes the event is life-threatening or serious, the 
event must be evaluated by the sponsor for expedited reporting (21CRF 312.32(a)) 
 
• Unexpected adverse event or unexpected suspected adverse reaction:  An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed, or, if an investigator brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. Thus, adverse events that 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
58 
occur as part of the disease process or underlying medical conditions are considered unexpected. 
 
• Unanticipated (unexpected) problems/events as defined by the University of Minnesota IRB are 
those that are not already described as potential risks in the consent form, not listed in the 
Investigator’s Brochure or not part of an underlying disease. 
 
9.2. AE Severity 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
Corrected Version 2.1 (July 2017) (http://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables) should be used to assess and grade AE severity, including laboratory abnormalities judged 
to be clinically significant.  
 
9.3. AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines in  
Table 8. 
 
Table 8: AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Related 
There is a reasonable possibility that the AE may be related to the study 
agent(s).  
Not related 
There is not a reasonable possibility that the AE is related to the study 
agent(s).  
 
 
9.4. Reporting Procedures 
The Investigator, or study staff, will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents. Adverse events will be 
recorded in the participant CRF. Adverse events will be described by duration (start and stop dates and 
times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. All lab values 
will be frequently monitored by the Principal Investigator or qualified Co-Investigator in a timely manner. 
They will review these data, assess degree of severity, and make a relationship assessment to study drug. 
Study sites will document all AEs that occur (whether or not related to study drug). The collection period 
for all AEs will begin after informed consent is obtained and end after procedures for the final study visit 
have been completed. 
 
All SAEs will be evaluated to assess if the event meets reporting criteria in accordance with the standard 
operating procedures and policies of the local Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). SAEs will also be reported to the U.S. Food and Drug Administration (FDA) per the 
reporting requirements specified by 21 CFR 312.32, with copy to the DAIDS Medical Officer (MO). 
Details of all related SAEs will be sent to the SMC and DAIDS MO no later than 3 reporting days after 
the investigators become aware of the event. For the purposes of expedited reporting to the SMC and the 
DAIDS Medical Officer, the definition of a “reporting day” in Version 2.0 (January 2010) of the DAIDS 
EAE Manual https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-
daids will be used. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
59 
 
Safety Monitoring Committee Reporting 
  
The following adverse events will be reported to the SMC:  
• Adverse events graded 3 and above;  
• Any related, unexpected, and serious adverse events.  
 
Details of all severe, life-threatening, or fatal adverse events will be sent to the SMC within 24 hours for 
review.  
 
If a death occurs during the study and it is determined to be related either to the study drug(s) or to a study 
procedure, the Investigator or his/her designee must notify the SMC Chair (or qualified alternate) within 1 
business day of knowledge of the event. The contact may be by phone or e-mail 
 
IRB Reporting Requirements 
 
Investigators must assess problems and events that occur on a study and comply with the appropriate 
reporting requirement. 
 
Events that require prompt reporting to the University of Minnesota IRB: 
 
Refer to the University of Minnesota’s toolkit for what events are considered promptly reportable and 
should be submitted to the IRB via the appropriate forms within 5 working days of when the researcher 
receives knowledge of the event. 
 
 
 
 
9.5. Summary of Reporting Guidelines and Timeframes 
 
Agency 
Criteria for 
Reporting 
Timeframe 
Form to Use 
Submission 
address/fax numbers 
IRB 
 
 
 
UPIRTSO: any 
adverse event which in 
the opinion of the local 
investigator was 
unanticipated, reflects 
new or increased risk 
to the subjects and was 
possibly related to the 
research procedures 
5 Working Days 
IRB Reporting 
Form 
ETHOS Submission 
IRB 
Other Problems or 
Events meeting the 
definition of Prompt 
Reporting in HRP103 
5 Working Days 
IRB Reporting 
Form 
ETHOS Submission 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
60 
 
FDA 
Unexpected and fatal 
or life threatening 
suspected adverse 
As soon as possible 
but no later than 7 
Calendar-Days 
MedWatch 3500A 
U.S. Food and Drug 
Administration 
Center for Biologics 
Evaluation and 
Research  
Document Control 
Center 
10903 New Hampshire 
Avenue 
WO71, G112 
Silver Spring, MD 
20993-0002 
FDA 
1) Serious and 
unexpected suspected 
adverse reaction or 
2)  increased 
occurrence of serious 
suspected adverse 
reactions over that 
listed in the protocol or 
investigator 
brochure or 
3) findings from other 
sources (other studies, 
animal or in vitro 
testing) 
As soon as possible 
but no later than 15 
Calendar-Days 
MedWatch 3500A 
U.S. Food and Drug 
Administration 
Center for Biologics 
Evaluation and 
Research  
Document Control 
Center 
10903 New Hampshire 
Avenue 
WO71, G112 
Silver Spring, MD 
20993-0002 Form 
FDA 
All other events per 
CFR 312.33 
At time of IND 
annual report 
Summary report 
Submit as part of the 
IND annual report 
SMC 
All severe, life-
threatening, or fatal 
adverse events 
24 hours 
IRB report form 
SMC Chair 
 
SMC 
All other Adverse 
events meeting 
reporting criteria per 
section 9.4 
24 hours 
IRB report form 
SMC members 
 
 
The DAIDS MO and Program Officer (PO) will also receive all documents provided to the SMC and all 
reports form the SMC. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
61 
9.6. Procedures for Documenting Pregnancy During the Trial 
Potential participants who are pregnant or expect to become pregnant during the course of the trial will be 
excluded from participation in the trial. Participants should not become pregnant, breastfeed, father a 
baby, and/or donate eggs/sperm on this research study and for four months after receiving the final dose of 
study drug. Should a subject become pregnant after enrolling in the trial, she will not be given any further 
treatments with study drug and follow-up invasive procedures (LN biopsy, leukapheresis, and colon 
biopsy) will not be performed. The pregnancy will be reported to the antiretroviral pregnancy registry. A 
Pregnancy Form will be completed by the Investigator and submitted to the study team and DAIDS MO 
within 5 working days after learning of the pregnancy. The Investigator will also report this event to the 
IRB within 5 working days of becoming aware of the pregnancy. Sites must request the subject’s 
permission to query pregnancy outcome and follow each subject to determine the outcome of the 
pregnancy. When permission is received, participants will continue to be followed for safety assessments 
to trial discharge per protocol. Results will be summarized in the clinical study report (CSR). 
 
Participants who become pregnant at any point during the trial will continue to be followed for safety 
assessments without receiving further study drug. Procedures that are contraindicated during pregnancy, 
including additional treatments, must not be performed. Investigators should use clinical judgment 
regarding subsequent trial-related blood collection based on the presence or absence of anemia in each 
subject.  
 
All pregnancies that occur from the time of first screening procedure through four months after 
completing the study must be reported. The Investigator will monitor the participant and follow the 
outcome of the pregnancy. If the end of the pregnancy occurs after the trial has been completed, the 
outcome will be reported directly to the trial team and the DAIDS MO. 
 
Male participants will be instructed through the Informed Consent Form to immediately inform the 
Investigator if their partner becomes pregnant until the end of follow-up period. A Pregnancy Form will be 
completed by the Investigator and submitted to the study team within 5 working days after learning of the 
pregnancy. Attempts will be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study drug or device. The pregnant partner will 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow 
up on her pregnancy. Once the authorization has been signed, the Investigator will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy. An Investigator who is 
contacted by the male participant or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
 
9.7. Reporting Requirements to Nant Drug Safety 
Serious AEs (SAEs), whether related or not related to study drug, and pregnancies must be reported 
to Nant Drug Safety (Nant) within 24 hours with regards to Nant drug use. SAEs must be recorded on a 
SAE report form or MedWatch form; pregnancies on a Pregnancy Surveillance Form (Nant to provide). 
  
SAE Email Address: SAE.Reporting@NantBio.com 
SAE Facsimile Number: 1-800-853-3497 
  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
62 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in its 
intensity or relationship to study drug or if new information becomes available, a follow-up SAE report 
should be sent within 24 hours to Nant using the same procedure used for transmitting the initial SAE 
report. All SAEs should be followed to resolution or stabilization. The Sponsor/Investigator will ensure 
that all SAEs in the clinical database are reported to Nant and any applicable health authority during the 
conduct of the study. This reconciliation will occur at least quarterly and be initiated by the 
sponsor/investigator. 
  
Sponsor/investigator will request a reconciliation report from: SAE.Reporting@NantBio.com 
During reconciliation, any events found to not be reported previously to Nant must be sent 
to: SAE.Reporting@NantBio.com. 
  
The Sponsor/Investigator will be responsible for submitting all safety correspondence to the 
FDA.  Nant will be provided with a simultaneous copy of all Serious adverse event submissions filed 
with the FDA. 
  
All SAEs submitted to the FDA should simultaneously be faxed or e-mailed to NANT at: 
Fax Number: 1-800-853-3497 
Email: SAE.Reporting@NantBio.com 
 
10. CLINICAL MANAGEMENT ISSUES 
 
Injection Site Reaction 
Reaction at the injection site, characterized as “Injection Site Erythema or Redness” and/or” Injection Site 
Induration or Swelling”, is an expected and clinically insignificant toxicity. Per the arrangement made 
with the FDA during the course of the previous dose escalation study, all Grade 3 injection site reactions 
will be reported in the annual report. A Grade 4 injection site reaction will be reported immediately in 
accordance with the standard reporting procedures. 
 
Lymph Node Adenopathy 
Inguinal lymph node adenopathy in the draining, inguinal lymph node has been observed in HIV 
participants that have received N-803 via subcutaneous injection. All events have been reversible and have 
returned to baseline within 5-10 days of dosing.  Grading for lymph node adenopathy is not contained in 
the DAIDS toxicity grading scale, therefore, we will grade all lymph node adenopathy with the following 
grading scheme: 
  
 
Parameter 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Lymph Node 
Adenopathy 
No increase in 
Adenopathy 
Increase in size 
of nodes to >5 
cm by 
palpation 
Increase in size 
of adenopathy 
of > 5 cm that 
lasts > 7 days 
but < 14 days 
or; 
Increase in 
size of nodes 
to >5 cm for 
> 14 days or; 
Adenitis 
diagnosed by 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
63 
Ultrasound 
evidence of 
necrosis 
CT with 
fever >101.5° 
F or; 
Any other 
evidence of 
infection 
 
Administration of study drug should be put on hold until resolved if the lymphadenopathy is a Grade 3 or    
greater. 
 
Impaired kidney and liver functions 
Kidney and liver functions may be impaired during N-803 treatment. Use of concomitant nephrotoxic or 
hepatotoxic medications may further increase toxicity to the kidney and liver.  Administration of study 
drug should be put on hold if Grade 4 or greater. Subject will be followed to resolution, and a consultation 
will be obtained if further assessment is required. 
 
Infection 
Antibiotics can be administered to treat infections.  
 
Fever and chills 
Acetaminophen, indomethacin and hydromorphone can be administered to reduce fever and chills.  
Administration of study drug should be put on hold if Grade 3 or greater. A clinical assessment will be 
done. 
 
Diarrhea, nausea and vomiting 
Antidiarrheals can be used to combat diarrhea; antiemetics can be used to attenuate nausea and vomiting. 
Steroid-based anti-emetics are not allowed.  
 
Pruritus and dermatitis 
Hydroxyzine or diphenhydramine can be used to control the symptoms from pruritus. Lotions, topical 
creams, and ointments should be applied as needed for skin manifestations (see section 5.2.3).  
 
Life-threatening toxicities 
Life-threatening toxicities, if they are attributed to inflammatory reactions of N-803 in the judgment of the 
investigators, may be ameliorated by the intravenous administration of dexamethasone or other steroid-
based medications.  No further injections of study drug will be administered to that participant. This 
would trigger a study pause. 
 
Other supportive care  
Other supportive care deemed necessary by the Principal Investigator will be used to ensure participant’s’ 
welfare. This will include any isolated deviations or modifications of the care plans outlined above. If it is 
the case that the same modifications are apparently needed more systematically, then a protocol 
modification will be considered in consultation with the Sponsor and co-investigators. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
64 
Previous editions of the ALT-803 Investigator’s Brochure relied heavily on clinical experience with the 
related cytokine therapeutic Proleukin® Interleukin2 to anticipate potential risks associated with ALT-803 
(N-803) administration. This approach was based on the fact that N-803 and IL-2 are both γ chain 
cytokines and thus could reasonably be predicted to have similar immunostimulatory properties. However, 
the substantial accumulated information on N-803 effects in humans presented the most recent IB (version 
6 dated April 2019) indicates that many side effects of IL-2 are not observed in patients treated with N-
803 at the doses being used clinically. For this reason, side effects observed in subjects treated with IL-2 
but not N-803, such as capillary leak syndrome, pulmonary dysfunction, acidosis, and gastritis, have been 
removed from the IB and are reflected in this protocol and its consent form. Refer to the current 
Investigator Brochure (April 2019 version 6) for additional information 
 
 
11. DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
11.1. 
Early Removal 
A participant may be removed from study treatment at any time if the participant or the study team feels 
that it is not in the participant’s best interest to continue. The following is a list of possible reasons for 
study removal: 
• Participant withdrawal of consent  
• Participant is not compliant with study procedures 
• Adverse event that in the opinion of the investigator would be in the best interest of the subject to 
discontinue study treatment 
o Including but not limited to a Grade 4 injection site reaction, sustained use of steroids, any 
life-threatening AE, a Grade 3 QTc prolongation, and/or EKG evidence for ischemia at 
Days 21 & 42. 
• Protocol violation requiring discontinuation of study treatment 
• Lost to follow-up 
• Sponsor request for early termination of study 
• 
Positive pregnancy test (females) 
• A protocol violation 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and treated 
by the Investigator until the abnormal parameter or symptom has resolved or stabilized.  
All participants who discontinue study treatment should come in for an early discontinuation visit as soon 
as possible and then should be encouraged to complete all remaining scheduled visits and procedures. 
 
11.2. 
Withdrawal of Participants from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the Sponsor 
feels that it is not in the subject’s best interest to continue.  
 
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
65 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. The 
reason for the subject’s withdrawal from the study will be specified in the subject’s source documents. As 
noted above, participants who discontinue study treatment early should have an early discontinuation visit. 
 
11.3. 
Replacement of Participants 
If a participant discontinues participation for any reason they will be replaced so that there are 10 
evaluable participants. Participants will be discontinued and replaced if they:  
• fail to receive all 3 injections of N-803 
• fail to receive an injection of N-803 within the dose administration window as defined in section 
5.3 
• fail to have one or all of the procedures (i.e. colon biopsy, lymph node biopsy, and leukapheresis) 
at both indicated timepoints 
• initiate systemic steroids or other prohibited medications per section 6.1 
• have any change in ART regimen that demonstrates a loss of viral control by measurements of 
plasma viral load greater than 200 copies/mL on two consecutive measures separated by at least 
two weeks 
• 
receive a clinical vaccination during the study period (other than influenza or SARS-CoV-2) 
 
The safety data from all of the participants will be reported regardless of whether or not they completed 
the study or if they were withdrawn and/or replaced. Safety results will be reported for all enrolled and 
treated participants. 
 
11.4. 
Study Pause Criteria 
Enrollment of new participants and the administration of study drug for enrolled participants will be 
paused and the study plan re-evaluated after consultation with the SMC if: 
• any single grade >4 adverse event, laboratory abnormality, and/or life-threatening toxicity.  
• 
if > 2 participants experience a study drug-related Grade 3 AE. (Grade 3 injection site reactions 
are excluded from these criteria) or 
• a pattern of significant symptoms, physical findings, or laboratory abnormalities (adverse events) 
that, although individually minor, collectively represent a safety concern in the opinion of the 
investigator. The team of investigators will review all AEs every 14 days to monitor for any safety 
concerns. Any safety concern will be reported by the PI to the SMC. 
 
If the study is paused for safety reasons, notify FDA immediately. Obtain written consent from the 
FDA before resuming the study. 
 
12. PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety, and or primary endpoint criteria. Protocol 
violations for this study include, but are not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 
• Use of a prohibited concomitant medication 
• Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
66 
violation.  
When a protocol violation occurs, it will be discussed with the study team and a Note to File detailing the 
violation will be generated. A copy of the note to file will be filed in the site’s regulatory binder. All 
critical events must be written up by the study team with corrective actions. This will be filed with the 
DAIDS Medical Officer (MO), the institution’s IRB, and in the site’s regulatory binder. 
 
13. STATISTICAL METHODS AND CONSIDERATIONS 
Prior to database lock, a detailed Statistical Analysis Plan (SAP) will be written describing all analyses that 
will be performed. The SAP will contain any modifications to the analysis plan described below.  
 
13.1. 
Data Sets Analyzed 
The data set used for statistical analyses will contain hematology measures from all indicated visits;  height 
and weight from the physical exam (for calculation of BMI); HIV clinical laboratory measures collected at 
indicated study visits;  markers of T cell proliferation and activation from flow cytometry analysis; 
measures of NK activation and function from LT and blood samples; number of HIV transcribing cell 
equivalents from the EDITS assay measured in blood and LT; demographic information; and medical 
history for all participants who satisfy the inclusion criteria. 
 
13.2. 
Safety Analysis 
Any AEs will be reported in a study report that will document AEs and completeness of data. This report 
will include the total number of AEs and total number of participants experiencing an AE. AEs will be 
summarized in terms of severity and relatedness. Safety results will be reported for all enrolled and treated 
participants. 
 
13.3. 
Data Analysis Plan 
The primary endpoint for this study is change in frequency of CD8+ T cells in follicles as measured in the 
LN. Secondary endpoints include change in frequency of CD8+ T cells in GALT, change in frequency of 
vRNA+ TFH cells, frequency of viral RNA + cells as measured by the EDITS assay, and percent of NK 
cells expressing activation and ADCC function markers. Prior to analysis, measures reflecting cell count 
will be log-transformed and percentages will be arcsine transformed. Due to the exploratory nature of the 
proposed study, all analyses involving the secondary endpoints will be presented in entirety without 
adjustments for multiple comparisons using a significance level of 0.05. 
 
Linear regression models will be used to assess change in measurements collected only at two timepoints, 
before and after administration of N-803, including: LT measures of frequency of CD8 T+ cells in the 
follicles, frequency of vRNA+ TFH cells, amount of HIV RNA/DNA, and percent of NK cells expressing 
activation and ADCC function markers. The outcome for the models will be change in measurement and 
baseline level of the measure will be included as a covariate. We will use two-sided tests for assessing if the 
model intercepts deviate from zero. 
 
Mixed effects models with subject specific random intercepts will be used to evaluate measures collected 
throughout the study including: PB measures of plasma viral load, CD4+ and CD8+ T cell counts and 
percentages, CD4/CD8 ratios, and percent of NK cells expressing activation and ADCC function markers. 
These models will initially test for a linear change over time, but nonlinear trajectories using natural splines 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
67 
will also be investigated. Permutation p-values will be presented for all models.  
 
We will investigate how sex and other clinical factors, such as age, influence changes in B cell follicle 
structure, function, and HIV viral measures after N-803 therapy by including relevant clinical factors into 
our models. 
 
13.4. 
Sample Size and Randomization 
Because our study is the first of its kind to examine the impact of N-803 on CD8+ T cells in B cell follicles 
in humans, preliminary data is limited. In a recent study investigating changes in SIV-specific CD8+ T cells 
in response to N-803 (Webb et al., 2018), the investigators found that in 9 tissue samples from 6 SIV-
infected macaques the frequency of SIV-specific CD8+ T cells per mm2 in the B cell follicle drastically 
increased after N-803 administration. The average change divided by the standard deviation was 
approximately 1.11, resulting in a paired, 2-sided t-test p-value of 0.0102. Assuming N-803 has a similar 
response in humans (Cohen's d = 1.11), and using a type-I error rate of 0.05, our study with 10 participants 
would have approximately 87% power to detect an effect of this size or greater.  
 
As this is an uncontrolled study, no randomization will be conducted.  
 
14. DATA COLLECTION, RETENTION AND MONITORING 
14.1. 
Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each subject treated with the study drug.  
Detailed interviews will be conducted at each visit, including questions regarding current medications, 
medication adherence, intercurrent illnesses, and hospitalizations.  
 
The Investigator is responsible for all information collected on participants enrolled in this study. All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the Investigator.  
 
14.2. 
Data Management Procedures 
The data will be entered into a validated database. The Data Management group will be responsible for 
data processing, in accordance with procedural documentation. Database lock will occur once quality 
assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 
14.3. 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks will 
be implemented and applied to the database on a regular basis. 
 
All data will be managed and analyzed under the direction of Dr. Anne Eaton in the University of 
Minnesota Department of Biostatistics. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
68 
 
14.4. 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; appropriate 
backup copies of the database and related software files will be maintained. Databases are backed up by 
the database administrator in conjunction with any updates or changes to the database.  
 
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for analysis 
is locked and cleaned per established procedures. 
 
14.5. 
Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives of the 
Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request. A file for 
each subject must be maintained that includes the signed Informed Consent, HIPAA Authorization Form 
and copies of all source documentation related to that subject. The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
 
All study documents (subject files, signed informed consent forms, copies of CRFs, Study File, etc.) must 
be kept secured for a period of two years following marketing of the investigational product or for two 
years after centers have been notified that the IND has been discontinued. There may be other 
circumstances for which the Sponsor is required to maintain study records and, therefore, the Sponsor 
should be contacted prior to removing study records for any reason. 
 
14.6. 
Monitoring 
The site initiation visit will be conducted by a monitor from DAIDS, not the University of Minnesota.  
This study will be monitored at a minimum of every 6 months by the University of Minnesota Clinical 
and Translational Science Institute’s Clinical Trial Monitoring Program. This program will monitor both 
the University of Minnesota and Hennepin Healthcare study sites. The study monitor will review subject 
records to ensure protection of study subjects, compliance with the protocol and accuracy and 
completeness of the protocol. All subject records will be monitored for appropriate consent and eligibility. 
A minimum 10% of the case report form data for will be monitored against the source documents for data 
verification. The monitors also will inspect regulatory files to ensure that regulatory requirements are 
being followed and pharmacy to review product storage and management. 
 
Clinical site monitoring visits will be conducted according to the U.S. CFR Title 21 Parts 50, 56, and 312 
and ICH Guidelines for GCP (E6). By signing this protocol, the Investigator grants permission to the 
Sponsor (UMN), DAIDS, and appropriate regulatory authorities to conduct on-site monitoring and/or 
auditing of all appropriate study documentation. 
 
The study data manager and statistician will prepare a quarterly report of accrual, and study 
discontinuations (and related reasons), baseline characteristics, Grade ≥ 2 signs and symptoms, Grade ≥ 2 
laboratory abnormalities and reported SAEs. This report will be reviewed by the study team, including the 
DAIDS MO or designee, on a quarterly basis 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
69 
14.7. 
Safety Monitoring 
The Principal Investigator – Dr. Timothy Schacker, will be the primary person responsible for the 
monitoring of safety on this trial, which includes reporting of adverse events and unanticipated problems 
to the study Safety Monitoring Committee (SMC), University of Minnesota Institutional Review Board, 
and to the FDA. The committee will be composed of at least 3 independent scientists. These individuals 
were selected based on their expertise in either the clinical management of HIV infection and/or their 
expertise with clinical trials.  
 
Approximately 1 month after enrollment of the first participant, and then biannually, the SMC will meet 
and review accrual (including screening and enrollment), AE summaries, including all reported Grade ≥3 
AEs, retention of participants including off-study rates, and clinical laboratory data.  
 
In addition to the regularly scheduled reviews, the SMC will perform expedited reviews of the safety data 
whenever one of the study pause criteria (section 11.4) occurs.  
 
Whenever such an event as specified in 11.4 occurs, enrollment into the study and administration of study 
drug to enrolled participants will be paused until the SMC review has taken place and a determination has 
been made that enrollment can resume. The SMC will recommend, based on the results of the review, 
whether the study can proceed as planned, proceed with modifications, or should be discontinued.   Any 
changes to the study design will have to be approved by the DAIDS Clinical Science Review Committee 
(CRSC). 
 
The SMC may also be convened if a reason is identified by the study team, DAIDS MO, or study 
statistician. 
 
The SMC will review progress towards pre-specified benchmarks of enrollment and retention of 
participants, completion of study procedures, and collection of viable samples. If progress towards any 
benchmark is not adequate, as determined by the SMC, the SMC will recommend protocol modification or 
stopping the study if necessary.  
 
Any recommendation for modification of the protocol will be made to DAIDS as well as the protocol 
team, and any amendment to the protocol will require DAIDS Clinical Science Review Committee 
(CSRC) approval. All updated versions of the protocol, IB, and related documents will be provided to the 
DAIDS MO and DAIDS Program Officer (PO).  
 
The DAIDS MO and DAIDS PO will receive copies of all correspondence with the FDA about this study 
at the time they are reported to the FDA or earlier. The DAIDS MO and DAIDS PO will also receive 
copies of any correspondence received from the FDA. 
 
15. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers (21 
CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312). 
 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
70 
To maintain confidentiality, all information that identifies study subjects will be handled in accordance with 
HIPAA regulations, US State and Federal laws, and University of Minnesota policy. Our sites are 
committed to ensuring that appropriate measures are taken to protect the privacy and confidentiality of all 
Personally-Identifiable Health Information (PHI) for which it is responsible. Subjects will sign an 
authorization to use or disclose protected health info for research purposes. All staff will have been trained 
in the use of protected health information.  All study records will be kept in a locked file cabinet and code 
sheets linking a subject’s name to a subject identification number will be stored separately in another locked 
file cabinet. Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA and other local, US or international regulatory entities. The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
 
15.1. 
Protocol Amendments 
Any amendment to the protocol will be written by PI. Protocol amendments cannot be implemented 
without prior written IRB/IEC approval except as necessary to eliminate immediate safety hazards to 
subjects. Any amendment to the protocol requires CSRC approval. A protocol amendment intended to 
eliminate an apparent immediate hazard to subjects may be implemented immediately, provided the IRBs 
are notified within five working days.  
 
15.2. 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating center 
prior to study initiation. Serious adverse experiences regardless of causality will be reported to the 
IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, and the 
Investigator will keep the IRB/IEC informed as to the progress of the study. The Investigator will obtain 
assurance of IRB/IEC compliance with regulations. 
 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning participant recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB/IEC. 
The IRB/IECs written unconditional approval of the study protocol and the informed consent form will be 
in the possession of the Investigator before the study is initiated. The IRB/IECs unconditional approval 
statement will be transmitted by the Investigator to any sponsor prior to the shipment of study supplies to 
the site. This approval must refer to the study by exact protocol title and number and should identify the 
documents reviewed and the date of review. 
 
Protocol and/or informed consent modifications or changes may not be initiated without prior written 
IRB/IEC approval except when necessary to eliminate immediate hazards to the subjects or when the 
change(s) involves only logistical or administrative aspects of the study. Such modifications will be 
submitted to the IRB/IEC and written verification that the modification was submitted and subsequently 
approved should be obtained.  
 
The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious 
and/or unexpected adverse experiences occurring during the study in accordance with the standard 
operating procedures and policies of the IRB; new information that may affect adversely the safety of the 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
71 
subjects of the conduct of the study; an annual update and/or request for re-approval; and when the study 
has been completed. 
 
15.3. 
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Participants (21 CFR 50.25, CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local 
regulations. 
The Investigator at each study site will prepare an informed consent form and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the IRB/IEC. The 
consent form generated by the Investigator must be acceptable to the Sponsor and be approved by the 
IRB/IEC. The written consent document will embody the elements of informed consent as described in the 
International Conference on Harmonization and will also comply with local regulations. The Investigator 
will send an IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the 
study file. 
 
A properly executed, written, informed consent will be obtained from each subject prior to entering the 
subject into the trial. Information should be given in both oral and written form and participants must be 
given ample opportunity to inquire about details of the study. If a subject is unable to sign the informed 
consent form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.  A copy 
of the signed consent form will be given to the subject and the original will be maintained with the 
subject’s records. 
 
Per the ICF, any incidental findings that, in opinion of the principal investigator (or co-investigator who is 
a physician), will be disclosed to the participant in a timely manner. The participant will be given the 
option to opt out of such information sharing within the ICF. 
 
15.4. 
Subject Compensation 
 
Subjects will be compensated for their time and travel costs for each study visit. Compensation amounts 
are specified in the study’s informed consent form. 
 
15.5. 
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the study Sponsor and 
participating institutions. The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
 
15.6. 
Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with   contaminated 
needles, blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and shipping and handling of all specimens for this study, as currently 
recommended by the Centers for Disease Control and Prevention and the National Institutes of Health.  

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
72 
All dangerous goods materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
Biohazard waste that is produced in the context of this study will be disposed of in compliance with 
biohazard waste disposal guidelines at each study site. 
 
15.7. 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of participants. 
 
2. Personally conduct or supervise the study (or investigation). 
 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64. 
 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee). 
 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study. 
 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity and 
all unanticipated problems involving risks to participants or others (to include amendments and 
IND safety reports). 
 
9. Seek IRB approval before any changes are made in the research study, except when necessary to 
eliminate hazards to the patients/participants. 
 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
16. REFERENCES 
 
1. 
Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, Kong L, Jeng EK, Han K, Marcus WD, 
Rubinstein MP, Rhode PR, Wong HC. Efficacy and mechanism-of-action of a novel superagonist interleukin-
15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
73 
Cancer Res. 2013;73(10):3075-86. Epub 2013/05/07. doi: 10.1158/0008-5472.CAN-12-2357. PubMed PMID: 
23644531; PMCID: 3914673. 
2. 
Wong RL, Liu B, Zhu X, You L, Kong L, Han KP, Lee HI, Chavaillaz PA, Jin M, Wang Y, Rhode PR, 
Wong HC. Interleukin-15:Interleukin-15 receptor alpha scaffold for creation of multivalent targeted immune 
molecules. Protein Eng Des Sel. 2011;24(4):373-83. Epub 2010/12/24. doi: 10.1093/protein/gzq116. PubMed 
PMID: 21177283; PMCID: 3049345. 
3. 
Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, Vyas VV, Marcus WD, Chavaillaz PA, Romero 
CA, Rhode PR, Wong HC. IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in 
recombinant mammalian cells, purification and characterization. Cytokine. 2011;56(3):804-10. Epub 
2011/10/25. doi: 10.1016/j.cyto.2011.09.028. PubMed PMID: 22019703; PMCID: 3221918. 
4. 
Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, Liu B, Zhu X, Wen J, You L, Kong L, 
Edwards AC, Han K, Shi S, Alter S, Sacha JB, Jeng EK, Cai W, Wong HC. Comparison of the Superagonist 
Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models. Cancer Immunol Res. 
2016;4(1):49-60. doi: 10.1158/2326-6066.CIR-15-0093-T. PubMed PMID: 26511282; PMCID: PMC4703482. 
5. 
Estes JD, Kityo C, Ssali F, Swainson L, Makamdop KN, Del Prete GQ, Deeks SG, Luciw PA, Chipman 
JG, Beilman GJ, Hoskuldsson T, Khoruts A, Anderson J, Deleage C, Jasurda J, Schmidt TE, Hafertepe M, 
Callisto SP, Pearson H, Reimann T, Schuster J, Schoephoerster J, Southern P, Perkey K, Shang L, Wietgrefe 
SW, Fletcher CV, Lifson JD, Douek DC, McCune JM, Haase AT, Schacker TW. Defining total-body AIDS-
virus burden with implications for curative strategies. Nat Med. 2017. Epub 2017/10/03. doi: 10.1038/nm.4411. 
PubMed PMID: 28967921. 
6. 
Jones RB, Mueller S, O'Connor R, Rimpel K, Sloan DD, Karel D, Wong HC, Jeng EK, Thomas AS, 
Whitney JB, Lim SY, Kovacs C, Benko E, Karandish S, Huang SH, Buzon MJ, Lichterfeld M, Irrinki A, Murry 
JP, Tsai A, Yu H, Geleziunas R, Trocha A, Ostrowski MA, Irvine DJ, Walker BD. A Subset of Latency-
Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes. 
PLoS Pathog. 2016;12(4):e1005545. doi: 10.1371/journal.ppat.1005545. PubMed PMID: 27082643; PMCID: 
PMC4833318. 
7. 
Webb GM, Li S, Mwakalundwa G, Folkvord JM, Greene JM, Reed JS, Stanton JJ, Legasse AW, Hobbs 
T, Martin LD, Park BS, Whitney JB, Jeng EK, Wong HC, Nixon DF, Jones RB, Connick E, Skinner PJ, Sacha 
JB. The human IL-15 superagonist ALT-803 directs SIV-specific CD8(+) T cells into B-cell follicles. Blood 
Adv. 2018;2(2):76-84. Epub 2018/01/25. doi: 10.1182/bloodadvances.2017012971. PubMed PMID: 29365313; 
PMCID: PMC5787870. 
8. 
Nguyen K, Das B, Dobrowolski C, Karn J. Multiple Histone Lysine Methyltransferases Are Required 
for the Establishment and Maintenance of HIV-1 Latency. MBio. 2017;8(1). Epub 2017/03/02. doi: 
10.1128/mBio.00133-17. PubMed PMID: 28246360; PMCID: PMC5347344. 
9. 
Josefsson L, King MS, Makitalo B, Brannstrom J, Shao W, Maldarelli F, Kearney MF, Hu WS, Chen J, 
Gaines H, Mellors JW, Albert J, Coffin JM, Palmer SE. Majority of CD4+ T cells from peripheral blood of 
HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A. 
2011;108(27):11199-204. doi: 10.1073/pnas.1107729108. PubMed PMID: 21690402; PMCID: PMC3131354. 
10. 
Haase AT. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in 
lymphatic tissues. Annual review of immunology. 1999;17:625-56. PubMed PMID: 10358770. 
11. 
Haase AT, Henry K, Zupancic M, Sedgewick G, Faust RA, Melroe H, Cavert W, Gebhard K, Staskus K, 
Zhang ZQ, Dailey PJ, Balfour H, Jr., Erice A, Perelson AS. Quantitative image analysis of HIV-1 infection in 
lymphoid tissue. Science. 1996;274(5289):985-9. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
74 
12. 
Pantaleo G, Graziosi C, Butini L, Pizzo PA, Schnittman SM, Kotler DP, Fauci AS. Lymphoid organs 
function as major reservoirs for human immunodeficiency virus. Proceedings of the National Academy of 
Sciences of the United States of America. 1991;88(21):9838-42. 
13. 
Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci 
AS. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. 
Nature. 1993;362(6418):355-8. 
14. 
Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, Muro-Cacho C, Fauci AS. 
Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 
1994;140:105-30. Epub 1994/08/01. PubMed PMID: 7821924. 
15. 
Schacker T, Little S, Connick E, Gebhard-Mitchell K, Zhang ZQ, Krieger J, Pryor J, Havlir D, Wong 
JK, Richman D, Corey L, Haase AT. Rapid accumulation of human immunodeficiency virus (HIV) in 
lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral 
therapy. J Infect Dis. 2000;181(1):354-7. PubMed PMID: 10608788. 
16. 
Pantaleo G, Graziosi C, Fauci AS. The role of lymphoid organs in the immunopathogenesis of HIV 
infection. Aids. 1993;7(Suppl 1):S19-23. 
17. 
Picker LJ, Reed-Inderbitzin EF, Hagen SI, Edgar JB, Hansen SG, Legasse A, Planer S, Piatak M, Jr., 
Lifson JD, Maino VC, Axthelm MK, Villinger F. IL-15 induces CD4 effector memory T cell production and 
tissue emigration in nonhuman primates. J Clin Invest. 2006;116(6):1514-24. Epub 2006/05/13. doi: 
10.1172/JCI27564. PubMed PMID: 16691294; PMCID: 1459071. 
18. 
Mueller YM, Petrovas C, Bojczuk PM, Dimitriou ID, Beer B, Silvera P, Villinger F, Cairns JS, Gracely 
EJ, Lewis MG, Katsikis PD. Interleukin-15 increases effector memory CD8+ t cells and NK Cells in simian 
immunodeficiency virus-infected macaques. J Virol. 2005;79(8):4877-85. Epub 2005/03/30. doi: 
10.1128/JVI.79.8.4877-4885.2005. PubMed PMID: 15795273; PMCID: 1069542. 
19. 
Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, Streeck H, Waring M, Meier 
A, Brander C, Lifson JD, Allen TM, Carrington M, Altfeld M. Differential natural killer cell-mediated 
inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. The Journal of experimental medicine. 
2007;204(12):3027-36. Epub 2007/11/21. doi: 10.1084/jem.20070695. PubMed PMID: 18025129; PMCID: 
2118524. 
20. 
Apps R, Qi Y, Carlson JM, Chen H, Gao X, Thomas R, Yuki Y, Del Prete GQ, Goulder P, Brumme ZL, 
Brumme CJ, John M, Mallal S, Nelson G, Bosch R, Heckerman D, Stein JL, Soderberg KA, Moody MA, 
Denny TN, Zeng X, Fang J, Moffett A, Lifson JD, Goedert JJ, Buchbinder S, Kirk GD, Fellay J, McLaren P, 
Deeks SG, Pereyra F, Walker B, Michael NL, Weintrob A, Wolinsky S, Liao W, Carrington M. Influence of 
HLA-C expression level on HIV control. Science. 2013;340(6128):87-91. doi: 10.1126/science.1232685. 
PubMed PMID: 23559252; PMCID: PMC3784322. 
21. 
Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira, II, Nguyen AT, Malide D, Combs CA, 
Hall G, Zhang J, Raffeld M, Rogers TB, Stetler-Stevenson W, Frank JA, Reitz M, Finkel T. Human 
mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. Journal Of 
Experimental Medicine. 2006;203(5):1235-47. doi: 10.1084/jem.20051921. PubMed PMID: 16636132; 
PMCID: PMC2121206. 
22. 
Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, Colombo S, Brown EE, Shupert WL, Phair 
J, Goedert JJ, Buchbinder S, Kirk GD, Telenti A, Connors M, O'Brien SJ, Walker BD, Parham P, Deeks SG, 
McVicar DW, Carrington M. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nature 
genetics. 2007;39(6):733-40. Epub 2007/05/15. doi: 10.1038/ng2035. PubMed PMID: 17496894. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
75 
23. 
Le Gall S, Erdtmann L, Benichou S, Berlioz-Torrent C, Liu L, Benarous R, Heard JM, Schwartz O. Nef 
interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I 
molecules. Immunity. 1998;8(4):483-95. PubMed PMID: 9586638. 
24. 
Cohen GB, Gandhi RT, Davis DM, Mandelboim O, Chen BK, Strominger JL, Baltimore D. The 
selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected 
cells from NK cells. Immunity. 1999;10(6):661-71. Epub 1999/07/14. PubMed PMID: 10403641. 
25. 
Lisovsky I, Isitman G, Song R, DaFonseca S, Tremblay-McLean A, Lebouche B, Routy JP, Bruneau J, 
Bernard NF. A Higher Frequency of NKG2A+ than of NKG2A- NK Cells Responds to Autologous HIV-
Infected CD4 Cells irrespective of Whether or Not They Coexpress KIR3DL1. J Virol. 2015;89(19):9909-19. 
doi: 10.1128/JVI.01546-15. PubMed PMID: 26202228; PMCID: PMC4577891. 
26. 
Korner C, Granoff ME, Amero MA, Sirignano MN, Vaidya SA, Jost S, Allen TM, Rosenberg ES, 
Altfeld M. Increased frequency and function of KIR2DL1-3(+) NK cells in primary HIV-1 infection are 
determined by HLA-C group haplotypes. European Journal Of Immunology. 2014;44(10):2938-48. doi: 
10.1002/eji.201444751. PubMed PMID: 25043727; PMCID: PMC4197106. 
27. 
Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and 
vaccine design. Nat Rev Immunol. 2006;6(8):595-601. Epub 2006/07/27. doi: 10.1038/nri1901. PubMed PMID: 
16868550. 
28. 
Parihar R, Dierksheide J, Hu Y, Carson WE. IL-12 enhances the natural killer cell cytokine response to 
Ab-coated tumor cells. J Clin Invest. 2002;110(7):983-92. Epub 2002/10/09. doi: 10.1172/JCI15950. PubMed 
PMID: 12370276; PMCID: PMC151155. 
29. 
Kobayashi H, Dubois S, Sato N, Sabzevari H, Sakai Y, Waldmann TA, Tagaya Y. Role of trans-cellular 
IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor 
immunosurveillance. Blood. 2005;105(2):721-7. Epub 2004/09/16. doi: 10.1182/blood-2003-12-4187. PubMed 
PMID: 15367431. 
30. 
Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA. In 
vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood. 2002;100(10):3633-
8. Epub 2002/10/24. doi: 10.1182/blood-2001-12-0293. PubMed PMID: 12393617. 
31. 
Oh S, Perera LP, Burke DS, Waldmann TA, Berzofsky JA. IL-15/IL-15Ralpha-mediated avidity 
maturation of memory CD8+ T cells. Proc Natl Acad Sci U S A. 2004;101(42):15154-9. Epub 2004/10/13. doi: 
10.1073/pnas.0406649101. PubMed PMID: 15477598; PMCID: 524066. 
32. 
Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, 
Klebanoff CA, Tagaya Y, Restifo NP. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. 
J Immunol. 2006;176(9):5255-66. PubMed PMID: 16621991; PMCID: PMC1473163. 
33. 
Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP, 3rd, Armand P, Cutler C, Ho 
VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ. 
Interleukin-2 and regulatory T cells in graft-versus-host disease. The New England journal of medicine. 
2011;365(22):2055-66. doi: 10.1056/NEJMoa1108188. PubMed PMID: 22129252; PMCID: PMC3727432. 
34. 
Ellis-Connell AL, Balgeman AJ, Zarbock KR, Barry G, Weiler A, Egan JO, Jeng EK, Friedrich T, 
Miller JS, Haase AT, Schacker TW, Wong HC, Rakasz E, O'Connor SL. ALT-803 Transiently Reduces Simian 
Immunodeficiency Virus Replication in the Absence of Antiretroviral Treatment. J Virol. 2018;92(3). Epub 
2017/11/10. doi: 10.1128/JVI.01748-17. PubMed PMID: 29118125; PMCID: PMC5774892. 
35. 
Felices M, Lenvik AJ, McElmurry R, Chu S, Hinderlie P, Bendzick L, Geller MA, Tolar J, Blazar BR, 
Miller JS. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight. 
2018;3(3). Epub 2018/02/09. doi: 10.1172/jci.insight.96219. PubMed PMID: 29415897; PMCID: 
PMC5821201. 

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
76 
36. 
Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber 
DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 
2007;27(4):670-84. Epub 2007/10/24. doi: 10.1016/j.immuni.2007.09.006. PubMed PMID: 17950003. 
37. 
Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-9. Epub 2011/07/09. PubMed PMID: 
21739672. 
38. 
Romera-Cardenas G, Thomas LM, Lopez-Cobo S, Garcia-Cuesta EM, Long EO, Reyburn HT. 
Ionomycin Treatment Renders NK Cells Hyporesponsive. PLoS One. 2016;11(3):e0150998. Epub 2016/03/24. 
doi: 10.1371/journal.pone.0150998. PubMed PMID: 27007115; PMCID: PMC4805247. 
39. 
Schacker T, Little S, Connick E, Gebhard K, Zhang ZQ, Krieger J, Pryor J, Havlir D, Wong JK, 
Schooley RT, Richman D, Corey L, Haase AT. Productive infection of T cells in lymphoid tissues during 
primary and early human immunodeficiency virus infection. J Infect Dis. 2001;183(4):555-62. PubMed PMID: 
11170980. 
40. 
Schacker TW, Nguyen PL, Beilman GJ, Wolinsky S, Larson M, Reilly C, Haase AT. Collagen 
deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest. 2002;110(8):1133-9. 
PubMed PMID: 12393849. 
41. 
Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, Larson M, Haase AT. Amount of 
lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 
cell count. AIDS. 2005;19(18):2169-71. Epub 2005/11/15. doi: 00002030-200512020-00016 [pii]. PubMed 
PMID: 16284469. 
42. 
Estes J, Reilly C, Trubey C, Fletcher C, Cory T, Piatak M, ERuss S, Anderson J, Reimann T, Star R, A 
S, Tracy R, Berglund A, Schmidt T, Coalter V, Chertova E, Smedley J, Haase A, Lifson J, Schacker T. 
Antifibrotic Therapy in SIV Infection Preserves CD4 T Cell Populations and Improves Immune Reconstitution 
With Antiretroviral Therapy. Journal of Infectious Diseases. 2014(in press). 
43. 
Davis ZB, Cogswell A, Scott H, Mertsching A, Boucau J, Wambua D, Le Gall S, Planelles V, Campbell 
KS, Barker E. A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly 
Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells. PLoS Pathog. 2016;12(2):e1005421. doi: 
10.1371/journal.ppat.1005421. PubMed PMID: 26828202; PMCID: PMC4735451. 
44. 
Ward J, Davis Z, DeHart J, Zimmerman E, Bosque A, Brunetta E, Mavilio D, Planelles V, Barker E. 
HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated 
DNA damage response. PLoS Pathog. 2009;5(10):e1000613. Epub 2009/10/03. doi: 
10.1371/journal.ppat.1000613. PubMed PMID: 19798433; PMCID: PMC2747015. 
45. 
Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, 
Kang SM, Norris PJ, Nixon DF, Lanier LL. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset 
during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2011;108(36):14725-32. doi: 
10.1073/pnas.1110900108. PubMed PMID: 21825173; PMCID: PMC3169160. 
46. 
Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes TD, Han H, Chiang SC, Foley B, 
Mattsson K, Larsson S, Schaffer M, Malmberg KJ, Ljunggren HG, Miller JS, Bryceson YT. Cytomegalovirus 
infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. 
Immunity. 2015;42(3):443-56. doi: 10.1016/j.immuni.2015.02.008. PubMed PMID: 25786176; PMCID: 
PMC4612277. 
47. 
O'Leary JG, Goodarzi M, Drayton DL, von Andrian UH. T cell- and B cell-independent adaptive 
immunity mediated by natural killer cells. Nat Immunol. 2006;7(5):507-16. doi: 10.1038/ni1332. PubMed 
PMID: 16617337. 
48. 
Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M. Human immunodeficiency virus type 
1 RNA Levels in different regions of human brain: quantification using real-time reverse transcriptase-

Effect of N-803 on B Cell Follicles in Antiretroviral Treated HIV Disease 
 
 
Protocol Version 4.4 
January 21, 2022 
 
77 
polymerase chain reaction. J Neurovirol. 2007;13(3):210-24. Epub 2007/07/07. doi: 
10.1080/13550280701327038. PubMed PMID: 17613711. 
49. 
Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, McNulty A, 
Ramgopal M, Michael N, Kim JH, Ananworanich J, Chomont N. Cross-clade ultrasensitive PCR-based assays 
to measure HIV persistence in large-cohort studies. J Virol. 2014;88(21):12385-96. doi: 10.1128/JVI.00609-14. 
PubMed PMID: 25122785; PMCID: PMC4248919.