A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-145/LN-145-S1) for the Treatment of Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Iovance Biotherapeutics, Inc.

LN-145 
 
Protocol: C-145-03 
 
Iovance Biotherapeutics, Inc. 
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 Version 2.0, Dated 30 August 2017 
 
 
 
CLINICAL PROTOCOL 
A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety of Autologous Tumor 
Infiltrating Lymphocytes (LN-145) for the Treatment of Patients with Recurrent and/or 
Metastatic Squamous Cell Carcinoma of the Head and Neck 
PROTOCOL NUMBER:   
C-145-03 
IND NUMBER: 
 
EudraCT NUMBER 
2016-003446-86 
SPONSOR: 
Iovance Biotherapeutics, Inc. 
999 Skyway Rd, Suite 150 
San Carlos, CA 94070 
PROTOCOL AMENDMENT: 
Protocol Amendment, Version 2.0, Dated 30 August 2017 
SUPERSEDES: 
Original Protocol, Version 1.0, Dated 16 August 2016 
MEDICAL MONITOR: 
 
Executive Medical Director, Clinical Science 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (CGP) and all other 
applicable regulatory requirements, including the archiving of essential documents. The specific contact 
details of the Iovance Biotherapeutics legal/regulatory entity within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application 
with the Competent Authority. 
 
 
CONFIDENTIAL INFORMATION 
This document contains confidential information and is proprietary property of Iovance Biotherapeutics, Inc 
(Sponsor) which must not be disclosed to anyone other than the recipient study staff and members of the 
participating Health Authorities and Institutional Review Board/Independent Ethics Committee. Any unauthorized 
use or disclosure of such information without the prior written authorization of the Sponsor or their representative is 
expressly prohibited. 

LN-145
Protocol: C-145-03
SPONSOR SIGNATURE PAGE
Iovance Biotherapeutics, Inc.
Protocol Title:
Protocol Number:
EudraCT Number:
Sponsor:
Protocol Version and Date:
A Phase 2, Multicenter Study to Evaluate the Efficacy and
Safety of Autologous Tumor Infiltrating Lymphocytes
(LN-145) for the Treatment ofPatients with Recurrent and/or
Metastatic Squamous Cell Carcinoma ofthe Head and Neck
C-145-03
2016-003446-86
Iovance Biotherapeutics, Inc.
Protocol Amendment, Version 2.0,30 August 2017
By my signature, I acknowledge my review and approval ofthis protocol.
Signature
dd-mon-yyyy
Executive Medical Director Clinical Science, Iovance Biotherapeutics, Inc.
dd-mon-yyyy
Science, Iovance Biotherapeutics, Inc.
Confidential and Proprietary
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LN-145 
 
Protocol: C-145-03 
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title:  
A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety 
of Autologous Tumor Infiltrating Lymphocytes (LN-145) for the 
Treatment of Patients with Recurrent and/or Metastatic Squamous 
Cell Carcinoma of the Head and Neck 
Protocol Number:  
C-145-03 
EudraCT Number: 
2016-003446-86 
Sponsor: 
Iovance Biotherapeutics, Inc. 
Protocol Version and Date: 
Protocol Amendment, Version 2.0, Dated 30 August 2017 
 
I agree to conduct the study as detailed in the protocol and in compliance with ICH Guidelines 
for Good Clinical Practice. 
I acknowledge that I am responsible for overall study conduct, and I agree to personally conduct 
or supervise the described clinical study. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study. 
Principal Investigator Signature 
Date 
Principal Investigator Printed Name 
Institution 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety of Autologous 
Tumor Infiltrating Lymphocytes (LN-145) for the Treatment of Patients with 
Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Protocol 
Number 
C-145-03 
Study Type 
Phase 2  
Indication 
Treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the 
head and neck (HNSCC) 
Investigational 
Agents 
• Nonmyeloablative lymphodepletion (NMA-LD) consisting of cyclophosphamide 
and fludarabine 
• LN-145:  autologous tumor infiltrating lymphocytes (TIL) derived from the 
patient’s own tumor  
• Interleukin-2 (IL-2, aldesleukin, Proleukin®) 
Study 
Objectives 
Primary Objective 
• 
To evaluate the efficacy of LN-145 in patients with recurrent and/or metastatic 
HNSCC using the objective response rate (ORR) as assessed by investigators 
per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)  
Secondary Objectives 
• To characterize the safety profile of LN-145 in patients with metastatic and/or 
recurrent HNSCC 
• To evaluate efficacy of LN-145 in patients with recurrent and/or metastatic 
HNSCC such as complete response (CR) rate, duration of response (DOR), 
disease control rate (DCR), and progression-free survival (PFS) by investigators’ 
review per RECIST v1.1, and overall survival (OS)  
Exploratory Objectives 
• To explore the persistence of LN-145 and immune correlates of response, survival, 
toxicity of the treatment 
• To explore efficacy based on immune-related RECIST (irRECIST) as assessed by 
independent review 
• To assess health-related quality of life (HRQoL) 
• To assess quality-adjusted time without symptoms of disease or toxicity of 
treatment (Q-TWiST) 
Study Design 
This is a Phase 2, multicenter prospective, open-label, interventional study using 
autologous TIL infusion (LN-145) followed by IL-2 after a NMA-LD pretreatment 
regimen.  

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Doses and 
Treatment 
Schedule  
The adoptive cell therapy (ACT) used in this study consists of administering a NMA-
LD preparative regimen consisting of cyclophosphamide intravenous (IV) (60 mg/kg 
× 2 doses) with mesna and fludarabine IV (25 mg/m2 × 5 doses, as tolerated), followed 
by the infusion of autologous TIL (LN-145) and administration of IL-2 (600,000 
IU/kg) every 8 to 12 hours, starting between 3 and 24 hours of the completion of the 
LN-145 infusion, continuing for up to a maximum of 6 doses, as tolerated. Patients 
may be eligible for retreatment if they relapse or do not respond following LN-145 
therapy or had a TIL manufacturing failure. 
Patients will be evaluated for response at approximately 4 weeks (Day 28), 8 weeks 
(Day 56), 12 weeks (Day 84), 18 weeks (Day 126), 6 months, 9 months, 12 months, 
18 months, and 24 months following the LN-145 therapy.  
Duration of 
Participation 
The study will consist of 3 phases: 
• Pretreatment Phase (approximately 8 weeks) 
o 
Screening visit (up to 28 days) 
o 
Tumor resection visit (1 day) 
o 
LN-145 manufacturing period (approximately 3 to 7 weeks) 
• Treatment Phase (approximately 2 weeks) 
o 
NMA lymphodepletion regimen (7 days) 
o 
LN-145 infusion (1 day) 
o 
IL-2 infusion (1 to 4 days) 
• Follow-Up Phase (3 years) 
o 
Efficacy follow-up for safety and efficacy evaluations (24 months) 
o 
Overall survival follow-up to assess disease status and survival (12 months) 
Number of 
Study Sites 
Approximately 15 clinical study sites in the United States 
Number of 
Planned 
Patients 
Approximately 47 patients who complete treatment. Complete treatment is defined as 
having received LN-145 post-NMA-LD followed by at least 1 dose of IL-2. 
Inclusion 
Criteria 
Patients must meet all of the following inclusion criteria: 
1. Must be ≥18 years of age at the time of consent 
2. Must understand and voluntarily sign informed consent prior to any study related 
assessments/procedures being conducted 
3. Must be able and willing to comply to the study visit schedule and protocol 
requirements 
4. Must have recurrent and/or metastatic HNSCC; histologic diagnosis of the 
primary tumor is required via the pathology report 
5. Must have at least 1 lesion that is resectable for TIL generation. The resected TIL 
generating lesion (or aggregate of lesions resected) should be least 1.5 cm3 in 
diameter after resection and can be surgically removed with minimal morbidity 
(defined as any operation for which expected hospitalization is ≤ 3 days). If the 
lesion is within a previously irradiated field, the irradiation must have occurred at 
least 3 months prior to resection.  
6. Must have measurable disease as defined by RECIST v1.1 following the surgical 
resection. If measurable target lesion(s) are in previously irradiated areas, 

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irradiation must have occurred at least 3 months prior to enrollment (tumor 
resection) and the lesions must have demonstrated evidence of progression since 
irradiation. 
7. Patients must have relapsed or refractory (no response) recurrent and/or metastatic 
carcinoma of the head or neck and have received at least 1 line of prior systemic 
immunotherapy and/or chemotherapeutic treatment. 
8. Any prior therapy directed at the malignant tumor, including radiation therapy, 
chemotherapy, biologic/targeted agents, and immunologic agents must be 
discontinued at least 28 days prior to lymphodepletion 
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 and an estimated life expectancy of ≥ 3 months 
10. Must meet the following laboratory criteria:  
• 
Absolute neutrophil count (ANC) > 1000/mm3 
• 
Hemoglobin > 9.0 g/dL 
• 
Platelet count > 100,000/mm3 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
< 3.0 × upper limit of normal (ULN) 
o Patients with liver metastases must have liver function tests (LFTs) 
< 5.0 × ULN 
• 
Total bilirubin ≤ 2.0 mg/dL 
o Patients with Gilbert’s Syndrome must have a total bilirubin 
≤ 3.0 mg/dL 
• 
Serum creatinine ≤ 1.5 mg/dL 
• 
An estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the 
Cockcroft-Gault formula at screening 
11. Patients must be seronegative for the HIV antibody 
12. Patients seropositive for hepatitis B virus surface antigen (HBsAg) or hepatitis C 
virus (HCV) indicating acute or chronic infection must have a negative 
(undetectable) viral load by polymerase chain reaction (PCR) with/without active 
treatment 
13. Patients of childbearing potential must be willing to practice an approved method 
of birth control starting at the time of informed consent and for 1 year after the 
completion of the study treatment regimen 
Exclusion 
Criteria 
1. Patients who have received prior cell transfer therapy, except for prior LN-145. 
Prior LN-145 therapy must have occurred at least 3 months prior to retreatment 
tumor resection. 
2. Patients who are on a systemic steroid therapy (> 10 mg of prednisone or 
equivalent daily) 
Note: A short course of higher dose steroid therapy is allowed in cases of 
exacerbation of known disease or for treatments of new acute symptoms. 
3. Patients who currently have prior therapy-related toxicities greater than Grade 1 
per National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03; except for alopecia or vitiligo prior to 
enrollment/tumor resection 

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• 
If toxicities have resolved to Grade 1 or less, a minimum of 4 weeks must 
elapse prior to enrollment (tumor resection) 
Note: Patients may undergo preplanned procedures if not within 2 to 3 weeks 
prior to the start of NMA-LD  
4. Patients with documented Grade 2 or greater diarrhea or colitis due to previous 
immunotherapy (eg, ipilimumab, tremelimumab, anti-programmed cell death 
protein 1 [PD-1 or anti-programmed cell death-ligand 1 [PD-L1] antibodies) 
within 6 months from screening 
Note: Patients who have been asymptomatic for at least 6 months or had a normal 
colonoscopy post anti-PD-1/anti-PD-L1 treatment, with uninflamed mucosa by 
visual assessment are not excluded 
5. Patients with history of severe immediate hypersensitivity reaction to 
cyclophosphamide, fludarabine, IL-2, or aminoglycosides (eg, gentamicin or 
streptomycin)  
6. Patients with active systemic infections (eg, syphilis), coagulation disorders or 
other active major medical illnesses of the cardiovascular, respiratory or immune 
system that, in the opinion of the Investigator would significantly increase the risk 
of participation. Examples of concerning conditions include, but are not limited 
to, history of a positive thallium stress test, myocardial infarction, cardiac 
arrhythmia, obstructive or restrictive pulmonary disease, or uveitis. 
7. Patients with symptomatic and/or untreated brain metastases (of any size and any 
number)  
• 
Patients with definitive treated brain metastases, may be considered for 
enrollment after discussion with the sponsor’s medical monitor/designee, and 
must be stable for 2 to 4 weeks and asymptomatic prior to the start of 
treatment (NMA-LD) 
8. Patients who have any form of primary immunodeficiency, such as severe 
combined immunodeficiency disease or acquired immune deficiency syndrome 
(AIDS)  
9. Patients who have a diagnosis of end-stage renal disease requiring hemodialysis  
10. Patients who have a left ventricular ejection fraction (LVEF) < 45% as determined 
by an echocardiogram (ECHO) or multiple gated acquisition scan (MUGA); and 
patients > 60 years of age or those with a history of ischemic heart disease, chest 
pain, or clinically significant atrial and/or ventricular arrhythmias who have a 
positive stress thallium test are excluded. Patients with an abnormal stress test 
may be enrolled following cardiology clearance and approval of the medical 
monitor  
11. Patients who have a forced expiratory volume in one second (FEV1) of less than 
or equal to 60% of predicted normal 
• 
If a patient is not able to perform reliable spirometry due to abnormal upper 
airway anatomy (ie, tracheostomy), a 6-minute walk test may be used to 
assess pulmonary function. Patients who are unable to walk a distance of at 
least 80% predicted for age and sex or demonstrates evidence of hypoxia at 
any point during the test (SpO2 < 90%) are excluded. 
12. Patients who have had another primary malignancy within the previous 3 years 
(except for curatively treated localized malignancy that has not required treatment 
for greater than 1 year, and in the judgment of the investigator, does not pose a 

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significant risk of recurrence including, but not limited to, non-melanoma skin 
cancer or bladder cancer)  
13. Patients who are pregnant or breastfeeding  
Efficacy 
Assessment 
The descriptive summary of the ORR, CR rate, DOR, DCR, PFS will be used to 
describe efficacy by investigator’s review per RECIST v1.1. Estimation of OS will 
depend on the date of death or the last known alive status date. 
Safety 
Assessment 
Treatment-emergent adverse events (TEAEs), clinical laboratory data assessment, and 
serious adverse events (SAEs) will be collected and evaluated for 6 months after last 
dose of IL-2 infusion, and AEs that are related to the study treatment (from the time of 
enrollment/tumor resection) will be collected for the duration of the study until 
resolution or permanent sequalae. 
Statistical 
Considerations 
The sample size is based on number of treated patients who receive the NMA-LD 
regimen, any amount of LN-145 therapy, and at least 1 dose of IL-2. 
A Simon 2-stage optimal design will be employed to have 80% power to detect an 
ORR difference from 5% to 20% using a 1-sided alpha of 0.025. 
The first stage will consist of 15 treated patients. If 1 or fewer patients respond within 
3 months (either a PR or CR), the study will be terminated. Otherwise, the study will 
continue to enroll for a total of 47 treated patients in Stage 2. The study would 
demonstrate a clinically meaningful response if 6 or more patients demonstrate an 
objective response. 
Patients meeting RECIST v1.1 criteria for CR or PR will be classified as responders in 
the analysis of the ORR. This rate will be summarized using both a point estimate and 
its 2-sided 95% confidence limits. 
The assessment of safety data will be based on the summarization of TEAEs, SAEs, 
AEs leading to discontinuation from study treatment or efficacy follow-up, and 
clinical laboratory tests. 
Data Safety 
Monitoring 
Board 
A data safety monitoring board (DSMB) will evaluate safety data after the first 
5 patients complete Week 4 (Day 28). An additional evaluation will be completed 
when the first 15 patients complete Week 4 (Day 28). A limited analysis may also be 
conducted reviewing all data available from these patients as specified in the DSMB 
charter. Enrollment will continue while under review. 
 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................................................ 2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE ............................................................................................ 3 
PROTOCOL SYNOPSIS ............................................................................................................................................ 4 
TABLE OF CONTENTS ............................................................................................................................................ 9 
LIST OF APPENDICES ........................................................................................................................................... 12 
LIST OF TABLES ..................................................................................................................................................... 12 
LIST OF FIGURES ................................................................................................................................................... 12 
LIST OF ABBREVIATIONS ................................................................................................................................... 13 
1.
INTRODUCTION ........................................................................................................................................ 16 
1.1. 
Head and Neck Cancer ................................................................................................................................ 16 
1.2. 
Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes as Cancer Immunotherapy ............................ 17 
1.3. 
TIL for Head and Neck Cancer ................................................................................................................... 18 
2.
STUDY DESIGN .......................................................................................................................................... 20 
2.1. 
Overview ..................................................................................................................................................... 20 
2.2. 
Production and Expansion of Tumor Infiltrating Lymphocytes .................................................................. 22 
3.
STUDY OBJECTIVES AND ENDPOINTS............................................................................................... 24 
3.1. 
Study Objectives .......................................................................................................................................... 24 
3.1.1. 
Primary Objective ........................................................................................................................................ 24 
3.1.2. 
Secondary Objectives .................................................................................................................................. 24 
3.1.3. 
Exploratory Objectives ................................................................................................................................ 24 
3.2. 
Study Endpoints........................................................................................................................................... 24 
3.2.1. 
Primary Endpoint......................................................................................................................................... 24 
3.2.2. 
Secondary Endpoints ................................................................................................................................... 24 
3.2.3. 
Exploratory Endpoints ................................................................................................................................. 25 
4.
SELECTION OF PATIENT POPULATION ............................................................................................ 26 
4.1. 
Inclusion Criteria ......................................................................................................................................... 26 
4.2. 
Exclusion Criteria ........................................................................................................................................ 27 
4.3. 
Patient Enrollment and Re-Screening .......................................................................................................... 29 
5.
STUDY ASSESSMENTS/PROCEDURES ................................................................................................. 30 
5.1. 
Informed Consent ........................................................................................................................................ 30 
5.2. 
Inclusion/Exclusion Criteria ........................................................................................................................ 30 
5.3. 
Demographic Data ....................................................................................................................................... 30 
5.4. 
Medical History ........................................................................................................................................... 30 
5.5. 
Documentation of Confirmation of Diagnosis............................................................................................. 30 
5.6. 
Documentation of HPV Tumor Status ......................................................................................................... 30 
5.7. 
Concomitant Medications ............................................................................................................................ 30 
5.8. 
Adverse Events ............................................................................................................................................ 30 
5.9. 
HRQoL Questionnaire – EORTC QLQ-30 Version 3.0 .............................................................................. 31 
5.10. 
Physical Examination .................................................................................................................................. 31 
5.11. 
Vital Signs ................................................................................................................................................... 31 
5.12. 
Eastern Cooperative Oncology Group Performance Status ......................................................................... 31 
5.13. 
Safety Blood and Urine Tests ...................................................................................................................... 31 
5.14. 
ß-HCG Serum Pregnancy Test .................................................................................................................... 32 
5.15. 
Infection Testing .......................................................................................................................................... 32 
5.16. 
Human Leukocyte Antigen Typing ............................................................................................................. 32 
5.17. 
HPV Subtype Serotype ................................................................................................................................ 32 
5.18. 
Estimated Creatinine Clearance ................................................................................................................... 33 
5.19. 
Eye Examination ......................................................................................................................................... 33 
5.20. 
Cardiac Evaluations ..................................................................................................................................... 33 
5.20.1. 
Stress Thallium ............................................................................................................................................ 33 

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5.20.2. 
Echocardiogram or Multigated Acquisition Scan ........................................................................................ 33 
5.20.3. 
Electrocardiogram ....................................................................................................................................... 33 
5.21. 
Pulmonary Function Tests ........................................................................................................................... 33 
5.22. 
Colonoscopy ................................................................................................................................................ 34 
5.23. 
Immune Monitoring and Peripheral Blood Mononuclear Cells ................................................................... 34 
5.24. 
Radiographic Assessments .......................................................................................................................... 34 
5.25. 
Tumor Resection / Harvest .......................................................................................................................... 35 
5.25.1. 
Additional Tumor Tissue from Resected Tumor ......................................................................................... 35 
6. 
STUDY TREATMENT ................................................................................................................................ 36 
6.1. 
Nonmyeloablative Lymphodepletion Regimen ........................................................................................... 36 
6.1.1. 
Preparation of Cyclophosphamide ............................................................................................................... 36 
6.1.2. 
Preparation of Mesna ................................................................................................................................... 36 
6.1.3. 
Infusion of Cyclophosphamide and Mesna ................................................................................................. 37 
6.1.4. 
Fludarabine .................................................................................................................................................. 37 
6.2. 
LN-145 Infusion .......................................................................................................................................... 37 
6.2.1. 
Description of LN-145 ................................................................................................................................ 37 
6.2.2. 
Composition of LN-145 .............................................................................................................................. 38 
6.2.3. 
Transport of LN-145 .................................................................................................................................... 38 
6.2.4. 
Receipt of LN-145 and Administration ....................................................................................................... 38 
6.3. 
Interleukin-2 ................................................................................................................................................ 39 
6.4. 
Retreatment ................................................................................................................................................. 40 
7. 
PERMITTED AND PROHIBITED CONCOMITANT MEDICATIONS .............................................. 41 
7.1. 
Permitted Medications ................................................................................................................................. 41 
7.2. 
Prohibited Medications and Prior Treatment Washout ................................................................................ 41 
7.2.1. 
Prohibited Medications ................................................................................................................................ 41 
7.2.2. 
Prior Treatment Washout............................................................................................................................. 41 
8. 
TOXICITIES MANAGEMENT GUIDELINES ....................................................................................... 42 
8.1. 
NMA-LD Regimen Toxicity Management.................................................................................................. 42 
8.1.1. 
Infection Prophylaxis ................................................................................................................................... 42 
8.1.1.1. 
Pneumocystis jirovecii Pneumonia ............................................................................................................................... 42 
8.1.1.2. 
Herpes Virus Prophylaxis ............................................................................................................................................. 42 
8.1.1.3. 
Fungal Prophylaxis (Fluconazole) ................................................................................................................................ 43 
8.1.2. 
Hemorrhagic Cystitis Prophylaxis ............................................................................................................... 43 
8.1.3. 
Febrile Neutropenia ..................................................................................................................................... 43 
8.1.4. 
Filgrastim..................................................................................................................................................... 43 
8.1.5. 
Blood Product Support ................................................................................................................................ 43 
8.2. 
LN-145 Toxicity Management .................................................................................................................... 44 
8.3. 
Interleukin-2 Toxicity Management ............................................................................................................ 44 
8.3.1. 
Neurologic Toxicity ..................................................................................................................................... 44 
8.3.2. 
Renal Toxicity ............................................................................................................................................. 44 
8.3.3. 
Capillary Leak Syndrome and Weight Gain ................................................................................................ 45 
8.3.4. 
Cardiac Arrhythmias and Myocarditis ......................................................................................................... 45 
8.3.5. 
Pulmonary ................................................................................................................................................... 45 
8.3.6. 
Sepsis/Febrile Neutropenia During IL-2 ..................................................................................................... 45 
8.3.7. 
Heparin-Induced Thrombocytopenia ........................................................................................................... 45 
8.4. 
Concomitant Medications to Control Side Effects ...................................................................................... 45 
9. 
COMPLETION/WITHDRAWAL OF PATIENTS................................................................................... 47 
9.1. 
Treatment Completion ................................................................................................................................. 47 
9.2. 
Study Completion ........................................................................................................................................ 47 
9.3. 
Criteria for Discontinuation Prior to or From Study Treatment .................................................................. 47 
9.4. 
Follow-Up ................................................................................................................................................... 48 
9.4.1. 
Efficacy Follow-Up ..................................................................................................................................... 48 
9.4.2. 
Overall Survival Follow Up ........................................................................................................................ 48 
9.5. 
Patient Withdrawal from Study ................................................................................................................... 48 
9.6. 
Early Termination of Study/Center Closure ................................................................................................ 49 

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10. 
TUMOR RESPONSE ASSESSMENTS ..................................................................................................... 50 
10.1. 
Response Criteria......................................................................................................................................... 50 
10.1.1. 
Baseline Documentation of Target and NonTarget Lesions ........................................................................ 50 
10.1.2. 
Evaluation of Target Lesions ....................................................................................................................... 50 
10.1.3. 
Evaluation of Nontarget Lesions ................................................................................................................. 51 
10.1.4. 
Evaluation of New Lesions.......................................................................................................................... 51 
10.1.5. 
Evaluation of Overall Response .................................................................................................................. 52 
10.2. 
Confirmation of Tumor Assessments .......................................................................................................... 53 
10.2.1. 
Confirmation of Response (PR or CR) ........................................................................................................ 53 
10.2.2. 
Confirmation of Progressive Disease .......................................................................................................... 53 
11. 
ADVERSE EVENTS .................................................................................................................................... 54 
11.1. 
Definitions ................................................................................................................................................... 54 
11.1.1. 
Adverse Event ............................................................................................................................................. 54 
11.1.2. 
Serious Adverse Event ................................................................................................................................ 55 
11.1.3. 
Relationship to the Investigational Product ................................................................................................. 55 
11.1.4. 
Severity ........................................................................................................................................................ 56 
11.2. 
Reporting Procedures for Adverse Events ................................................................................................... 56 
11.2.1. 
All Adverse Events ...................................................................................................................................... 56 
11.3. 
Reporting Procedures for Serious Adverse Events ...................................................................................... 57 
11.3.1. 
Investigator Reporting to Sponsor ............................................................................................................... 57 
11.4. 
Special Situations Reporting ....................................................................................................................... 58 
11.4.1. 
Definitions of Special Situations ................................................................................................................. 58 
11.4.2. 
Reporting Procedures for Special Situations ............................................................................................... 58 
11.4.2.1. Pregnancy Reporting ..................................................................................................................................................... 58 
11.4.2.2. Other Special Situations Reporting ............................................................................................................................... 59 
11.5. 
Regulatory Reporting Requirements ........................................................................................................... 59 
12. 
SAFETY ASSESSMENTS ........................................................................................................................... 60 
12.1. 
Data Safety Monitoring Board .................................................................................................................... 60 
12.2. 
Considerations ............................................................................................................................................. 60 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 62 
13.1. 
Introduction ................................................................................................................................................. 62 
13.2. 
Analysis Populations ................................................................................................................................... 62 
13.2.1. 
Efficacy Population ..................................................................................................................................... 62 
13.2.2. 
Safety Population......................................................................................................................................... 62 
13.3. 
Sample Size Justification ............................................................................................................................. 62 
13.4. 
Baseline Demographic and Clinical Characteristics .................................................................................... 63 
13.5. 
Study Endpoints and Planned Analyses ...................................................................................................... 63 
13.5.1. 
Primary Endpoint......................................................................................................................................... 63 
13.5.1.1. Efficacy ......................................................................................................................................................................... 63 
13.5.2. 
Secondary Endpoints ................................................................................................................................... 63 
13.5.2.1. Safety ............................................................................................................................................................................ 63 
13.5.2.2. Additional Measures of Efficacy................................................................................................................................... 63 
13.5.3. 
Exploratory Analyses .................................................................................................................................. 64 
13.5.3.1. Stage I Analysis ............................................................................................................................................................ 64 
14. 
ADMINISTRATIVE REQUIREMENTS .................................................................................................. 65 
14.1. 
Good Clinical Practice ................................................................................................................................. 65 
14.2. 
Protocol Modifications ................................................................................................................................ 65 
14.3. 
Regulatory Approval and Documentation ................................................................................................... 65 
14.4. 
Record Retention ......................................................................................................................................... 66 
14.5. 
Data Quality Assurance ............................................................................................................................... 66 
14.6. 
Data Processing and Recordkeeping ........................................................................................................... 67 
14.6.1. 
Electronic Data ............................................................................................................................................ 67 
14.6.2. 
Electronic Case Report Form Completion ................................................................................................... 67 
14.6.3. 
Study Monitoring......................................................................................................................................... 67 
14.7. 
Clinical Trial Insurance ............................................................................................................................... 68 

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15. 
INVESTIGATOR REGULATORY OBLIGATIONS .............................................................................. 69 
15.1. 
Institutional Review Board/Independent Ethics Committee ........................................................................ 69 
15.2. 
Informed Consent ........................................................................................................................................ 69 
15.3. 
Patient Data Protection ................................................................................................................................ 70 
15.4. 
Adverse Event Reporting............................................................................................................................. 70 
15.5. 
Investigator .................................................................................................................................................. 70 
15.6. 
Confidentiality ............................................................................................................................................. 71 
15.7. 
Publications ................................................................................................................................................. 71 
16. 
REFERENCES ............................................................................................................................................. 72 
 
LIST OF APPENDICES 
17. 
APPENDICES .............................................................................................................................................. 78 
17.1. 
Schedule of Assessments ............................................................................................................................. 78 
17.2. 
ECOG Performance Status Scale................................................................................................................. 83 
17.3. 
Calculation of BMI, BSA and Practical Weight .......................................................................................... 83 
17.4. 
Common Terminology Criteria for Adverse Events .................................................................................... 84 
17.5. 
Expected Aldesleukin Toxicities and Their Suggested Management .......................................................... 84 
17.6. 
Summary of Changes (Major/Minor) In Protocol C-145-03 Version 2.0 (Dated 30 August 2017) ............ 85 
 
LIST OF TABLES 
Table 1. 
Response at each Assessment Time Point for Patients ........................................................................... 52 
Table 2. 
Examples of Best Overall Response for each Patient Across All Assessments ..................................... 52 
LIST OF FIGURES 
Figure 1. 
Study Flow Chart ................................................................................................................................... 21 
Figure 2. 
LN-145 Manufacturing Process ............................................................................................................. 22 
 

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LIST OF ABBREVIATIONS 
Term 
Definition 
ACT 
adoptive cell therapy 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BSA 
body surface area 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMO 
contract manufacturing organization 
CMV 
cytomegalovirus 
CR 
complete response 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DOR 
duration of response 
DS 
double strength 
DMSO 
dimethyl sulfoxide 
DSMB 
data safety monitoring board 
EBNA 
Epstein Barr nuclear antigen 
EBV 
Epstein Barr virus 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCrCl 
Estimated creatinine clearance 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EKG 
Electrocardiogram 
ETV 
Early Termination visit 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 

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Term 
Definition 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HLA 
human leukocyte antigen 
HPV 
human papillomavirus 
HNSCC 
head and neck squamous cell cancer 
HRQoL 
health-related quality of life 
HSV 
herpes simplex virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ICOS 
inducible T-cell costimulator or CD278 
IFN-γ 
interferon-gamma 
IL-2 
interleukin-2 (aldesleukin) 
IEC 
independent ethics committee 
IRB 
institutional review board 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous 
LFT 
liver-function test 
LVEF 
left ventricular ejection fraction 
MRI 
magnetic resonance imaging 
MUGA 
multiple gated acquisition scan 
NCI 
National Cancer Institute 
NMA-LD 
nonmyeloablative lymphodepletion  
NE 
not evaluable  
OPC 
oropharyngeal Cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PIK3CA 
phosphatidylinositol 3-kinase, catalytic subunit alpha 
PR 
partial response 
pre-REP 
expansion of TIL from tumor fragments prior to REP 
PTT 
partial thromboplastin time 
Q-TWiST 
quality-adjusted time without symptoms of disease or toxicity of treatment 

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Term 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REP 
rapid expansion protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Stable Disease 
SLD 
sum of longest diameters 
SMX 
sulfamethoxazole 
SUSAR 
suspected unexpected serious adverse reaction 
TH 
tumor harvested 
TIL 
tumor infiltrating lymphocytes 
TEAE 
Treatment-emergent adverse event 
TMP 
trimethoprim 
Treg 
regulatory T cell 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
 
 

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1. 
INTRODUCTION 
1.1. 
Head and Neck Cancer 
Squamous cell cancers of the head and neck (HNSCCs) comprise malignancies of the nasal 
cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, salivary 
glands, and head and neck paraganglial tissues (1). Most of these tumors occur in older 
individuals who have a history of smoking or high alcohol use (more than 4 drinks per day) and 
are more frequent in men than in women (2, 3). The oropharyngeal cancer (OPC) subset of 
HNSCC appears to be a distinct disease with different risk associations (such as human 
papillomavirus [HPV] infection) than other HNSCC (4). OPC prevalence among HNSCC has 
increased worldwide over the last 2 decades; in the United States (US), the rate increased from 
18% of all HNSCC in 1973 to 31% in 2004 (5). Human papillomavirus-positivity also has 
increased over the same period, reaching an estimated 72% prevalence in OPC between 2005 
and 2009 (6-8). By contrast, fewer than 20% of other HNSCC are positive for HPV (8, 9). The 
increase in incidence of OPC is 4-fold greater in males than females, and among men, is 
associated with age less than 60 years and white race (3, 10). Of the many strains of HPV, 
type 16 (HPV16) has been found in more than 90% of HPV-positive OPC (10). Notably, genetic 
mutations in HPV-negative HNSCC appear to be more frequent and distinct from those in 
HPV-positive tumors (2). For example, mutations of p53, a key tumor suppressor gene, were 
almost always associated with an HPV-negative tumor (11, 12), consistent with the known 
association between smoking and p53 mutations in subjects with HNSCC (13). By contrast, 
activating mutations and amplifications of phosphatidylinositol 3-kinase, catalytic subunit alpha 
(PIK3CA) were more common in HPV-positive tumors (14). As most HPV oral infections are 
sexually acquired, the increase in HPV-positive OPC is thought to be associated with changes in 
sexual behavior over time (3). The current standard treatment for HNSCC typically involves 
combinations of surgery, radiation, and chemotherapy, typically with cisplatin (15). Surgery can 
be minimally invasive to preserve organ function. Radiation with hyperfractionation and 
accelerated fractionation has been found to improve survival (16) but has been associated with 
swallowing dysfunction (17). Five-year survival has significantly increased for all HNSCC sites 
over the past 20 years from 54.7% in 1992-1996 to 65.9% in 2002-2006 (18). By tumor site, 
estimated 5-year survival rates remain ≤ 63% for all sites other than the tongue or lip (19). 
Notably, outcome for subjects with HPV-positive tumors is better than outcome for HPV-
negative HNSCC (6, 20, 21), with reported 2- and 3-year survival rates of approximately 95% 
and 80%, respectively (6, 20). The improved outcome of subjects harboring HPV-positive 
tumors may be a result of enhanced activity of TIL at the tumor site (16).  
The rates of occurrence of a second primary tumor or recurrence of tumors is high in HNSCC, 
particularly among smokers, likely due to the “field cancerization” effect of tobacco-induced 
malignancy, whereby genetic alterations may be induced throughout the upper aerodigestive 
mucosa (3). Argiris et al. (22) estimated a recurrence rate of 50% for subjects in remission 
following treatment of a locally advanced HNSCC, and Chuang et al. estimated that 36% of 
subjects would develop a second primary tumor within 20 years (23). Recurrence is higher in 
HPV-negative than in HPV-positive OPC (3-year recurrence rates of 65.1% versus 13.6%; 

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p < 0.001). Additionally, the 3-year rates of second primary malignancy were 14.6% versus 5.9% 
(p = 0.02) in these groups (6).   
Outcome for recurrent HNSCC is poor across a variety of therapeutic modalities (24-26), 
although Strnad et al. (27) reported long-term high rates of local control of recurrent disease 
using interstitial pulsed-dose-rate brachytherapy combined with chemotherapy in a selected 
subject population. HPV-positive recurrent OPC disease has a higher overall survival (OS) rate 
than HPV-negative recurrent OPC: 2-year OS rates were 54.6% for subjects with HPV-positive 
tumors and 27.6% for those with HPV-negative tumors (p < 0.001) (28). 
The findings of survival rates of 63% or less among most subjects with HPV-negative HNSCC 
or recurrent HPV-positive HNSCC, and even lower survival rates among subjects with recurrent 
HPV-negative tumors, indicates a need for improved therapeutic options.  
1.2. 
Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes as Cancer 
Immunotherapy  
Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) represents an effective 
treatment and potentially durable complete response (CR) for patients with a variety of solid 
tumors. The treatment involves the isolation and ex vivo expansion of autologous antitumor 
lymphocytes that have infiltrated a patient’s tumor. The basic concept of using lymphoid cells 
for the immunotherapy of cancer arose from animal experiments that demonstrated, by histologic 
analysis, the presence of T-lymphocytes within the microenvironment of most solid tumors and 
their metastases (12-14). Recent findings have clearly shown a predictive relationship between 
the frequency and phenotype of TIL in solid tumors (especially CD8+ T cells) and an increased 
OS and progression-free survival (PFS) in patients with melanoma (15-17, 29), lung cancer 
(18-21), ovarian cancer (22-24), squamous cell carcinomas (25, 26), triple-negative breast 
cancer, HER2-positive breast cancer (30), basal-like breast cancer (27, 28, 31-36), and colorectal 
cancer (37-40). Notably, one study found that an increased Foxp3+ Treg/CD8+ ratio and the 
presence of intra-tumoral high Foxp3+ Treg each predicted worse OS (41). In addition, gene 
expression studies using DNA microarrays have indirectly correlated so-called “immune 
signature” genes and T-cell associated gene expression (eg, CD3, CD8, CD4, inducible 
costimulator [ICOS], granzyme B, DC-LAMP and chemokine and chemokine receptors) with 
improved OS and PFS in both primary and metastatic tumor settings (17, 37, 38, 42-44). 
These findings support the development of therapies based on the isolation and expansion of 
autologous TIL cells as a therapeutic agent against solid tumors. 
ACT has several theoretical and practical advantages over active immunization and nonspecific 
immune stimulation. First, the ex vivo environment allows expansion of CD8+ cytotoxic T cells 
to proceed to very high cell numbers in the absence of suppressive factors, such as CD4+ Treg 
(CD4+ Foxp3+) that inhibit antitumor immune responses in the tumor microenvironment (45-47); 
allowing infusion of much higher numbers of tumor-reactive TIL than is possible with other 
approaches. Second, the TIL product potentially recognizes a wider array of tumor antigens, such 
as mutated tumor neoantigens, rather than a single target (48-50) (51). Preparation of the host 

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patient with nonmyeloablative lymphodepletion (NMA-LD) immediately prior to the transfer of 
the antitumor cells also temporarily eliminates potentially suppressive influences (such as 
regulatory T cells and cytokine sinks) to provide an optimal milieu for the transferred TIL to 
proliferate and become activated in vivo.  
The feasibility of TIL preparation was demonstrated by early studies showing that metastatic 
melanoma tumors can be excised and placed in tissue culture under conditions in which tumor 
cells do not survive, but any TIL contained within the excised tumor tissue can survive and 
proliferate. TIL can be cultured in the presence of interleukin-2 (IL-2) and can be grown to very 
large numbers using standardized protocols (≥ 1 × 108 cells) (12, 14, 52, 53). These TIL were 
then shown to have the capacity to kill tumor cells in vitro and promote durable antitumor effects 
in vivo when infused back into the original tumor donor (12, 14, 52, 53). Further studies 
established that the efficacy of infusions of large numbers of TIL were enhanced by pretreatment 
of the tumor-bearing animals with cyclophosphamide to induce a transient drop in endogenous 
lymphocytes in the host and followed by IL-2 administration. With this combination, mice could 
be cured of advanced hepatic metastases (12). These findings set the stage for National Cancer 
Institute (NCI) clinical trials using TIL therapy for patients with metastatic melanoma that 
includes a NMA-LD preconditioning regimen consisting of fludarabine and cyclophosphamide 
combined with IL-2 following TIL Infusion. Across clinical studies conducted by the NCI, 
immunotherapy of patients with advanced melanoma with autologous TIL therapy has induced 
durable objective response rates (ORRs) by Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.0 criteria in 56% (52/93) of patients, including heavily pretreated patients, 
with 24 of the 101 patients (24%) achieving a CR. Nineteen of the 24 CRs were ongoing beyond 
3 years of follow-up (54, 55).  
1.3. 
TIL for Head and Neck Cancer 
The rationale for investigating the use of TIL for treatment of HNSCC is based on the high rate 
of recurrence and overall low survival rates for patients with recurrent disease following standard 
combinations of surgery, adjuvant chemotherapy, and radiation therapy. Furthermore, as 
described above for other solid tumors, a positive correlation between the presence of TIL in 
HNSCC tumor specimens and patient outcome has been reported by several investigators. For 
example, Balermpas et al. reported that among patients with HNSCC, those with high 
immunohistochemical CD3 and CD8 expression had significantly increased OS, PFS, and distant 
metastasis-free survival, but not local failure-free survival in multivariate analysis (46). 
Similarly, low CD8+ T-cell infiltration in the tumors of patients with laryngeal squamous cell 
cancer was correlated with decreased survival (56). TIL has shown prognostic value in both 
HPV-positive and HPV-negative HNSCC tumor specimens. For example, Kong et al. reported a 
survival benefit for higher CD3+ TIL in tumor specimens only for HNSCC with weak or no 
expression of HPV (57); whereas, Wansom et al. (58) and Ward et al. (59) found that higher 
numbers of CD8+ cells in tumors were positively correlated with improved survival in patients 
with HPV-positive HNSCC or HPV-positive OPC. An additional report by Wansom et al. found 
that among patients with advanced OPC, CD8+ cells, as well as Treg cells (CD8+ FOXP3) and 
total T-cell number all were positively correlated with improved OS and disease-free survival, 

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independently of the tumor’s HPV status (60). These data strongly suggest a beneficial role for 
TIL in the body’s response to HNSCC.  
The feasibility of generating TIL from HNSCC has been demonstrated by several investigators. 
Junker et al. (61) demonstrated the successful expansion of TIL bulk cultures were expanded in 
12 of 15 (80%) evaluable subjects; tumor specificity of the TIL were shown in 60%. Up to 
3500-fold expansion was achieved within 17 days. TIL from 60% of the subjects could kill 
human leukocyte antigen (HLA)-A-matched tumor cell lines. Additional characterization showed 
that the TIL expanded from an HNSCC were phenotypically like those from melanomas, ie, 
CD3+/CD8+ and were similar before and after rapid expansion (62). Moudgil et al. (63) reported 
a success rate of 50% for generation of TIL (33 of 63 cultures initiated). Of 22 tested TIL, 
20 secreted interferon-gamma (IFN-γ) in response to coculture with the autologous tumor cell 
target. These findings are consistent with those of a retrospective study that showed that that TIL 
were successfully generated in 677 (86%) of the 787 specimens from 402 subjects with 
melanoma (64). 
In summary, current methods for the expansion of autologous TIL from excised tumors are 
well established and are robust enough to ensure a high degree of success in consistently 
generating sufficient numbers of high-quality therapeutic cells, as described above. Further, 
clinical studies in melanoma and cervical cancer have demonstrated that the effects of the TIL 
persist in patients for weeks to months and even years after infusion, thereby potentially 
mediating highly durable complete remissions more than other current immunotherapies or 
standard therapies, as noted above. The large body of data from these studies justifies the 
development of adoptive TIL therapy as an approved therapeutic in other solid tumors, such as 
HNSCC. 

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2. 
STUDY DESIGN 
2.1. 
Overview 
This is a prospective single-arm interventional study evaluating patients with HNSCC who 
receive ACT with LN-145 (autologous TIL). The TIL therapy to be used in this study is similar 
to that developed for melanoma-derived and cervical cancer-derived TIL by Dr. Steven 
Rosenberg and colleagues at the NCI. Melanoma-derived TIL have demonstrated efficacy in the 
treatment of Stage IV melanoma, and Phase 2 clinical studies evaluating this product have shown 
an ORR of 56% or more (54, 55), exceeding rates reported by other immunotherapies in 
metastatic melanoma. In addition, long-term durable CRs of 24% in melanoma and 22% in 
cervical cancer patients were observed (54, 55, 65, 66). 
Protocols for the tumor resection/harvest and LN-145 administration for the current study are 
provided in separate operating manuals. TIL therapy comprises multiple interdependent phases:  
tumor resection for production of TIL; ex vivo expansion of TIL; NMA-LD; infusion of TIL; 
and administration of IL-2. A study flow chart is shown in Figure 1. 
The study will assess efficacy and safety for 47 patients who receive LN-145 treatment followed 
by at least 1 dose of IL-2. 
The study consists of 3 phases: 
• Pretreatment Phase (approximately 8 weeks) 
o 
Screening visit (up to 28 days) 
o 
Tumor resection visit (1 day) 
o 
LN-145 manufacturing period (approximately 3 to 7 weeks) 
 
• Treatment Phase (approximately 2 weeks) 
o 
NMA-LD regimen (7 days) 
o 
LN-145 Infusion (1 day) 
o 
IL-2 Infusion (1 to 4 days) 
 
• Follow-Up Phase (3 years) 
o 
Efficacy follow-up for safety and efficacy evaluations (24 months) 
o 
Overall survival follow-up to assess disease status and survival (12 months) 
 

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Figure 1. 
Study Flow Chart 
 

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2.2. 
Production and Expansion of Tumor Infiltrating Lymphocytes  
LN-145 is an autologous cellular investigational product composed of viable TIL derived from 
an individual patient’s own tumor (autologous cell product). The process for manufacturing 
LN-145 begins at the clinical site with the surgical resection of primary or secondary metastatic 
tumor material of 
 from the patient. The tumor specimen(s) is placed in biopreservation 
transport media and shipped (at 
 overnight to a Good Manufacturing Practice (GMP) 
manufacturing facility. Upon arrival at the GMP manufacturing facility, the tumor specimen is 
dissected into fragments of 
 
 from which TIL are expanded with
 
  
The expanded cells (TIL) are then harvested, washed, and formulated in blood transport and 
infusion bags for shipment by courier to the clinical site as either a fresh, chilled 
 
non-cryopreserved product or a cryopreserved 
 product. The dosage 
form of the investigational product is a live cell suspension of TIL for intravenous (IV) infusion 
into the patient from which they were derived (Figure 2). 
Figure 2. 
LN-145 Manufacturing Process 
TIL production requires approximately 3 to 6 weeks following excision of tumor specimens. 
The TIL product is manufactured ex vivo using autologous tumor as starting material. The key 
manufacturing steps include the following: 
• Surgical removal of autologous metastatic tumor and shipment to the sponsor-designated 
manufacturing facility 
• Fresh product 
o Initial TIL culture (pre-Rapid Expansion Protocol [pre-REP]) of up to 3 weeks) 
o Rapid Expansion Protocol (REP) of approximately 2 weeks 

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• Cryopreserved product 
o Single expansion process of approximately 3 weeks 
On protocol Day -8, the number of TIL successfully expanded will be determined. If the number 
of TIL is sufficient for administration, approval by the sponsor will be granted to begin the 
NMA-LD regimen. 
The lymphodepletion protocol is based on the method developed and tested by the NCI (67-72). 
Following lymphodepletion, patients will receive up to 
 cells of LN-145. The upper 
limit of the range for infusion (approximately
 viable cells) is based on the known 
published upper limit safely infused where a clinical response has been attained (73, 74).  
The LN-145 infusion will be followed by the administration of IL-2 (600,000 IU/kg) every 8 to 
12 hours starting between 3 and 24 hours after the completion of the LN-145 infusion and 
continuing for up to 6 doses as tolerated. Patients will be evaluated for response using RECIST 
v1.1. All responses are required to be confirmed with a follow-up assessment. See Section 5.24 
and Appendix 17.1 for specific time points.  
Patients who complete the Treatment Phase will continue to be evaluated for safety and efficacy 
during Efficacy Follow-Up visits (24 months following treatment). Once the patients complete 
the Efficacy Follow-Up or discontinue for any reasons indicated under Section 9.4.1, they will be 
followed in Overall Survival Follow-Up with quarterly telephone contact for 12 months to assess 
disease status and subsequent anticancer therapy as described in Section 9.4.2. Radiologic 
assessment of disease may also be performed at additional time points at the discretion of the 
investigator. 

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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
• To evaluate the efficacy of LN-145 in patients with recurrent and/or metastatic HNSCC 
using the ORR as assessed by investigators per RECIST v1.1 
3.1.2. 
Secondary Objectives 
• To characterize the safety profile of LN-145 in patients with recurrent and/or metastatic 
HNSCC 
• To evaluate efficacy parameters of LN-145 in patients with recurrent and/or metastatic 
HNSCC such as CR rate, duration of response (DOR), disease control rate (DCR), and 
PFS by investigator evaluation per RECIST v1.1, and OS 
3.1.3. 
Exploratory Objectives 
• To explore the persistence of LN-145 and immune correlations of response, survival, 
toxicity of the treatment 
• To explore efficacy based on immune-related RECIST (irRECIST) (75) as assessed by 
independent review 
• To assess Health-Related Quality of Life (HRQoL) 
• To assess the quality-adjusted time without symptoms of disease or toxicity of treatment 
(Q-TWiST) 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
• ORR as assessed by investigator per RECIST v1.1 
3.2.2. 
Secondary Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs), including serious adverse 
events (SAEs), therapy-related adverse events (AEs), AEs leading to early 
discontinuation of treatment or withdrawal from efficacy follow-up or death 
• CR rate 
• DOR 
• DCR 
• PFS 
• OS 

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3.2.3. 
Exploratory Endpoints 
• Immune correlations with respect to response, survival, toxicity of the treatment, and 
HPV status of the tumor 
• ORR, DOR, DCR, and PFS as assessed per irRECIST by independent review 
• HRQoL as assessed per EORTC QLQ-C30 questionnaire 
• Q-TWiST (76) using investigators’ assessments for PFS 

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4. 
SELECTION OF PATIENT POPULATION 
Patients with a diagnosis of recurrent and/or metastatic HNSCC who have undergone at least 
1 prior systemic immunotherapy or chemotherapy regimen will be selected for this study. 
Details concerning specific benefits and risks for patients participating in this clinical study may 
be found in the accompanying Investigator’s Brochure and informed consent documents. 
Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be 
eligible for enrollment into the study. 
Patients may be eligible for retreatment if they have progressed or have incomplete response to a 
prior treatment on this protocol with LN-145. A minimum of 3 months must have elapsed from 
the last infusion to be eligible. 
4.1. 
Inclusion Criteria 
1. 
Must be ≥18 years of age at the time of consent 
2. 
Must understand and voluntarily sign informed consent prior to any study related 
assessments/procedures being conducted 
3. 
Must be able and willing to comply to the study visit schedule and protocol requirements 
4. 
Must have recurrent and/or metastatic HNSCC; histologic diagnosis of the primary tumor 
is required via the pathology report  
5. 
Must have at least 1 lesion that is resectable for TIL generation. The resected TIL 
generating lesion (or aggregate of lesions resected) should be least 1.5 cm3 in diameter 
after resection, and can be surgically removed with minimal morbidity (defined as any 
operation for which expected hospitalization is ≤ 3 days). If the lesion is within a 
previously irradiated field, the irradiation must have occurred at least 3 months prior to 
resection. 
6. 
Must have measurable disease as defined by RECIST v1.1 following the surgical 
resection. If measurable target lesion(s) are in previously irradiated areas, irradiation 
must have occurred at least 3 months prior to enrollment (tumor resection) and the lesions 
must have demonstrated evidence of progression since irradiation 
7. 
Patients must have relapsed or refractory (no response) recurrent and/or metastatic 
carcinoma of the head or neck and have received at least 1 line of prior systemic 
immunotherapy and/or chemotherapeutic treatment 
8. 
Any prior therapy directed at the malignant tumor, including radiation therapy, 
chemotherapy, biologic/targeted agents, and immunologic agents must be discontinued at 
least 28 days prior to lymphodepletion.   
9. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 
an estimated life expectancy of ≥ 3 months 
10. Must meet the following laboratory criteria:  
• Absolute neutrophil count (ANC) > 1000/mm3 

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• Hemoglobin > 9.0 g/dL 
• Platelet count > 100,000/mm3 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper 
limit of normal (ULN) 
o Patients with liver metastases must have liver function tests (LFTs) < 5.0 × ULN 
• Total bilirubin ≤ 2.0 mg/dL 
o Patients with Gilbert’s Syndrome must have a total bilirubin ≤ 3.0 mg/dL 
• Serum creatinine ≤ 1.5 mg/dL 
• An estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the Cockcroft-Gault 
formula at screening 
11. Patients must be seronegative for the HIV antibody 
12. Patients seropositive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) 
indicating acute or chronic infection must have a negative (undetectable) viral load by 
polymerase chain reaction (PCR) with/without active treatment 
13. Patients of childbearing potential must be willing to practice an approved method of birth 
control starting at the time of informed consent and for 1 year after the completion of the 
study treatment regimen 
Approved methods of birth control are as follows: 
• Total abstinence  
• Hormonal contraception (ie, birth control pills, injection, implant, transdermal patch, 
vaginal ring)  
• Intrauterine device (IUD)  
• Tubal ligation 
• Vasectomy  
• Implantable or injectable contraceptives  
• Use of a male or female condom with spermicide 
• Cervical cap or contraceptive sponge with spermicide 
4.2. 
Exclusion Criteria 
1. Patients who have received prior cell transfer therapy, except for prior LN-145. Prior 
LN-145 therapy must have occurred at least 3 months prior to retreatment tumor 
resection. 
2. Patients who are on a systemic steroid therapy (> 10 mg of prednisone or equivalent 
daily). 
• Note: A short course of higher dose steroid therapy is allowed in cases of 
exacerbation of known disease or for treatments of new acute symptoms.   

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3. Patients who currently have prior therapy-related toxicities greater than Grade 1 per 
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03; (see 
Appendix 17.4), except for alopecia or vitiligo prior to enrollment/tumor resection. 
• If toxicities have resolved to Grade 1 or less, a minimum of 4 weeks must elapse prior 
to enrollment (tumor resection). 
• Patients may undergo preplanned procedures if not within 2 to 3 weeks prior to the 
start of NMA-LD.  
4. 
Patients with documented Grade 2 or greater diarrhea or colitis due to previous 
immunotherapy (eg, ipilimumab, tremelimumab, anti-PD-1 or anti-PD-L1) within 
6 months from screening. 
• Patients who have been asymptomatic for at least 6 months or had a normal 
colonoscopy post anti-PD-1/anti-PD-L1 treatment, with uninflamed mucosa by visual 
assessment are not excluded. 
5. 
Patients with history of severe immediate hypersensitivity reaction to cyclophosphamide, 
fludarabine, IL-2, or aminoglycosides (eg, gentamicin or streptomycin).  
6. 
Patients with active systemic infections (eg, syphilis), coagulation disorders or other 
active major medical illnesses of the cardiovascular, respiratory or immune system that, 
in the opinion of the investigator, would significantly increase the risk of participation. 
Examples of concerning conditions include, but are not limited to, history of a positive 
thallium stress test, myocardial infarction, cardiac arrhythmia, obstructive or restrictive 
pulmonary disease, or uveitis. 
7. 
Patients with symptomatic and/or untreated brain metastases (of any size and any 
number).  
• Patients with definitive treated brain metastases may be considered for enrollment 
after discussion with the sponsor’s medical monitor/designee, and must be stable for 
2 to 4 weeks and asymptomatic prior to the start of treatment (NMA-LD). 
8. 
Patients who have any form of primary immunodeficiency, such as severe combined 
immunodeficiency disease or acquired immune deficiency syndrome (AIDS).  
9. 
Patients who have a diagnosis of end-stage renal disease requiring hemodialysis.  
10. Patients who have a left ventricular ejection fraction (LVEF) < 45% as determined by an 
echocardiogram (ECHO) or multiple gated acquisition scan (MUGA); and patients 
> 60 years of age or those with a history of ischemic heart disease, chest pain, or 
clinically significant atrial and/or ventricular arrhythmias who have a positive stress 
thallium test are excluded. Patients with an abnormal stress test may be enrolled 
following cardiology clearance and approval of the medical monitor. 
11. Patients who have a forced expiratory volume in 1 second (FEV1) of less than or equal to 
60% of predicted normal 
• If a patient is not able to perform reliable spirometry due to abnormal upper airway 
anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary 
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and sex or demonstrates evidence of hypoxia at any point during the test 
(SpO2 < 90%) are excluded. 
12. Patients who have had another primary malignancy within the previous 3 years (except 
for curatively treated localized malignancy that has not required treatment for greater 
than 1 year, and in the judgment of the investigator, does not pose a significant risk of 
recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer).  
13. Patients who are pregnant or breastfeeding. 
4.3. 
Patient Enrollment and Re-Screening 
Patients who meet all inclusion criteria and do not meet any of the exclusion criteria will be 
enrolled in the study. Enrollment is defined as patients who began or completed tumor 
resection/tumor harvest procedure. Patients cannot enroll in the study without documented 
approval from the sponsor’s medical monitor or designee on the Patient Eligibility Form. 
Patients who sign an informed consent form (ICF) and fail to meet the inclusion and/or exclusion 
criteria or do not have a tumor resection/harvest within 28 days of signing the informed consent 
are defined as screen failures.  
Patients who failed the initial screening process may be re-screened for enrollment and will be 
registered as a new patient. The investigator and medical monitor will discuss the patient’s status 
prior to any re-screening procedures.  
Once the patient is approved to enroll in the study, the patient must continue to meet eligibility 
criteria until the NMA-LD visit (Day -7/Visit 4). The investigator must confirm the patient’s 
health status based at baseline (Day -21/Visit 3) laboratory values and computed tomography 
(CT) scans to ensure the patient is stable to proceed with NMA-LD.   
Patients may rescreen for a second tumor resection and LN-145 treatment if they meet all 
inclusion and exclusion Criteria. These patients will have a second tumor harvest and TIL 
(LN-145) therapy. Examples of patients who may be eligible for retreatment are prior responders 
to LN-145 who relapse, nonresponders, and patients with manufacturing failures. The medical 
monitor will have authority to adjudicate enrollment for retreatment (second TIL therapy).  
 

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5. 
STUDY ASSESMENTS/PROCEDURES 
5.1. 
Informed Consent  
The applicable and approved ICF(s) must be signed before any study related assessments are 
performed. 
5.2. 
Inclusion/Exclusion Criteria 
Patients must meet all inclusion criteria (Section 4.1) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.2). Patients must continue to meet eligibility criteria 
until start of NMA-LD pretreatment regimen Day -7 (Visit 4).   
5.3. 
Demographic Data 
The demographic data will include date of birth (as allowed per local regulations), age, gender, 
and race/ethnic origin. 
5.4. 
Medical History 
Relevant and significant medical/surgical history and concurrent illnesses will be collected for all 
patients at screening (Visit 1) and updated as applicable. Any worsening from pre-existing 
conditions should be reported as AEs. 
5.5. 
Documentation of Confirmation of Diagnosis 
Patients must have a documented diagnosis of primary HNSCC via pathology report. 
5.6. 
Documentation of HPV Tumor Status 
Patients must have documented HPV tumor status prior to tumor resection (Visit 2). 
If documentation is not available, testing for HPV status of the tumor may be determined 
locally or at Iovance at the time of tumor resection (Visit 2). 
5.7. 
Concomitant Medications 
All medications and therapies (prescription and nonprescription, including herbal supplements) 
taken by the patient up to 28 days prior to screening (Visit 1) will be collected in the electronic 
case report form (eCRF), including the stop dates for medications prohibited in the study, at the 
time of consent. All medications and therapies being taken by the patients, or changes thereof, 
at any time during the study, must also be recorded. 
5.8. 
Adverse Events 
All AEs for all patients will be assessed as per NCI CTCAE Version 4.03 during all visits once 
the ICF is signed. Any events occurring after screening, but prior to enrollment/tumor resection, 
will be recorded as medical history in the eCRF, unless the events are related to protocol- 
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AEs in the eCRF until Day 168 (Visit 21/Month 6) and as clinically indicated. Additional safety 
reporting requirements are described under Section 11.  
5.9. 
HRQoL Questionnaire – EORTC QLQ-30 Version 3.0  
The HRQoL Questionnaire will be conducted at baseline (Day -21/Visit 3) and be performed as 
the first procedure on the subsequent visits. See Appendix 17.1 for specific time points. 
5.10. Physical Examination 
Physical examination will be conducted for all visits except for the tumor resection visit (Visit 2) 
and shall include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, 
nose, and throat, respiratory system, skin, psychiatric (mental status), and general nutritional 
status. Physical examination conducted during follow-up will be symptom-directed. Clinically 
significant changes in the physical examination findings will be recorded as AEs. 
5.11. Vital Signs 
Vital signs shall include height, weight, pulse, respirations, blood pressure and temperature. 
Height will be measured at screening (Visit 1) only. All other vital signs will be measured at 
applicable time points. See Appendix 17.1.  
Body surface area (BSA) and body mass index (BMI) will be calculated at Day -7 (Visit 4) only. 
On Day 0 (Visit 11/LN-145 infusion), vital signs will be monitored every 30 minutes during 
infusion, then hourly (+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless 
otherwise clinically indicated, for up to approximately 24 hours post LN-145 infusion. 
5.12. Eastern Cooperative Oncology Group Performance Status 
An ECOG performance status will be assessed at screening (Visit 1) through Visits 4, 11, and 
17 through 25 (see Appendix 17.1). 
5.13. Safety Blood and Urine Tests 
The following safety blood and urine tests will be collected and analyzed locally at every visit: 
• Chemistry - sodium, potassium, chloride, total CO2 or bicarbonate, serum creatinine, 
glucose, blood urea nitrogen, albumin, calcium, magnesium, phosphorus, alkaline 
phosphatase, ALT, AST, total bilirubin, direct bilirubin, lactate dehydrogenase, total 
protein, total creatine kinase, uric acid 
• Hematology – complete blood count (CBC) with differential 
• Coagulation - Measurement of prothrombin time (PT)/international normalized ratio 
(INR), and partial thromboplastin time (PTT)/activated PTT will be performed at 
screening only and analyzed locally. 

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• Thyroid panel inclusive of thyroid stimulating hormone (TSH) and free T4 shall be done 
only at screening (Visit 1) and Day 84 (Visit 19/Week 12) or as clinically indicated. 
• Urinalysis dipstick will be completed at every visit. Abnormal, clinically significant 
findings shall be recorded as AEs. A complete urine culture shall be performed if 
clinically indicated. 
5.14. ß-HCG Serum Pregnancy Test 
All women of childbearing potential will have serum pregnancy tests at screening (Visit 1) and 
baseline (Day -21/Visit 3). 
5.15. Infection Testing 
Blood samples will be collected for the following virus testing at screening (Visit 1) only:  
• HIV antibody titer; 
• Hepatitis - HBsAg IgG and anti-HCV IgG 
• Syphilis assay (as per local standard; eg, rapid plasma reagent, venereal disease research 
laboratory, or other) at screening, and thereafter as clinically indicated; 
• Herpes simplex virus (HSV) serology determination (HSV-1 IgG and HSV-2 IgG) 
• Cytomegalovirus (CMV) serology (IgG and IgM) 
• Epstein Barr virus (EBV) panel (VCA-IgG, and/or EBNA IgG [tests conducted to 
confirm absence of acute or active EBV infection] may have been done within 3 months 
prior to tumor resection [Visit 2]). 
5.16. Human Leukocyte Antigen Typing 
Sample collection for HLA typing will be conducted at screening (Visit 1) and analyzed by the 
central laboratory. Refer to the Laboratory Manual for details. 
5.17. HPV Subtype Serotype 
Tumor sample (obtained at Visit 2) collection for HPV subtype serotyping will be managed by 
the central laboratory if not done locally. Refer to the Laboratory Manual for details. 

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5.18. Estimated Creatinine Clearance 
The creatinine clearance will be calculated by the site using the Cockcroft-Gault formula at 
screening only. 
5.19. Eye Examination 
For patients with a history of uveitis, a slit-lamp eye examination is required within 28 days of 
screening (Visit 1) or up to 30 days prior to consent signing to rule out active uveitis.  
5.20. Cardiac Evaluations 
All cardiac evaluations (Echo/MUGA and electrocardiogram) will be performed during 
screening (Visit 1). Evaluations completed within 6 months prior to screening (Visit 1) will be 
accepted. 
5.20.1. Stress Thallium 
A stress thallium test will be done for all patients ≥ 60 years of age or any patient with a history 
of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias. 
5.20.2. Echocardiogram or Multigated Acquisition Scan 
An ECHO or MUGA will be done for all patients within screening. These may have been 
performed up to 60 days prior to signing of ICF. 
5.20.3. Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed locally. Patients must be supine for the 
examination. 
5.21. Pulmonary Function Tests 
Pulmonary evaluation will be completed within 28 days from screening (Visit 1). Evaluations 
completed within 6 months prior to screening (Visit 1) will be accepted.  
Patients who are unable to conduct reliable pulmonary function test measurements due to 
abnormal upper airway anatomy may undergo a 6-minute walk test to assess pulmonary function.   

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5.22. Colonoscopy 
Colonoscopy is only required for patients who have had a documented Grade 2 or greater 
diarrhea or colitis due to previous immunotherapy within 6 months of screening.  
5.23. Immune Monitoring and Peripheral Blood Mononuclear Cells  
Peripheral blood mononuclear cells (PBMC), serum, and plasma will be collected to test for 
cellular and soluble factors. 
Blood for immune monitoring will be drawn at tumor resection (Visit 2) and subsequent 
collections will be drawn at applicable time points (see Appendix 17.1). 
Blood draw for PBMC biomarker analysis is only to be collected at tumor resection (Visit 2). 
Refer to the study Laboratory Manual for details. 
5.24. Radiographic Assessments 
Radiographic assessments by CT scans with contrast of the chest, abdomen, and pelvis are 
required for all patients for tumor assessments. CT scans are performed throughout the study 
until progressive disease by investigator assessment per RECIST v1.1 is noted (or if the patient 
withdraws full consent).  
Radiographic assessments of additional anatomical locations will be conducted at the 
protocol-specified or unscheduled visits (see Appendix 17.1 for specific time points) if prior or 
suspected disease is clinically indicated (eg, brain). Response assessments should be evaluated 
and documented by a qualified investigator participating in the study. 
Magnetic resonance imaging (MRI) or positron emission tomography (PET) scans of the chest, 
abdomen, and pelvis in lieu of CT scans may be allowed for patients who have an intolerability 
to contrast media.  
The same method of assessment (CT or MRI) and the same technique for acquisition of 
radiographic images should be used to characterize each identified and reported lesion at Day -21 
to Day -14 (Visit 3/baseline) and then each subsequent assessment throughout the course of the 
study. Patients will be evaluated for response at approximately every 4 weeks from LN-145 
administration for the first 3 months, and at 4.5 months, 6 months, 9 months, 12 months, 
18 months, and 24 months. Additional radiological assessments may be performed per the 
investigator’s discretion. 
Although response for primary analysis will be per the investigator’s assessment, imaging will be 
collected for evaluation by a central imaging service to provide independent review. 
All patients should have radiographic tumor measurements performed at the participating study 
center or an acceptable alternate imaging facility using an identical imaging protocol and similar 

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equipment that has been qualified by a central imaging vendor. The same imaging equipment 
and parameters should be utilized for all scans throughout the study. 
5.25. Tumor Resection / Harvest 
Prior to tumor resection (Visit 2), following confirmation of patient eligibility, the medical 
monitor or designee will provide approval for patient enrollment into the clinical study and 
subsequent tumor resection. Ideally, the targeted tumor should be in a visceral location (sterile 
site) and have not been previously irradiated. If it has been previously irradiated, then the tumor 
must have demonstrated growth over the last 3 months since the last dose of radiation. If 
enrolled, tumor resection is expected to occur approximately 3 to 6 weeks prior to the LN-145 
infusion at Day 0 (Visit 11) and is dependent on the rate of cell growth of TIL at the 
sponsor-designated contracted manufacturing organization (CMO) facility. 
LN-145 is an autologous investigational product which is procured and administered by means 
that have more in common with autologous blood product delivery than those of traditional drug 
production.  
It is imperative that only the patient’s own (autologous) study treatment (LN-145) be 
administered to the same individual patient. For these reasons, the patient specimen must be 
procured and handled per a strict protocol to ensure optimal quality of the specimen and 
minimum transport time to and from the processing CMO facility, as well as to ensure the 
appropriate identification of the study product at all times including infusion back into the 
patient.  
Refer to the Tumor Procurement & Shipping Manual for details. 
5.25.1. Additional Tumor Tissue from Resected Tumor 
If there is an excess of tumor tissue after resection for TIL manufacturing, then a portion of the 
remaining viable tumor tissue is to be sent to the central laboratory as outlined in the Tumor 
Procurement & Shipping Manual. 
The tumor tissue sent to the central laboratory will be analyzed for 1) immunohistochemistry to 
identify individual immune cell populations, 2) mRNA extraction for profiling of immune and 
tumor gene expression, 3) isolation of DNA which will be used for “exome” (not whole genome) 
sequencing for neoepitope interrogation, and 4) HPV typing as necessary. 
Provision of adequate amount of tumor tissue for TIL manufacturing sent to the CMO takes 
priority over the collection of additional tumor tissue that is sent to the central laboratory. 
However, every effort should be made to obtain adequate tumor tissue for both TIL 
manufacturing and additional analyses. The patient may be requested to sign the substudy 
consent (eg, Genetic Research Substudy ICF) for additional tumor tissue and specimen collected 
during the study. 
Refer to the Laboratory Manual for details. 

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6. 
STUDY TREATMENT 
6.1. 
Nonmyeloablative Lymphodepletion Regimen 
The NMA-LD regimen is scheduled to start on Day -7 (Visit 4). Approval from the sponsor is 
required to start the NMA-LD regimen. Patients are typically hospitalized for administration of 
the cyclophosphamide due to concomitant mesna administration. Hospitalization for the rest of 
NMA-LD is at the discretion of the investigator. Modification of the lymphodepletion regimen is 
allowed as clinically indicated and should be guided by daily hematological parameters as 
described below for fludarabine in patients with a history of irradiation or delayed hematologic 
recovery. 
The NMA-LD regimen comprises 2 daily doses of cyclophosphamide (with continuous mesna) 
followed by 5 daily doses of fludarabine and should be administered as per institutional 
protocol/standards for nonmyeloablative chemotherapy. Guidelines for preparation and 
administration are described below. For consistency in dosing, obese patients (defined as having 
a BMI > 35 kg/m2) should be dosed as recommended in this protocol (using Practical Weight, 
Appendix 17.3.3). 
6.1.1. 
Preparation of Cyclophosphamide 
The dose of cyclophosphamide is 60 mg/kg. Reconstitute cyclophosphamide per institutional 
standard to deliver calculated dose in a final concentration of 20 mg/mL. Add dextrose 5% water 
(D5W) to the required volume of cyclophosphamide to reach a total infusion volume of 250 mL. 
If the volume of reconstituted cyclophosphamide is > 250 mL, additional D5W is not necessary. 
If the patient is obese (BMI > 35.0 kg/m2), the dose of cyclophosphamide will be calculated 
using practical weight as described in Appendix 17.3.3. Infuse with mesna as described below. 
6.1.2. 
Preparation of Mesna 
Mesna is administered to prevent the occurrence of hemorrhagic cystitis related to 
cyclophosphamide. Mesna may be administered per local protocol or as per the following 
regimen (15 mg/kg). Actual weight should be used to calculate the mesna dose, even if the 
patient’s BMI > 35.0 kg/m2. Dilute the volume of mesna injection per institutional standard, or in 
any of the following fluids (per mesna current prescribing information) to obtain a final 
concentration of 20 mg/mL: 
• 5% Dextrose Injection, USP 
• 5% Dextrose and 0.2% Sodium Chloride Injection, USP 
• 5% Dextrose and 0.33% Sodium Chloride Injection, USP 
• 5% Dextrose and 0.45% Sodium Chloride Injection, US 
• 0.9% Sodium Chloride Injection, USP 
• Lactated Ringer’s Injection, USP 

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6.1.3. 
Infusion of Cyclophosphamide and Mesna 
Cyclophosphamide (60 mg/kg) in a total volume of 250 mL (or greater if required), plus mesna 
(15 mg/kg) are to be infused together over 2 hours on Day -7 and -6 (Visits 4 and 5). Mesna 
infusion will continue as per institutional standards or at a rate of 3 mg/kg/hour over 22 hours 
after each cyclophosphamide dose during Days -7 and -6 (Visits 4 and 5) to prevent hemorrhagic 
cystitis. Higher doses of mesna can be administered as per local standards for the prevention of 
hemorrhagic cystitis. 
6.1.4. 
Fludarabine  
The fludarabine dose of 25 mg/m2 is administered intravenously over approximately 30 minutes 
once daily for 5 consecutive days during Days -5 through -1 (Visits 6 through 10). Effort should 
be made to administer the fifth dose of fludarabine by 10 AM on Day -1 to ensure 24 hours elapse 
before infusion of LN-145. 
Hematological parameters (CBC and differential) are to be reviewed daily during 
lymphodepletion. If after 3 or 4 doses of fludarabine, the absolute lymphocyte count falls below 
100 cells/mm3 the remaining dose(s) of fludarabine may be omitted following discussion with 
the sponsor’s medical monitor.   
Note: If the patient is obese (BMI > 35.0 kg/m2), fludarabine dosage will be calculated using 
practical weight as described in Appendix 17.3.3. 
6.2. 
LN-145 Infusion 
Upon completion of the manufacturing process, the investigational product will be labeled with a 
patient-specific label (including subject ID and manufacturing number) and shipped overnight by 
courier to the clinical site. The product will be shipped under quarantine and received by the 
appropriate clinical staff at the site. Additional details for handling and administration of the 
investigational product can be found in the Investigational Product Administration Manual. 
If not already hospitalized, the patient will be admitted the day prior to planned LN-145 
administration and prepared with overnight intravenous hydration prior to the investigational 
product administration. Patients will remain hospitalized until the completion of the IL-2 
therapy, as per institutional standards. 
6.2.1. 
Description of LN-145 
LN-145 is a cellular investigational product comprising a live cell suspension of autologous TIL 
derived from the patient's own tumor that is shipped either as a non-cryopreserved product or as 
a cryopreserved product. A summary of the TIL manufacturing process is described in Figure 2. 
For details about tumor handling, see Tumor Procurement and Shipping Manual. 
Each dose contains up to 
 total viable lymphocytes. The total volume to be infused will 
be dependent on total cell dose (generally between 250 mL and 500 mL). 

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At the time of completion of TIL manufacturing, the appropriate number of cells will be 
harvested and provided in the final investigational product. The upper limit of the number of 
cells for infusion 
viable cells) is based on the known published upper limit safely 
infused where a clinical response has been attained (73, 74). There is no evidence that moving 
beyond this upper limit will have more clinical benefit. 
6.2.2. 
Composition of LN-145 
Both non-cryopreserved and cryopreserved formulations of LN-145 have been developed for use 
in clinical studies. The non-cryopreserved investigational product (fresh) is a live cell suspension 
that is formulated in
 
 
The cryopreserved investigational TIL product is a sterile product formulated i
 
 
 
 
6.2.3. 
Transport of LN-145 
Each dose of the live suspension LN-145 will be shipped/sent by courier to the clinical site from 
the CMO the day before planned administration using a method that is intended to support 
24-hour delivery and expected to arrive on the morning of scheduled infusion (Day 0). 
Additional details are specified in the Pharmacy & Investigational Product Administration 
Manual. 
The cryopreserved LN-145 investigational product will be shipped to the clinical site in a 
 
 temperature monitoring device will be used to continuously monitor the product 
temperature during shipment. The product is shipped to the clinical site by expedited courier, and 
is stored in 
 until the patient is ready for infusion. 
6.2.4. 
Receipt of LN-145 and Administration 
A single LN-145 dose is given intravenously approximately 24 hours after lymphodepletion 
chemotherapy followed by IL-2 therapy every 8 to 12 hours for up to 6 doses beginning 3 to 
24 hours after LN-145 infusion.  
LN-145 will be received at the clinical site in the pharmacy on the day of administration. LN-145 
will be shipped to clinical sites under quarantine while awaiting results of release tests. Receipt is 
defined as the moment the LN-145 package is signed for by site personnel and released from 
courier’s custody.  

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After receiving, verifying, and re-labeling with the clinical sites’ specific labels at the pharmacy, 
the non-cryopreserved investigational product, LN-145, will be transferred to the patient bedside 
in its original shipping container
 
 Prior to administration, 
the cryopreserved LN-145 investigational product is to be thawed according to the detailed 
instructions provided in the Pharmacy & Investigational Product Administration Manual. 
Patients may be premedicated with antihistamines and non-steroidal anti-inflammatory 
medications (eg, indomethacin and diphenhydramine) prior to administration of LN-145. Clinical 
investigators will be instructed to administer autologous LN-145 as soon as feasible but at least 
approximately 24 hours since the last dose of fludarabine. Administration of LN-145 is 
recommended within 24 hours from the time of manufacture but no later than 48 hours. The 
investigational product is infused by gravity within 45 minutes as tolerated and can be slowed as 
clinically appropriate. If the infusion is slowed or interrupted for medical reasons, the product 
infusion should be completed within 3 hours of the start of the infusion. Refer to the Pharmacy & 
Investigational Product Administration Manual for details. 
6.3. 
Interleukin-2  
IL-2 will be administered at a dose of 600,000 IU/kg (based on total body weight) and will be 
administered by IV infusion at a frequency of every 8 to 12 hours following the initial dose as 
per institutional standard of care and continued for up to a maximum of 6 doses as tolerated.  
The first dose of IL-2 should be administered between 3 and 24 hours following the completion 
of the LN-145 infusion. If a dose is not administered within 24 hours, this first dose will be 
marked as “skipped” and the next dose will be administered within 36 hours of the end of 
LN-145 infusion. If 36 hours elapse from the end of LN-145 infusion without a dose of IL-2 
being administered, no IL-2 will be given and therapy will have been completed.   
IL-2 doses will be skipped if patient experiences a Grade 3 or 4 toxicity due to IL-2, except for 
reversible Grade 3 toxicities common to IL-2 such as diarrhea, nausea, vomiting, hypotension, 
skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory 
changes. Suggested management of IL-2 toxicity is detailed in Section 8.3 and Appendix 17.5. 
If these toxicities can be easily reversed within 24 hours by supportive measures, then additional 
doses may be given. If greater than 2 doses of IL-2 are skipped, IL-2 administration will be 
stopped. In addition, dosing may be held or stopped at the discretion of the treating investigator.  
Refer to Interleukin-2/aldesleukin (Proleukin®) current package insert for additional 
information. 

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6.4. 
Retreatment 
Patients may rescreen for a second tumor resection and LN-145 treatment if they meet all 
inclusion and exclusion criteria. These patients will have a second tumor harvest and TIL 
(LN-145) therapy. Examples of patients who may be eligible for retreatment are prior responders 
to LN-145 who relapse, nonresponders, and patients with manufacturing failures. The medical 
monitor will have authority to adjudicate enrollment for retreatment (second TIL therapy). Prior 
to enrollment for retreatment, patients must undergo an abbreviated screening procedure. 

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7. 
PERMITTED AND PROHIBITED CONCOMITANT MEDICATIONS 
7.1. 
Permitted Medications  
• Current medications for conditions other than HNSCC are permitted. 
• Antitumor therapy is permitted up until 4 weeks prior to start of NMA lymphodepletion 
regimen. No other subsequent antitumor therapy is permitted during participation in the 
study.   
• Palliative radiation therapy is permitted between tumor resection and lymphodepletion if it 
does not affect target and nontarget lesions. 
• Patients may undergo preplanned procedures if 2 to 3 weeks prior to the start of NMA-LD. 
• Use of systemic steroid therapy ≤ 10 mg/day of prednisone or equivalent is permitted. 
o Use of > 10 mg/day of prednisone or equivalent is permitted in cases of exacerbation of 
known disease or for treatment of new symptoms on study per investigator’s discretion. 
Any changes in concomitant medications also will be recorded in the site’s source 
documentation and the patient’s eCRF throughout the trial. 
7.2. 
Prohibited Medications and Prior Treatment Washout 
7.2.1. 
Prohibited Medications 
The following treatments are prohibited during the study: 
• Systemic therapies and radiation intended to treat HNSCC must have been discontinued or 
completed at least 28 days prior to start of NMA-LD. Further therapies are not permitted 
thereafter while the patient remains on study. Palliative radiation may be allowed if it is not 
directed at any target or nontarget lesions. 
• Other investigational drugs 
• Patients who complete the NMA-LD should not receive a live or attenuated vaccine until 
ALC is ≥ 1000/mm3 
7.2.2. 
Prior Treatment Washout 
Patients will enter a washout period prior to NMA-LD and must stop treatments as follows: 
• All chemotherapy or biologic therapy must have been discontinued 28 days prior to start of 
NMA-LD (Day -7/Visit 4). 
• Radiation therapy must have been completed at least 3 months prior to enrollment (tumor 
harvest). Radiation therapy following tumor harvest must be completed at least 28 days 
prior to NMA-LD.  
• Systemic steroid therapy (> 10 mg of prednisone or equivalent) within 28 days prior to 
tumor resection (Visit 2) is prohibited. Patients weaned from a higher dose of steroid 
therapy must be ≤ 10 mg of prednisone or equivalent for at least 28 days prior to 
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8. 
TOXICITIES MANAGEMENT GUIDELINES 
8.1. 
NMA-LD Regimen Toxicity Management 
The use of the NMA-LD regimen (cyclophosphamide and fludarabine) prior to cell 
administration is expected to lead to myelosuppression in all patients. Therefore, a high index of 
suspicion for occult bacteremia should be maintained until marrow recovery. 
Refer to cyclophosphamide and fludarabine current package inserts for additional information. 
8.1.1. 
Infection Prophylaxis 
8.1.1.1. 
Pneumocystis jirovecii Pneumonia  
All patients should receive appropriate pneumocystis jirovecii pneumonia (PJP) prophylaxis per 
institutional standards for patients receiving chemotherapy-induced immunosuppression. This 
may include any of the following regimens and should begin by Day 14 (Visit 16), or as the 
investigator deems appropriate and continue until the absolute lymphocyte count is 
> 1000 cells/mm3 (typically for at least 6 months) or as per institutional standards.    
One acceptable regimen includes trimethoprim (TMP) and sulfamethoxazole (SMX) as double 
strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) by mouth twice daily 
3 times a week on nonconsecutive days, beginning on the first Monday, Wednesday, or Friday 
on or after the first dose of chemotherapy. 
Pentamidine may be substituted for TMP/SMX DS in patients with sulfa allergies and may be 
administered either IV or aerosolized monthly using standard doses indicated for PJP 
prophylaxis. 
Note: Other appropriate PJP prophylactic schedules or agents may be substituted at the 
discretion of the treating investigator. 
8.1.1.2. 
Herpes Virus Prophylaxis 
Patients with positive HSV serology should receive appropriate reactivation prophylaxis with 
either valacyclovir or acyclovir. 
Herpes prophylaxis should begin by Day 14 (Visit 16), or as the investigator deems appropriate 
and continue until the absolute lymphocyte count is > 1000/mm3 (typically for at least 6 months) 
or as per institutional practice. 
Note: Other appropriate viral prophylactic agents may be substituted at the discretion of the 
treating investigator. 

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8.1.1.3. 
Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (by mouth) from Day 1 (Visit 12) and continue until the 
absolute neutrophil count is >1000/mm3, or another suitable fungal prophylaxis regimen as per 
standard of care at the treating institution. 
8.1.2. 
Hemorrhagic Cystitis Prophylaxis 
Patients will receive mesna to prevent cyclophosphamide-associated hemorrhagic cystitis in 
addition to intravenous fluids. Please refer to treatment guidelines for recommended mesna 
dosing. Alternative dosing regimens of mesna are allowed per institutional standards and 
investigator discretion. 
8.1.3. 
Febrile Neutropenia 
Patients are expected to become neutropenic following the lymphodepletion regimen.  
Furthermore, IL-2 causes neutrophil migration dysfunction putting patients at risk for 
pseudomonas infection as well as severe occult bacteremia. Therefore, for FIRST fever 
> 38.3 °C (or 38.0 °C or above at least 1 hour apart) at any point following lymphodepletion 
(from Day 0 onward), patients will be started on empiric broad-spectrum antibiotics with 
adequate pseudomonas coverage (as per local institutional antibiogram) regardless of neutrophil 
count. Empiric antibiotics should continue at least until the neutrophil count becomes 
> 500 cells/mm3 even if no blood-stream infectious agent is identified. If a blood-stream agent is 
identified, broad-spectrum antibiotics may be tailored to treat the infection as per institutional 
standard of care. Infectious disease consultation will be obtained for all patients with 
unexplained fever, any infectious complications, or as per standard of care at the treating 
institution. 
8.1.4. 
Filgrastim 
Patients will receive filgrastim 5 mcg/kg/day (recommended maximum dose of 300 mcg/day or 
per institutional standard) subcutaneously daily starting from Day 1 (Visit 12) until the ANC is 
>1000/mm3 for 3 consecutive days, or as per standard of care at the treating institution. 
8.1.5. 
Blood Product Support  
Using daily CBC as a guide, the patient will receive platelets and packed red blood cells as 
clinically indicated. As a general guideline, patients may be transfused to maintain: 
• Hemoglobin ≥ 7.5 g/dL 
• Platelets ≥ 10,000/mm3 
Note: Patients may be transfused for different parameters as clinically indicated, eg: increased 
risk for bleeding such as undergoing an invasive procedure or presence of metastatic lesion likely 
to bleed (such as in the brain), high-grade fever, or sepsis. 

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All blood products must be irradiated. Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused white blood cells and decrease the risk of 
CMV infection. 
8.2. 
LN-145 Toxicity Management 
Infusion of LN-145 must occur before the expiration time (recommended within 24 hours, but no 
later than 48 hours of manufacture). Please refer to the Pharmacy & Investigational Product 
Administration Manual for specific infusion instructions. Overall, toxicities or AEs during the 
LN-145 infusion have almost entirely been associated with either the NMA-LD regimen or the 
IL-2 therapy given after TIL infusion. The following AEs have been observed in published 
studies that treated patients with TIL products prepared by a process like that being used to 
prepare LN-145: 
• Short-term, transient/reversible effects of TIL infusion include fever, chills, shortness of 
breath, increased heart rate, hypotension (prolonged hypotension necessitating pressor 
treatment has been reported) (55) following TIL infusion.  
For the cryopreserved LN-145 product only, patients may experience severe allergic reaction 
(anaphylaxis) due to DMSO contained therein. Thus, appropriate emergency medications 
(eg, epinephrine and diphenhydramine) should be available at bedside during time of 
administration. High-dose systemic steroids should be avoided if at all possible. 
Refer to current LN-145 Investigator’s Brochure for additional information. 
8.3. 
Interleukin-2 Toxicity Management 
Interleukin-2 (Proleukin, aldesleukin) can affect nearly every organ system, but essentially every 
abnormality will most often normalize following discontinuation of IL-2 dosing. Please see 
Appendix 17.5 for suggested management guidelines for the treatment of expected toxicities of 
IL-2 administration. 
8.3.1. 
Neurologic Toxicity 
Decreased mental status may occur and can range from somnolence to obtundation. IL-2 should 
be discontinued for any significant mental status changes or hallucinations. Agitation may be 
observed due to mild hallucinations. Appropriate psychiatry consultation would be warranted for 
guidance in management. 
8.3.2. 
Renal Toxicity 
Renal toxicity defined by rapid rise in creatinine levels or clinical symptoms is a risk that is 
commonly observed (1.5 to 2.0 for mild elevation, or greater than 3.0 for marked elevation). 
If patients exhibit signs or symptoms of renal toxicity, manage as per institutional standard of 
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hemofiltration). Hemodialysis should be reserved for life-threatening renal failure such as 
prolonged anuria, hyperkalemia, and profound uremia. 
8.3.3. 
Capillary Leak Syndrome and Weight Gain 
Capillary leak syndrome is expected to occur with IL-2 dosing. Resultant intravascular volume 
depletion should be managed with intravenous fluids. Diuresis should be initiated as tolerated 
following completion of IL-2 dosing. Hypotension not responsive to IV fluids should raise 
suspicion for occult bacteremia and associated sepsis. 
8.3.4. 
Cardiac Arrhythmias and Myocarditis 
All new cardiac arrhythmias should be promptly evaluated and continuously monitored with 
intensive management. 
8.3.5. 
Pulmonary 
TIL can remain in the pulmonary circulation for 24 to 48 hours following infusion and may 
cause transient shortness of breath. In addition, pulmonary edema is commonly observed with 
IL-2 dosing. Supplemental oxygen may be administered as needed. Subsequent IL-2 dosing 
should be delayed until supplemental oxygen has been weaned or is minimal (< 2 L/min per 
nasal cannula). If hypoxia persists or is significant, IL-2 should be discontinued. 
8.3.6. 
Sepsis/Febrile Neutropenia During IL-2 
Sepsis can mimic IL-2 side effects. Fever symptoms may be masked during IL-2 dosing due to 
scheduled indomethacin and acetaminophen. In neutropenic patients exhibiting hypotension or 
oliguria unresponsive to intravenous fluids, a high degree of suspicion for infection should be 
entertained and broad-spectrum antibiotics should be initiated. 
8.3.7. 
Heparin-Induced Thrombocytopenia  
Heparin-induced thrombocytopenia has been observed with IL-2 administration. To minimize 
this risk, heparin flushes should not be used during IL-2 dosing. 
Refer to Interleukin-2/aldesleukin (Proleukin®) current package insert for additional 
information. 
8.4. 
Concomitant Medications to Control Side Effects 
Nausea/vomiting 
Nausea and vomiting should be controlled with ondansetron or similar medication. Other second 
and third line medications (eg, prochlorperazine, promethazine, lorazepam, scopolamine, and 
aprepitant) can be used per institutional guidelines. Steroids should NOT be used as an 
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Fever 
Premedication for fever should be initiated as per institutional standards. Recommend initiating 
nonsteroidal anti-inflammatory medication the night prior to LN-145 administration (Day -1) and 
continue throughout IL-2 treatment. Medications may include indomethacin 50 mg every 8 hours 
and/or acetaminophen every 4 to 6 hours. Indomethacin 75 mg may be used for persistently 
febrile patients. 
Rigors 
IL-2 associated rigors can routinely be treated with meperidine. An initial dose of 25 mg can be 
initiated and followed with an additional 25 mg 15 minutes later if rigors persist or as per 
institutional standards. Prophylactic use of meperidine is discouraged. 
Diarrhea 
IL-2 associated diarrhea may be observed. Anti-motility agents such as loperamide and lomotil 
may be used as per institutional standards (after testing for infectious etiologies such as 
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9. 
COMPLETION/WITHDRAWAL OF PATIENTS 
9.1. 
Treatment Completion 
Patients will be considered to have completed treatment if they complete the tumor harvest, 
receive the NMA-LD regimen, LN-145 infusion, and at least 1 dose of IL-2. 
9.2. 
Study Completion 
The study is expected to be completed approximately 1 year after the last patient completes the 
efficacy follow-up (3 years from last patient’s last dose of IL-2), the time point all patients have 
exited the study for any reasons, or study termination at the sponsor’s discretion, whichever 
occurs first. 
9.3. 
Criteria for Discontinuation Prior to or From Study Treatment  
Patients who discontinue prior to receiving the study treatment (NMA-LD) or from the study 
treatment for any reasons are to complete the Early Termination visit (ETV). ETV is not required 
if the same procedures are done within 2 weeks from the previous visit (see Appendix 17.1). 
Appropriate reasons of the discontinuation must be documented in the patient’s source 
documentation and eCRF page. 
A patient may be discontinued prior to or from further investigational product administration for 
the following reasons: 
• Patient has become ineligible for study participation after tumor resection (Visit 2) and 
prior to lymphodepletion, LN-145 infusion, or IL-2 administration 
• Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, liver, 
colon, adrenal gland, lungs) with symptoms emerging prior to first IL-2 administration  
• Grade 3 or greater allergic reaction including bronchospasm or generalized urticaria that 
does not resolve after medical management in the opinion of the investigator  
• Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 or less within 
96 hours of management  
• Investigator’s decision 
• Withdrawal of consent (reasons must be documented in patient’s source documents): 
o Partial withdrawal of consent: The patient may withdraw from study treatment but 
agree to continue for safety and efficacy follow-up evaluations. 
o Full withdrawal of consent: No additional data to be collected. 
• Pregnancy 
• Death 
• Study terminated by sponsor 

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9.4. 
Follow-Up 
9.4.1. 
Efficacy Follow-Up 
Once the patient discontinues/completes the Treatment Phase, the patient will enter Efficacy 
Follow-up and undergo efficacy assessments and continued safety monitoring.   
The patient may discontinue the Efficacy Follow-up at any time for any of the following reasons. 
Appropriate reasons must be documented in the patient’s source documentation and eCRF page: 
• Disease progression 
• Investigator’s decision 
• Withdrawal of consent (reasons must be documented in patient’s source documents): 
o Partial withdrawal of consent: The patient may withdraw to in-clinic visits but agree to 
be contacted via phone for disease and survival status assessment. 
o Full withdrawal of consent: No additional data to be collected. 
• Study terminated by sponsor  
• Death 
In the event of a patient’s full withdrawal of consent from the Efficacy Follow-up, the 
investigator will promptly notify the sponsor’s medical monitor or designee and will make every 
effort to complete the ETV as appropriate. All AEs attributable to the investigational product 
may be followed until resolution or permanent sequalae. The final outcome of unrelated AEs 
ongoing at the time of the ETV will be captured as “Not Recovered/Not Resolved.” 
9.4.2. 
Overall Survival Follow Up 
Approximately every 3 months following the discontinuation/completion of Efficacy Follow-up, 
patients will be contacted (eg, via phone) to assess disease status and subsequent (current) 
anticancer therapies. Disease progression occurring during OS Follow-up will only be assessed if 
the patient did not progress during the Efficacy Follow-up. Quarterly follow-up will continue 
until death, full withdrawal of consent by patient, lost to follow-up, or study termination by the 
sponsor, but not more than 5 years following the last dose of IL-2. 
Efforts will be made to follow all patients who are lost to follow-up. Patients can only be 
considered lost to follow-up after 3 documented attempts to contact the patient.  
9.5. 
Patient Withdrawal from Study  
Patients may discontinue the trial at any time, for any reasons, without prejudice to further 
treatment. 

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Patients may be withdrawn from the study for any of the following reasons but may be followed 
up for safety until resolution or permanent sequalae of all toxicities attributable to the 
investigational product: 
• Full withdrawal of consent by patient (reasons must be documented in patient’s source 
documents) 
• Lost to follow-up 
• Study terminated by sponsor 
• Death  
9.6. 
Early Termination of Study/Center Closure 
The study may be terminated at any time by the sponsor. The study may be terminated at a study 
site if the investigator does not adhere to the protocol. 

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10. 
TUMOR RESPONSE ASSESSMENTS 
10.1. Response Criteria 
Response assessment will be based on investigator evaluation per RECIST v1.1 with a 
modification to require confirmation of progressive disease (PD). Refer to Table 1 and Table 2 
for RECIST v1.1 response criteria definitions (77). 
10.1.1. Baseline Documentation of Target and NonTarget Lesions 
Baseline documentation of all lesions will occur with scans occurring at the baseline visit 
(Day -21). Measurable disease is defined as the presence of at least 1 measurable lesion of 
≥ 10 mm in long diameter of nonnodal lesions or ≥ 15 mm in short diameter for lymph node 
lesions by CT scan. When more than 1 measurable lesion is present at baseline, all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) should be identified as 
target lesions and will be recorded and measured at baseline. Target lesions should be selected 
based on their size (lesions with the longest diameter) and be representative of all involved 
organs. 
Pathological lymph nodes which are defined as measurable may be identified as target lesions 
and must meet the criterion of a short axis diameter of ≥ 15 mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered nontarget lesions. Nodes that have a short axis 
< 10 mm are considered nonpathological and should not be recorded or followed. 
The sum of the longest diameters (SLD) at baseline (long axis for non-nodal target lesions and 
short axis for nodal target lesions) for all target lesions will be calculated and reported as the 
baseline SLD. The baseline SLD will be used as reference to evaluate changes in the measurable 
dimension of the disease, and thus, response assessment as per RECIST v1.1 guidelines. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as present, absent, or in rare cases unequivocal progression. 
10.1.2. Evaluation of Target Lesions 
This section provides the definition of the criteria used to determine objective tumor response for 
target lesions. 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) must have a reduction in short 
axis to <10 mm). 
Partial Response (PR) 
At least a 30% decrease in the SLD of target lesions taking as 
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Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of 1 or 
more new lesions is also considered progression). 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum 
diameters while on study. 
10.1.3. Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions. While some nontarget lesions may be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points of radiographic 
assessments. 
Complete Response (CR) 
Disappearance of all nontarget lesions. All lymph nodes must be 
nonpathological in size (<10 mm short axis). 
Non-Complete Response /  
Non-Progressive Disease 
Persistence of 1 or more nontarget lesion(s). 
Progressive Disease (PD) 
Unequivocal progression of existing nontarget lesions. (Note: 
the appearance of 1 or more new lesions is also considered 
progression). 
10.1.4. Evaluation of New Lesions 
New measurable lesions may be identified if the new lesions meet criteria as defined for baseline 
target lesion selection and meet the same minimum RECIST v1.1 size requirements of 10 mm in 
long diameter for non-nodal lesions and a minimum of 15 mm in short axis for nodal lesions. 
New measurable lesions shall be prioritized according to size with the largest lesions selected as 
new measured lesions. 
All new lesions not selected as new measurable lesions (eg, new nodal lesions less than 15 mm 
in short diameter) are considered new nonmeasurable lesions and are followed qualitatively.  
Only an unequivocal progression of new nonmeasurable (eg, nodal enlargement to greater than 
15 mm in short diameter) lesions leads to an overall assessment of PD for that time point. 
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show PR or CR. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm a 
definite new lesion, then progression should be declared using the date of the initial scan (see 
Section 10.2.1). 
10.1.5. Evaluation of Overall Response 
The best overall response for each patient is the best response recorded from the start of 
treatment until disease progression/recurrence, the initiation of subsequent anticancer therapy, 
death or 24 months post-treatment, whichever occurs first (taking reference for PD the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. The assignment of 
response for an individual patient, based on both target and nontarget lesions, at each assessment 
time point is shown in Table 1. The best overall response for each patient is determined as shown 
in Table 2.   
Table 1. 
Response at each Assessment Time Point for Patients 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Responsea 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease 
a If investigator’s response assessment is difficult to determine due to presence of confounding factors (ie, tumor 
flare), then overall response should be SD until proven otherwise.  
 
Table 2. 
Examples of Best Overall Response for each Patient Across All Assessments  
Overall Response at 
Time point 1 
Overall Response at  
Time point 2 
Overall Response at 
Time point 3 
Best Overall Response 
Across Assessment 
Time Points 
CR 
CR 
CR 
CR 
PR 
PR 
CR 
CR 
SD 
SD 
PR 
PR 
SD 
PR 
SD 
PR 
SD 
SD 
PD 
SD 

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10.2. Confirmation of Tumor Assessments 
10.2.1. Confirmation of Response (PR or CR) 
Confirmation of response (either PR or CR) is required. Changes in tumor measurements must 
be confirmed by repeat assessments that should be performed ≥ 4 weeks apart after the criteria 
for response are first met. If the confounding factor/tumor flare is considered at subsequent 
assessment points, as the previous assessment was SD or PR, then the response should be SD or 
PR, until proven otherwise. The response assessment should be updated, if needed, based on the 
consecutive observation. ‘Not Evaluable/NE’ should only be selected if the response was truly 
not evaluable (eg, scan was not done). 
10.2.2. Confirmation of Progressive Disease  
All PD assessed by the investigator must be confirmed by objective measures per RECIST v1.1.  
For patients with a minimal increase of over 20% in the sum of diameters of target lesions taking 
as reference the smallest sum on study or for nontarget or new nonmeasurable lesions, a 
confirmation scan is recommended at least 4 weeks after the first PD assessment. 
 

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11. 
ADVERSE EVENTS 
Toxicities will be recorded as AEs and SAEs in the patient’s source documents and on the 
Adverse Events eCRF and must be graded using NCI CTCAE Version 4.03 dated 14 June 2010 
(see Appendix 17.4).  
11.1. Definitions 
11.1.1. Adverse Event 
An AE as defined by International Council on Harmonisation (ICH)-Good Clinical Practice 
(GCP) is any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal/investigational product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal product, whether considered related to the medicinal/investigational product or not. 
Events meeting the definition of an AE include: 
• Adverse event(s) temporally associated with the use of any of the investigational products 
or TIL treatment whether or not considered related to the use of any of the investigational 
products or TIL treatment 
• Any abnormal laboratory test results (eg, hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, EKGs, radiological scans, vital signs measurements), that 
worsen from baseline, and are felt to be clinically significant in the medical and scientific 
judgment of the investigator 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after investigational product administration 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with investigational 
product 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication 
Events that do not meet the definition of an AE include: 
• Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the patient’s condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
• Overdose without clinical sequelae (see Section 11.4) 

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• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
11.1.2. Serious Adverse Event 
An AE is considered serious if, in the view of either the investigator or the sponsor, it results in 
any of the following outcomes:  
• Death 
• Is life-threatening 
• Inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Important medical events: such events may not directly result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based on Investigator decision, they 
may jeopardize the patient and may require intervention to prevent one of the above outcomes as 
listed in this definition. 
Hospitalization including admission to a telemetry unit or intensive care unit specifically for 
administration of study treatment is not considered an SAE. 
11.1.3. Relationship to the Investigational Product 
The investigator is responsible for assessing the relationship to study treatment using clinical 
judgement and the following considerations: 
• Definite: There is a known causal relationship between the investigational product and the 
AE/SAE. The event responds to withdrawal of study treatment (de-challenge), and recurs 
with re-challenge when clinically feasible. 
• Probable: There is reasonable causal relationship between the investigational product and 
the AE/SAE. The event responds to de-challenge. 
• Possible: There is reasonable causal relationship between the investigational product and 
the AE/ SAE. De-challenge information is lacking or unclear.  
• Not likely: There is temporal relationship to the investigational product administration, but 
there is not a reasonable causal relationship between the study drug and the AE/SAE.  
• Not related: There is not a temporal relationship to investigational product administration 
(too early, or late, or investigational product not administered), or there is known causal 

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relationship between the AE/SAE and another drug, concurrent disease, or other 
circumstance. 
11.1.4. Severity 
The severity of an event describes the degree of impact and/or the need for medical care 
necessary to treat an event.  
AE grading will be defined by the CTCAE Version 4.03 (see Section 17.4). In the event the 
CTCAE Version 4.03 does not apply, the severity descriptions below will be used. 
• Mild:  Asymptomatic; clinical or diagnostic observations only; intervention not indicated. 
• Moderate:  Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
activities of daily life. 
• Severe:  Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization may be required; disabling; limiting activities of daily life. 
• Life-threatening:  Urgent intervention is required. 
• Death:  Outcome of AE is death 
11.2. Reporting Procedures for Adverse Events 
11.2.1. All Adverse Events 
AEs/SAEs will be assessed by the investigator and must be recorded on the appropriate eCRF. 
Adverse events will be reported starting immediately after the patient has been consented. 
All AEs occurring after the patient has consented, but before enrollment (prior to tumor 
resection), will be collected on the medical history eCRF unless the event is new and attributed 
to protocol-mandated procedures and assessments. All AEs occurring on or after enrollment/ 
tumor resection in the study and either observed by the investigator or reported by the patient 
(whether attributed to the use of lymphodepletion drugs, LN-145 or IL-2 or not) must be reported 
on the AE eCRF.  
Monitoring and reporting AEs/SAEs, regardless of cause or relationship, will be conducted 
through Day 168 (Visit 21/Month 6) from the last dose of IL-2 or until the first dose of the 
subsequent anticancer therapy, whichever occurs first. All AEs attributed to protocol-required 
procedures or treatment will be collected through Day 672 (Visit 25/Month 24) study visit. AEs 
that occur after the treatment and follow-up period with a reasonable possibility that the event 
may have been caused by the study treatment may be reported at the investigator’s discretion. 
Medically significant AEs considered related to the study treatment by the investigator or the 
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If any patient should die while on the study, the investigator will inform the sponsor within 
24 hours of awareness and report the cause of death as an SAE. The cause of death should be 
recorded in details on the SAE Report Form. Disease progression itself is not an AE, but the 
clinical signs or symptoms leading to death should be reported as an SAE with an outcome of 
death. 
Each site will be responsible for reporting SAEs occurring at the site to the applicable 
institutional review board (IRB)/independent ethics committee (IEC) per the IRB’s/IEC’s 
reporting guidelines. Sites that are required to utilize a local IRB/IEC will be responsible for 
their own local IRB/IEC submissions.   
It will be left to the investigator’s clinical judgment whether an AE is of sufficient severity to 
require the patient’s removal from the study treatment or not. This should be captured in the 
eCRF. If either of these occurs, the patient must undergo an early termination visit and be given 
appropriate care under medical supervision until symptoms cease or the condition becomes 
stable and returns for Efficacy Follow-up visits. If the patient is removed from the investigational 
product or post-treatment follow-up due to an SAE, this information must be included in either 
the initial or follow-up SAE Report Form and in the eCRF. 
11.3. Reporting Procedures for Serious Adverse Events 
11.3.1. Investigator Reporting to Sponsor 
All SAEs, regardless of relationship to study treatment, must be collected while on the study 
(from patient signing of informed consent through 6 months from the last dose of IL-2 or until 
the first dose of the next anticancer therapy, whichever occurs first). All AEs/SAEs attributed to 
protocol-required procedures or treatment will be collected through Month 24 of the study. If the 
Investigator learns of any SAEs that occur after the follow-up period and there is a reasonable 
possibility that the event may have been caused by the study treatment, then the SAE should be 
promptly reported to the Sponsor or designated Safety CRO. 
All SAEs that occur during the study must be reported by the investigator to the sponsor or 
designee within 24 hours of learning of the event. The initial notification should be as complete 
as possible with the information available and include the investigator’s assessment of study 
treatment causality, as defined in Section 11.1.3. 
SAE terminology and severity grading will be based on the NCI CTCAE Version 4.03 
guidelines. All AEs and SAEs will be recorded in the eCRF within the timelines outlined in the 
eCRF completion guideline. 
Each site is responsible for reporting SAEs occurring at the site to the applicable IRB/IEC per 
the IRB/IEC’s reporting requirements. 

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All SAEs will also be reported on the SAE report form, and submitted by email or fax within 
24 hours of knowledge of the event to the attention of the CRO contact below. 
CRO 
Contact Information for Submission of SAE Report Form 
SynteractHCR 
E-mail: SafetyFax@SynteractHCR.com 
Fax: 
760-268-6500 
11.4. Special Situations Reporting 
11.4.1. Definitions of Special Situations 
Special situation reports include reports of medication error, overdose, AEs associated with 
product complaints, occupational exposure, and pregnancy reports regardless of an associated 
AE. The special situation reports will be reported as an SAE but not considered an AE/SAE 
unless associated with an AE/SAE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.  
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (as it applies to the daily dose of the subject in 
question).  
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.   
Occupational exposure is defined as the exposure to a medicinal product as a result of one’s 
professional or nonprofessional occupation. 
11.4.2. Reporting Procedures for Special Situations 
11.4.2.1. Pregnancy Reporting 
Any pregnancy that occurs while on the study through 12 months from the last dose of IL-2 or 
until the first dose of the subsequent anticancer therapy, whichever comes first, must be reported 
using the Pregnancy Report form within 24 hours of becoming aware of the pregnancy. The 
pregnancy itself is not considered an AE nor is an induced abortion to terminate a pregnancy 
without medical reasons. Any premature termination of pregnancy (eg, a spontaneous abortion, 
an induced therapeutic abortion due to complications or other medical reasons) must be reported 
within 24 hours as an AE or SAE. The underlying medical reason for this procedure should be 
recorded as the AE or SAE term. A spontaneous abortion is always considered to be an SAE and 
will be reported as described in Section 11.3.  

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The patient should receive appropriate monitoring and care until the conclusion of the pregnancy 
to determine the outcome and status of the patient and child. The outcome should be reported to 
the Safety CRO using the Pregnancy Outcome form. Any SAE occurring in association with a 
pregnancy, brought to the investigator’s attention after the patient has completed the study 
treatment and efficacy follow-up visits, must be promptly reported to the sponsor or their 
representative. 
The pregnancy must be followed up until discharge following delivery or premature termination 
to determine outcome and status of mother and child. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Any SAE occurring in 
association with a pregnancy, brought to the Investigator’s attention after the patient has 
completed the study and considered by the investigator as possibly related to the investigational 
product, must be promptly reported to the sponsor or their representative. 
11.4.2.2. Other Special Situations Reporting 
All other special situation reports involving the study treatment must be reported to the Safety 
CRO using the SAE report form within 24 hours of becoming aware of the situation. Special 
situations involving concomitant medications do not need to be reported; however, any AE 
resulting from a special situation should be reported on the AE eCRF page. 
11.5. Regulatory Reporting Requirements  
In the event of a suspected unexpected serious adverse reaction (SUSAR), the sponsor, or their 
designee, will notify the appropriate regulatory authorities and all appropriate parties as per the 
regulations. 
Assessment of expectedness for SAEs will be determined by Iovance using reference safety 
information in the Investigator’s Brochure and relevant prescribing information, as applicable.   
In addition, the sponsor must submit expedited reports of potential serious risks from clinical 
trials or any other source based on relevant local legislation or regulations, including the 
applicable US FDA Code of Federal Regulations and the EU Clinical Trial Directive 
(2001-20/EC) and relevant updates. The sponsor will notify participating sites of relevant 
SUSAR reports and other applicable serious safety findings which occur during the trial 
including the efficacy follow-up phase. The investigator should notify the IRB or IEC of SUSAR 
reports as soon as is practical where required by local regulatory agencies and in accordance with 
the local institutional policy. 

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12. 
SAFETY ASSESSMENTS 
12.1. Data Safety Monitoring Board  
An independent DSMB will monitor the patient safety during the study. The DSMB will 
evaluate safety data after the first 5 patients complete Week 4 (Day 28). An additional evaluation 
will be completed when the first 15 patients complete Week 4 (Day 28). A limited analysis may 
also be conducted reviewing all data available from these patients as specified in the DSMB 
charter. Enrollment will continue while under review. Additional roles, responsibilities, and 
conduct are described in an independent charter. 
12.2. Considerations 
Adverse events are detailed in Section 11. Other measures of safety include the following: 
physical exam including weight (calculate BSA using Dubois formula and BMI), ECOG 
performance status, vital signs (pulse, respirations, blood pressure and temperature), blood and 
urine tests (prior to cyclophosphamide administration), hematology (CBC with differential), 
serum chemistry (see below), urinalysis (complete urine culture if indicated), and ongoing 
assessment of CMV infection, as clinically indicated. 
In particular, the expected toxicities of the NMA-LD pre-treatment regimen and IL-2 
administration will be closely monitored. 
Serum chemistry parameters include the following: 
• Sodium 
• Potassium 
• Chloride 
• Total CO2, or bicarbonate 
• Creatinine 
• Glucose 
• Bun 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Alkaline phosphatase 
• ALT 
• AST 
• Bilirubin (total and direct) 

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• Lactate dehydrogenase 
• Total protein 
• Creatine kinase 
• Uric acid 
• Thyroid panel (including TSH and free T4) 

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13. 
STATISTICAL CONSIDERATIONS 
13.1. Introduction 
The primary statistical plan of analysis is based on use of descriptive methods unless mentioned 
otherwise. Continuous data will be summarized as the number of patients with nonmissing data 
(N), mean, standard deviation, median, minimum, and maximum values. Categorical data will be 
summarized as counts and their related percentages, where applicable. Estimation of confidence 
limits will use two-sided, 95%. Missing data will not be imputed unless mentioned otherwise.  
A more detailed description of the analyses and reporting plan of the data will be provided in the 
statistical analysis plan (SAP).  
13.2. Analysis Populations 
Three analysis populations will be defined to summarize the data. The tumor harvested (TH) 
population will consist of all patients with resection of tumor for production of TIL. The TH 
population is further divided into the following analysis populations: 
13.2.1. Efficacy Population 
Primary: All-treated population that consists of patients in the safety population who have been 
successfully treated with NMA-LD regimen, any amount of LN-145 followed by IL-2 (at least 
1 dose).   
Secondary: Efficacy-evaluable population consists of patients in the all-treated population with 
an adequate baseline and at least one postbaseline radiological assessments by investigators. 
Patients who are clinically/unequivocally progressed or expired prior to reaching the first 
radiological assessment will be included. 
13.2.2. Safety Population 
Primary: Safety population consists of patients in the TH population who have tumor harvested 
successfully and received at least 1 component of the study treatment; cyclophosphamide, 
fludarabine, any amount of LN-145 or IL-2.   
Secondary: Nontreated population consists of patients who are in the TH population but not a 
part of the primary safety population.  
13.3. Sample Size Justification 
The planned sample size of the treated patients for this single arm study is 47 patients. Given a 
potential 16% attrition rate, approximately 56 patients will be enrolled/resected. A Simon’s 
optimal 2-stage design will be used to test the null hypothesis that ORR will be ≤5% (not 
considered clinically meaningful). Fifteen patients will be included in the first stage, and if there 
are 1 or fewer patients responding to therapy, the study will terminate. Expansion into Stage 2 to 
a total of 47 patients will occur concurrently with the Stage 1 analysis. If at least 6 of those 

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47 patients respond to therapy, the study therapy would be considered to have met its primary 
study goal. This 2-stage design has 80% power to detect a difference of an ORR of 5% versus 
20% using a 1-sided 0.025 alpha level test.  
13.4. Baseline Demographic and Clinical Characteristics 
 
Age will be derived as a function of the date of informed 
consent. Patients among the resected untreated population will be summarized by the primary 
reason of not receiving the treatment. 
13.5. Study Endpoints and Planned Analyses 
13.5.1. Primary Endpoint 
13.5.1.1. Efficacy  
The ORR is defined as the proportion of patients who achieve either a confirmed PR or CR 
within 6 months following treatment as best response as assessed by investigator evaluation per 
RECIST v1.1 among the all-treated population. Objective response will be evaluated per each 
disease assessment and the ORR will be calculated with the corresponding 95% two-sided 
confidence interval (CI).  
13.5.2. Secondary Endpoints 
13.5.2.1. 
Safety 
The primary safety data will be descriptive and based on the summarization of TEAEs including 
SAEs and AEs leading to discontinuation from the study treatment. 
 
AE 
summaries will be based on patient incidence counts and percentages per the safety population. 
In addition to the overall summary of AEs, breakdown summaries will be made by NCI CTCAE 
grade of severity, and relationship to the study treatment. All laboratory results will be 
summarized using descriptive statistics. SAEs will also be summarized. 
 
 
 
13.5.2.2. Additional Measures of Efficacy  
• CR rate is based on responders who achieved confirmed CR as assessed by investigators. 
• DOR is measured among responders from the first-time response (PR/CR) criteria are met 
until the first date that recurrent or PD is objectively documented, or receipt of subsequent 
anticancer therapy or the patient expires (whichever is first recorded). Patients not 
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will have their event times censored on the last date that an adequate assessment of tumor 
status is made. 
• DCR is derived as the sum of the number of patients who achieved confirmed PR/CR or 
sustained SD (at least 6 weeks) divided by the number of patients in the all-treated 
population × 100%.   
• PFS is defined as the time (in months) 
 to PD, or death 
due to any cause, whichever event is earlier. Patients not experiencing PD or not having 
expired at the time of the data cut or the final database lock will have their event times 
censored on the last date that an adequate assessment of tumor status is made. 
• OS is defined as the time 
 due to any 
cause. Patients not having expired by the time of data cut or the final database lock will 
have their event times censored on the last date of their known survival status. 
• DOR, DCR, PFS, and OS will be subjected to right censoring. Kaplan-Meier methods will 
apply. 
13.5.3. Exploratory Analyses 
• Correlations of immune factors with efficacy and safety of the TIL therapy and HPV status 
of the tumor will be explored. The results will be reported in a separate report.     
• Evaluation of ORR, DOR, DCR, and PFS as assessed per irRECIST by independent 
review. 
• HRQoL will be assessed using the EORTC QLQ-C30 instrument and analyzed per the 
published evaluation manual. 
• Q-TWiST will be calculated as sum of the three health state periods (Toxicity, TWiST, and 
Relapse) (76) with each multiplied by the appropriate utility score (78). 
13.5.3.1. Stage I Analysis 
• The Stage 1 analysis will occur when the fifteenth treated patient has an opportunity to 
reach the second tumor assessment (Day 56 assessment). The study will move forward to 
Stage 2 with 2 or more confirmed response as assessed by investigator evaluation per 
RECIST v1.1.   
 

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14. 
ADMINISTRATIVE REQUIREMENTS 
14.1. Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor, its authorized representative, 
and Investigator abide by GCP, as described in ICH Guideline E6 and in accordance with the 
general ethical principles outlined in the Declaration of Helsinki. The study will receive approval 
from an IRB/IEC prior to commencement. The investigator will conduct all aspects of this study 
in accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities. 
14.2. Protocol Modifications 
The investigator will not modify this protocol without obtaining the concurrence of the sponsor. 
All protocol amendments must be issued by the sponsor, signed and dated by the investigator, 
and should not be implemented without prior IRB/IEC approval, except where necessary to 
eliminate immediate hazards to the patients or when the change(s) involves only logistical or 
administrative aspects of the study (eg, change in monitor[s], change of telephone number[s]). 
Responsibilities for reporting protocol amendments to any regulatory authority (if applicable) 
and/or IRB/IEC are further described in Section 15 of the protocol. 
In situations requiring a departure from the protocol, the investigator or other physician in 
attendance will contact the sponsor or its representative for approval prior to any intended 
departure from the protocol.  
14.3. Regulatory Approval and Documentation 
Documents that must be provided to the sponsor prior to investigational product shipment are as 
follows: 
• Up-to-date curriculum vitae for each investigator 
• Signed and dated investigator agreement 
• Applicable local regulatory documentation (eg, Form FDA 1572) 
• Signed financial disclosure Form 
• A copy of the formal written notification to the Investigator regarding approval of the 
protocol by the IRB/IEC is required. The written notification is to be signed by the 
chairman or authorized designee and must identify the specific protocol. In cases where an 
IRB/IEC member has a known conflict of interest, abstention of that individual from voting 
should be documented; an investigator may be a member of the IRB/IEC, but may not vote 
on any research in which he or she is involved. 

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• Name and address of the IRB/IEC with a statement that it is organized and operates 
according to GCP and the applicable laws and regulations, and a current list of the IRB/IEC 
members. If accompanied by a letter of explanation from the IRB/IEC, a general statement 
may be substituted for this list. 
• A copy of the IRB/IEC approved informed consent and other adjunctive materials 
(eg, advertising) to be used in the study, including written documentation of IRB/IEC 
approval of these items. 
• Name and address of any local laboratory conducting tests for the study, a dated copy of 
the laboratory reference values for tests to be performed during the study and a copy of the 
certification or other documentation establishing adequacy of the facility. 
• Required financial agreement (Clinical Trial Agreement). 
• In addition to the documents required prior to the study, other documentation may be 
required during the study. 
14.4. Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will be responsible for 
all information in the eCRF and will maintain the source documents that support the data 
collected from each patient, and all trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial and as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. Essential documents must be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
will be retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. If the 
responsible investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. 
14.5. Data Quality Assurance  
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2008) and all revisions thereof, and in accordance with FDA regulations (21 CFR 
Parts 11, 50, 54, 56, and 312, Subpart D- Responsibilities of Sponsors and Investigators) and 
with the ICH guidelines on GCP (ICH E6 R2). 
Steps to be taken to assure the accuracy and reliability of data include; the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the investigator 
and associated personnel prior to the study, periodic monitoring visits by the sponsor or designee 
and direct transmission of clinical study data into the database.  

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Agreements made by the sponsor with the investigator/institution and any other parties involved 
in the clinical trial will be in writing as a separate agreement. On-site audits representatives of 
the sponsor may visit the site to carry out an audit of the study in compliance with regulatory 
guidelines and company policy. Such audits will require access to all study records, including 
source documents, for inspection and comparison with the eCRFs. Patient privacy must, 
however, be respected. Sufficient prior notice will be provided to allow the investigator to 
prepare properly for the audit. 
14.6. Data Processing and Recordkeeping 
14.6.1. Electronic Data 
When using electronic data processing, the sponsor or their designee will ensure that systems 
comply with 21CFR Part 11, CTR EU No. 536/2014 and General Data Protection 
Regulation (GDPR) EU 2016/679) requirements, as applicable. Documentation regarding the 
electronic data systems used in this protocol is described in the relevant study-specific plans or 
standard operating procedures. 
14.6.2. Electronic Case Report Form Completion 
Electronic data capture (EDC) will be used for the study. The site will be suitably trained on the 
use of the eCRF and appropriate site personnel will be provided electronic signatures. Data must 
be entered into the eCRF in English. The eCRFs are to be completed at the time of the patient's 
visit, except for the results of tests performed outside the investigator's office, so that they always 
reflect the latest observations on the patients participating in the study. 
Data must be recorded first on a source document that can be verified before it is entered in the 
EDC system. Completed eCRFs are to be signed off by the Investigator as per the eCRF 
Completion Guidelines written for the study. 
All eCRF corrections are to be made by the investigator or other authorized study site personnel. 
The investigator must authorize changes to the recorded safety and efficacy data and changes 
must reflect in source documents. 
14.6.3. Study Monitoring 
In accordance with 21 CFR Part 312.56, the clinical monitor will periodically inspect all eCRFs, 
study documents, research facilities, and clinical laboratory facilities associated with this study 
at mutually convenient times during and after completion of the study. As required by 21 CFR 
Part 312, Subpart D: Responsibilities of Sponsors and Investigators, the monitoring visits 
provide the sponsor with the opportunity to evaluate the progress of the study; verify the 
accuracy and completeness of eCRFs against source documentation; ensure that all protocol 
requirements, applicable to FDA regulations, and investigator’s obligations are being fulfilled; 
and resolve any inconsistencies in the study records. This includes inspection of all documents 
and records related to the study that are required to be maintained by the investigator, including 

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but not limited to medical records (office, clinic, or hospital) and investigational pharmacy 
records for the patients participating in this study. The names and identities of all research 
patients will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by the sponsor. The IND regulations also require the Investigator to allow 
authorized representatives of sponsor, the FDA or regulatory authorities to inspect and make 
copies of the same records. The investigator should immediately notify the sponsor if they have 
been contacted by a regulatory agency concerning an upcoming inspection. The names and 
identities of the patients need not be divulged to the sponsor; however, the records must 
nevertheless be inspected. This can be accomplished by blacking out the patient’s name and 
replacing the name with the patient’s study identification (ID) number. If these requirements 
conflict with the local regulatory restrictions or institutional requirements, the investigator must 
inform the sponsor of these restrictions before initiation of the study. 
14.7. Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
investigator/designee will be provided.  
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. 

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15. 
INVESTIGATOR REGULATORY OBLIGATIONS 
15.1. Institutional Review Board/Independent Ethics Committee 
Before enrollment of patients into the study, as required by Federal regulations (21 CFR 56) and 
international regulations (ICH GCP Guidelines), the protocol and informed consent form must be 
reviewed and approved by an appropriate IRB/IEC. By signing the FDA Statement of 
Investigator Form 1572, the investigator assures that all aspects of the institutional review will be 
conducted in accordance with current federal regulations. A letter documenting the IRB/IEC 
approval with the names and titles of the IRB/IEC members must be received by the sponsor 
before the initiation of the study. Amendments to the protocol will be subject to the same 
requirements as the original protocol. 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB/IEC by the 
investigator at intervals stipulated in their guidelines. 
15.2. Informed Consent 
Each patient (or a legally authorized representative) must give written consent (and sign other 
locally required documents) according to local requirements after the nature of the study has 
been fully explained. The consent form must be signed prior to performance of any study-related 
activity. The consent form that is used must be approved both by the sponsor and by the 
reviewing IRB/IEC. The informed consent should be in accordance with the current revision of 
the Declaration of Helsinki, current International Council on Harmonization (ICH) and Good 
Clinical Practice (GCP) guidelines, Directive 2001/20/EC (and when in force EU Regulation 
536/2014), and Regulation 2016/679 (GDPR), as interpreted by the national laws and regulatory 
bodies, and the sponsor’s policies. 
The investigator must explain to potential patients or their legal representatives the purpose, 
methods, reasonably anticipated benefits and potential hazards of the trial, its duration, and any 
discomfort it may entail. Patients will be informed in their native language, comprehensive, 
concise, clear, relevant and understandable to a layperson, that their participation is voluntary 
and that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time. They will be told which alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that their records may be examined by competent authorities and authorized persons but their 
personal data will be treated as strictly confidential and will not be publicly available. Patients 
must be given the opportunity to ask questions. After this explanation and before entry into the 
trial, consent should be appropriately recorded by means of the patient's or his/her legal 
representative's dated signature. If a patient and his/her legal representative are unable to read, an 
impartial witness must be present during the entire informed consent discussion. The signature of 
the impartial witness will certify the patient's consent. The patient and their legally designated 
representative must receive a signed and dated copy of the informed consent. The informed 
consent process should be documented in the patient’s medical record. Adequate time shall be 

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given for the subject or his or her legally designated representative to consider his or her decision 
to participate in the study. 
In accordance with HIPAA, the written ICF must include a patient authorization to release 
medical information to the sponsor or their representative and/or allow the sponsor or their 
representative, a regulatory authority, or IRB/IEC access to patient’s medical information that 
includes all hospital records relevant to the study, including a patient’s medical history and other 
data that may identify him/her. 
15.3. Patient Data Protection 
The investigator at each site and designees, employees, and agents involved with the study will 
comply with relevant state, federal national and regional regulations relating to the 
confidentiality, privacy, and security of patient’s personal health information (PHI). They will 
only create, maintain, use, or disclose any data that is generated by the trial or other information 
disclosed to the investigator or their employees or agents during the study to the sponsor, 
IRB/IEC, FDA, EMA, regulatory agencies, or other authorized recipients as appropriate for the 
execution, analysis, review, and reporting of this study. Such information shall not be used for 
any other purposes and will remain confidential. Patient will not be individually identified but 
will be referred to in records by the study-assigned number and patient initials (if applicable by 
local regulations). 
15.4. Adverse Event Reporting 
The investigator agrees to report all AEs/SAEs to the sponsor as described in Section 11. 
Furthermore, the investigator is responsible for ensuring that any co-investigator or 
subinvestigator promptly bring AEs to the attention of the principle investigator. The investigator 
shall promptly notify the IRB/IEC of any SAEs, or any other information that may affect the safe 
use of the investigational product during the course of the study as applicable per the local 
IRB/IEC requirements. 
15.5. Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. The investigator must 
notify the sponsor when contacted by a regulatory authority regarding inspection of her/his study 
site. 
All required data will be recorded in the eCRFs in a timely manner. All eCRF data must be 
submitted to the sponsor throughout and at the end of the study. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution. Regulatory 
authorities will be notified with the appropriate documentation detailing the person to whom the 
responsibility has been transferred. 

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15.6. Confidentiality 
Unless otherwise specified in the clinical study agreement, the following process shall occur: 
The investigator must assure that patients’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. In the eCRFs or other documents submitted to the 
sponsor, patients should not be identified by their names, but by an identification code. The 
investigator should keep a site enrollment log showing codes, names, and addresses. Documents 
not for submission to the sponsor (eg, patients’ written consent forms) should be maintained by 
the investigator in strict confidence, in accordance with all applicable local and national 
regulations. All information provided to the investigator prior to the study, as well as all data 
developed during the study, is confidential and remains the property of the sponsor. The 
investigator agrees that no information based on the conduct of this study (including the 
protocol, the data resulting from this study, or the fact that this study is/was conducted) will be 
released without prior written consent of the sponsor unless this requirement is superseded by 
local or national regulations. 
15.7. Publications 
The sponsor will be responsible for determining when the study results should be published. The 
sponsor will work jointly with the investigators to publish information. The investigator shall not 
submit a publication or abstract to journals or professional societies without the prior written 
approval of the sponsor, except as permitted by the agreed terms of the Clinical Trial Agreement, 
including after the reporting of the results of this study by the sponsor and other institutions. 

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16. 
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Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are 
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38. 
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39. 
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40. 
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response to chemotherapy in patients with advance non-small cell lung cancer. Cancer 
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42. 
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lymphocyte count is associated with survival in ovarian cancer independent of tumor-
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expressing the tissue resident memory marker CD103 are associated with increased 
survival in high-grade serous ovarian cancer. Clin Cancer Res. 2014;20(2):434-44. 
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tumor-infiltrating neutrophils and neutrophil-to-CD8+ lymphocyte ratio in patients with 
resectable esophageal squamous cell carcinoma. J Transl Med. 2014;12:7. 
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infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and 
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47. 
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between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann 
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52. 
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Type, density, and location of immune cells within human colorectal tumors predict 
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17. 
APPENDICES 
17.1. Schedule of Assessments 
 
Pretreatment Phase 
Treatment Phase 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visits 6, 7, 8, 9, 10 
Visit 11 
Visit Name 
Screening Visit 
Tumor Resection 
Visit 
Day -21 to -14 
(Baseline) 
Day -7 
Day -6 
Days -5, -4, -3, -2, -1 
Day 0 (LN-145 
Infusion Visit) 
Visit window 
Up to 28 days 
 
N/A 
N/A 
N/A 
N/A 
N/A 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Documentation of diagnosis 
X 
 
 
 
 
 
 
Documentation of HPV status 
X 
 
 
 
 
 
 
HRQoL Questionnaireb 
 
 
X 
 
 
 
 
Physical examinationc 
X 
 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
Xe 
ECOG performance status 
X 
X 
X 
X 
 
 
X 
Safety blood and urine testsf 
X 
Xg 
X 
X 
X 
X 
X 
ß-HCG serum pregnancy test 
X 
 
X 
 
 
 
 
Infection testingh 
X 
 
 
 
 
 
 
HLA typingi 
X 
 
 
 
 
 
 
HPV serotype 
 
X 
 
 
 
 
 
Serum creatininej 
X 
Xg 
X 
X 
X 
X 
X 
Eye examination 
X 
 
 
 
 
 
 
Cardiac evaluationsk 
X 
 
 
 
 
 
 
Pulmonary function testsl 
X 
 
 
 
 
 
 
Colonoscopym 
X 
 
 
 
 
 
 
Tumor assessments (CT/MRI)n 
X 
 
X 
 
 
 
 
Response assessments (RECIST v1.1) 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse eventso 
X 
X 
X 
X 
X 
X 
X 
Tumor harvestp 
 
X 
 
 
 
 
 
NMA lymphodepletionq 
 
 
 
X 
X 
X 
 
LN-145 infusionr 
 
 
 
 
 
 
X 
IL-2 600,000 IU/kgs 
 
 
 
 
 
 
 
PJPt 
 
 
 
 
 
 
 
Filgrastimu 
 
 
 
 
 
 
 
Fungal prophylaxisv 
 
 
 
 
 
 
 
Herpes virus prophylaxisw 
 
 
 
 
 
 
 
Immune monitoring & PBMCx 
 
Xg 
 
X 
 
 
 

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Visit Name 
Treatment Phase 
Efficacy Follow-Up 
Visits 12, 13, 14, 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Days 1, 2, 3, 4 
Day 14 
Day 28 (Week 4) 
Day 56 (Week 8) 
Day 84 (Week 12) 
Visit window 
N/A 
(+/- 3 days) 
(+/- 3 days) 
(+/- 3 days) 
(+/- 3 days) 
Informed consent 
  
  
  
  
  
Inclusion/exclusion 
  
  
  
  
  
Demographic data 
  
  
  
  
  
Medical history 
  
  
  
  
  
Documentation of diagnosis 
  
  
  
  
  
Documentation of HPV status 
  
  
  
  
  
HRQoL Questionnaireb 
 
 
 
 
X 
Physical examinationc 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
ECOG performance status 
  
  
X 
X 
X 
Safety blood and urine testsf 
X 
X 
X 
X 
X 
ß-HCG serum pregnancy test 
  
  
  
  
  
Infection testingh 
  
  
  
  
  
HLA typingi 
  
  
  
  
  
HPV serotype 
  
  
  
  
  
Serum creatininej 
X 
X 
X 
X 
X 
Eye examination 
  
  
  
  
  
Cardiac evaluationsk 
  
  
  
  
  
Pulmonary function testsl 
  
  
  
  
  
Colonoscopym 
  
  
  
  
  
Tumor assessments (CT/MRI)n 
  
  
X 
X 
X 
Response assessments (RECIST v1.1) 
  
  
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Adverse eventso 
X 
X 
X 
X 
X 
Tumor harvestp 
  
  
  
  
  
NMA lymphodepletionq 
  
  
  
  
  
LN-145 infusionr 
  
  
  
  
  
IL-2 600,000 IU/kgs 
X 
  
  
  
  
PJPt 
X 
X 
X 
X 
Filgrastimu 
X 
Fungal prophylaxisv 
X 
X 
X 
X 
X 
Herpes virus prophylaxisw 
X 
X 
X 
X 
Immune monitoring & PBMCx 
X 
X 
X 
X 

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Visit Name 
Efficacy Follow-up 
Overall Survival 
Follow-up 
(Quarterly 
Contact) 
Visit 20 
Visit 21 
Visit 22 
Visit 23 
Visit 24 
Visit 25 
ETVa 
Day 126  
(Month 4.5/Wk 18) 
Day 168 
(Month 6) 
Day 252 
(Month 9) 
Day 336 
(Month 12) 
Day 504 
(Month 18) 
Day 672 
(Month 24) 
Visit Window 
(+/- 7 days) 
(+/- 7 days) 
(+/- 7 days) 
(+/- 7 days) 
(+/- 21 days) 
(+/- 21 days) 
(+/- 21 days) 
Informed consent 
  
  
  
  
  
  
  
 
Inclusion/exclusion 
  
  
  
  
  
  
  
 
Demographic data 
  
  
  
  
  
  
  
 
Medical history 
  
  
  
  
  
  
  
 
Documentation of diagnosis 
  
  
  
  
  
  
  
 
Documentation of HPV status 
  
  
  
  
  
  
  
 
HRQoL Questionnaireb 
 
X 
 
X 
 
X 
 
 
Physical examinationc 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsd 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
Safety blood and urine testsf 
X 
X 
X 
 
ß-HCG serum pregnancy test 
  
  
  
  
  
  
  
 
Infection testingh 
  
  
  
  
  
  
  
 
HLA typingi 
  
  
  
  
  
  
  
 
HPV serotype 
  
  
  
  
  
  
  
 
Serum creatininej 
X 
X 
X 
 
Eye examination 
  
  
  
  
  
  
  
 
Cardiac evaluationsk 
  
  
  
  
  
  
  
 
Pulmonary function testsl 
  
  
  
  
  
  
  
 
Colonoscopym 
  
  
  
  
  
  
  
 
Tumor assessments (CT/MRI scans)n 
X 
X 
X 
X 
X 
X 
X 
 
Response assessments (RECIST v1.1) 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
 
Adverse eventso 
X 
X 
 
 
 
 
X 
 
Tumor harvestp 
  
  
  
  
  
  
  
 
NMA lymphodepletionq 
  
  
  
  
  
  
  
 
LN-145 infusionr 
  
  
  
  
  
  
  
 
IL-2 600,000 IU/kgs 
  
  
  
  
  
  
  
 
PJPt 
      Xt 
    Xt 
  
  
  
  
  
 
Filgrastimu 
  
  
  
  
  
  
 
Fungal prophylaxisv 
  
  
  
  
  
  
  
 
Herpes virus prophylaxisw 
       Xw 
   Xw 
  
  
  
  
  
 
Immune monitoring & PBMCx 
X 
X  
 X 
  
  
X 
 
Survival follow-up y 
 
 
 
 
 
 
 
X 

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ß-HCG = beta human chorionic gonadotropin; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ETV = Early Termination visit; HLA = human 
leukocyte antigen; HPV = human papillomavirus; HRQoL = health-related quality of life; IL-2 = interleukin-2; MRI = magnetic resonance imaging; N/A = not applicable; 
NMA = nonmyeloablative; PBMC = peripheral Blood Mononuclear Cells; PJP = pneumocystis jirovecii pneumonia; RECIST = Response Evaluation Criteria in Solid Tumors; 
Wk = Week 
a 
The ETV is completed if discontinuation prior to/from the study treatment or post-treatment follow-up occurs at any time after Visit 2 and before Visit 25. 
b HRQoL Questionnaire is to be performed as the first procedure at baseline Day -21 (Visit 3) and be performed as the first procedure on Day 84 (Visit 19/Week 12), Day 168 
(Visit 21/Month 6), Day 336 (Visit 23/Month 12), and Day 672 (Visit 25/Month 24). See Section 5.9. 
c 
Physical examination will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, skin, psychiatric (mental 
status), general nutrition. Physical examinations conducted during follow-up will be symptom directed. See Section 5.10. 
d Vital signs will include height, weight, heart rate, respiratory rate, blood pressure, and temperature. Height will be measured at screening only. Body surface area and body 
mass index will be calculated at Day -7 (Visit 4) only. See Section 5.11. 
e  On Day 0 (LN-145 infusion), vital signs will be monitored every 30 minutes during infusion then hourly (+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), 
unless otherwise clinically indicated, for up to approximately 24 hours post TIL infusion. See Section 5.11.  
f  Chemistry: sodium, potassium, chloride, total CO2, or bicarbonate, creatinine, glucose, BUN, albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT, AST, 
total bilirubin, direct bilirubin, lactate dehydrogenase, total protein, total creatine kinase, uric acid. Thyroid panel (to include TSH and Free T4) is to be done at Visits 1 and 19 
or as clinically indicated. See Section 5.13. 
 
Hematology:  CBC with differential. 
Urinalysis Dipstick:  A complete urine culture shall be conducted if indicated.  
Coagulation: Measurement of prothrombin time (PT)/international normalized ratio (INR), and partial thromboplastin time (PTT)/activated PTT will be performed at screening 
only and analyzed locally. 
g Laboratory samples may be collected within 2 days prior to the tumor resection visit. 
h    HIV antibody titer; Hepatitis - HBsAg determination and anti HCV; CMV serology (IgG and IgM), HSV serology determination (HSV-1 IgG and HSV-2 IgG); EBV viral 
capsid antigen (VCA) IgG and/or Epstein Barr nuclear antigen (EBNA) IgG (may be within previous 3 months to Tumor Resection/Visit 2). Syphilis testing (VDRL or other). 
Syphilis screening (as per local standard; eg, Rapid Plasma Reagin [RPR] venereal disease research laboratory [VDRL] or other) at screening, and thereafter as clinically 
indicated. See Section 5.15.  
i 
HLA typing by central laboratory. See Section 5.16.  
j  Estimated CrCl is calculated at screening only by site based on the Cockcroft-Gault calculation. See Section 5.18. 
  
k  Cardiac Evaluations consist of ECHO or MUGA and ECG, and if patient is > 60 years of age or with a history of ischemic heart disease, chest pain, or clinically significant 
atrial and/or ventricular arrhythmias, patient must have had a stress thallium test. See Section 5.20.  
l  Pulmonary evaluation using spirometry or 6-minute walk test will be completed for all patients. See Section 5.21. 
 
m  Colonoscopy is only required for documented Grades 2 or greater diarrhea or colitis as a result of previous immunotherapy within 6 months from screening. Patients that have 
been asymptomatic for at least 6 months from screening or had a normal colonoscopy post anti-PD-1/anti-PD-L1 treatment, with uninflamed mucosa by visual assessment will 
not need to repeat the colonoscopy. See Section 5.22.  
n  CT Scans of the chest, abdomen, and pelvis, are required at the indicated time points. Baseline scans may occur between Day -21 (Visit 3) and Day -7 (Visit 4). Additional 
radiological assessments may be performed per investigator’s discretion. MRI may be used if patients are intolerable to contrast media. See Section 5.24. 
o  Any AEs occurred after screening, but prior to enrollment/tumor resection, will be recorded as medical history in the eCRF. Any AEs occurred after enrollment/tumor resection 
will be captured as AEs through Day 168 (Visit 21/Month 6) and as clinically indicated, or until the first dose of the subsequent anticancer therapy, whichever occurs first. 
All AEs attributed to protocol-required procedures or treatment will be collected through Day 672 (Visit 25/Month 24). See Section 11. 
p  See Section 5.25 for tumor harvest for TIL manufacturing and additional tumor tissue to central laboratory.  
q  Cyclophosphamide with mesna for 2 days at Day -7 and Day -6 (Visits 4 thru 5) followed by 5 days of fludarabine at Day -5 thru Day -1 (Visits 6 thru 10). See Section 6.1.  
r  LN-145 infusion is to be done 1 to 2 days after the last dose of agent in the NMA lymphodepletion regimen.  See Section 6.2.  
s 
Initiate IL-2 at 600,000 IU/kg within approximately 3 to 24 hours after LN-145 infusion and continue every 8 to 12 hours for up to 6 doses. See Section 6.3. 
t 
PJP prophylaxis should be given by Day 14 (Visit 16) or as the investigator deems appropriate and continue until the absolute lymphocyte count is > 1000 cells/mm3. 
See Section 8.1.1.1. 

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u Filgrastim 5 μg/kg/day subcutaneous should be administered daily starting from Day 1 (Visit 12) until the absolute neutrophil count is > 1000/mm3 for 3 consecutive days, or 
as per institutional standard. See Section 8.1.4. 
v Fungal prophylaxis (fluconazole 400 mg by mouth daily) should be administered each day starting from Day 1 (Visit 12) until the absolute neutrophil count is > 1000/mm3 or 
as per the institutional standard. See Section 8.1.1.3. 
w Herpes prophylaxis should begin by Day 14 or as the investigator deems appropriate and continue for 6 months post-treatment, or in general, until the absolute lymphocyte 
count is > 1000/mm3. See Section 8.1.1.2. Patients with positive HSV serology will be given valacyclovir or acyclovir for prophylaxis. 
x Blood draw for immune monitoring is to be collected at tumor resection (Visit 2), Day -7 (Visit 4), Day 14 (Visit 16) through Day 84 (Visit 19/Week 12), and Day 168 
(Visit 21/Month 6) through Day 336 (Visit 23/Month 12) and ETV. Blood draw for PBMC analysis is only to be collected at tumor resection (Visit 2). See Section 5.23 and the 
Laboratory Manual. 
y Patients are to be contacted quarterly (approximately every 3 months) after discontinuing/completing the post-treatment Efficacy Follow-up to assess disease status and 
subsequent anticancer therapy. See Section 9.4.2. 
 
 

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17.2. ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
Adapted from Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
17.3.  Calculation of BMI, BSA and Practical Weight 
Unless otherwise specified in this protocol, actual body weight is used for dose calculations of 
treatment agents. In patients who are determined to be obese (BMI > 35.0 kg/m2), the practical 
weight will be used. 
17.3.1. BMI 
BMI = weight (kg)/[height (m)]2 
17.3.2. BSA  
BSA = 0.007184 x height (cm)0.725 x weight (kg)0.425 
17.3.3. Practical Weight 
Practical body weight (average of the actual weight and ideal body weight) is to be used when 
dosing cyclophosphamide and fludarabine in patients who have a BMI > 35.0 kg/m2. 
Note: Practical weight will NOT be used in the calculation of dose for IL-2. 
17.3.4. Ideal Body Weight 
Male = 
50 kg + 2.3 x (number of inches over 60 inches) 
Example:  ideal body weight of 5’10’’male  
50 + 2.3 x 10 = 73 kg 
Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’3’’female  
45.5 + 2.3 x (3) = 57 kg 

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17.4. Common Terminology Criteria for Adverse Events 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
17.5. Expected Aldesleukin Toxicities and Their Suggested Management 
Expected Toxicity  
Expected Grade 
Supportive Measures  
Stop Treatment*  
Chills  
3 
IV Meperidine 25-50 mg, IV q1h, prn  
No  
Fever  
3 
Acetaminophen 650 mg, po, q4h; 
Indomethicin 50-75 mg, po, q8h  
No  
Pruritis  
3 
Hydroxyzine HCL 10-20 mg po q6h, 
prn; Diphenhydramine HCL25-50 
mg, po, q4h, prn  
No  
Nausea/ Vomiting/ 
Anorexia  
3 
Ondansetron 10 mg, IV, q8h, prn; 
Granisetron 0.01 mg/kg IV daily prn; 
Droperidol 1 mg, IV q4-6h, prn; 
Prochlorperazine 25 mg q4h pr, prn or 
10 mg IV q6h prn  
No  
Diarrhea  
3 
Loperamide 2 mg, po, q3h, prn; 
Diphenoxylate HCl 2.5 mg and 
atropine sulfate 25 mcg, po, q3h, prn; 
codeine sulfate 30-60 mg, po, q4h, 
prn  
If uncontrolled after 
24 hours despite all 
supportive measures  
Malaise  
3 or 4 
Bedrest interspersed with activity  
If other toxicities occur 
simultaneously  
Hyperbilirubinemia  
3 or 4 
Observation  
If other toxicities occur 
simultaneously  
Anemia  
3 or 4 
Transfusion with PRBCs  
If uncontrolled despite all 
supportive measures  
Thrombocytopenia  
3 or 4 
Transfusion with platelets  
If uncontrolled despite all 
supportive measures  
Neutropenia  
4 
Observation  
No  
Edema/Weight gain  
3 
Diuretics prn  
No  
Hypotension  
3 
Fluid resuscitation;  
Vasopressor support  
If uncontrolled despite all 
supportive measures 
Dyspnea  
3 or 4 
Oxygen or ventilatory support  
If requires ventilatory 
support  
Oliguria  
3 or 4 
Fluid boluses or dopamine at renal 
doses  
If uncontrolled despite all 
supportive measures  
Increased creatinine  
3 or 4 
Observation  
Yes (grade 4)  
Renal failure  
3 or 4 
Dialysis  
Yes  
Pleural effusion  
3 
Thoracentesis  
If uncontrolled despite all 
supportive measures  
Bowel perforation  
3 
Surgical intervention  
Yes  
Confusion  
3 
Observation  
Yes  
Somnolence  
3 or 4 
Intubation for airway protection  
Yes  

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Expected Toxicity  
Expected Grade 
Supportive Measures  
Stop Treatment*  
Arrhythmia  
3 
Correction of fluid and electrolyte 
imbalances; chemical conversion or 
electrical conversion therapy  
If uncontrolled despite all 
supportive measures  
Elevated Troponin 
levels  
3 or 4 
Observation  
Yes  
Myocardial Infarction  4 
Supportive care  
Yes  
Elevated 
transaminases  
3 or 4 
Observation  
For grade 4 without liver 
metastases  
Electrolyte 
imbalances  
3 or 4 
Electrolyte replacement  
If uncontrolled despite all 
supportive measures  
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to Grade 2 or less by next retreatment 
 
17.6. Summary of Changes (Major/Minor) In Protocol C-145-03 Version 2.0 
(Dated 30 August 2017) 
The major changes and purposes for revising the C-145-03 protocol are the following: 
• Updated and clarified the primary, secondary, and exploratory objectives and endpoints 
• Clarified investigational product doses and treatment schedule 
• Updated the durations for each of the study phases 
• Revised the long-term follow-up to include an overall survival follow-up period 
• Revised the number and location of study sites to reflect current study design 
• Clarified the planned patient population, including multiple clarifications made to the 
inclusion and exclusion eligibility criteria  
• Revised required diagnosis to primary HNSCC via pathology report 
• Allowed for patients who progress or who have an incomplete response to treatment on 
this protocol to be rescreened and retreated 
• Allowed for patients who cannot undergo pulmonary function tests alternatives for 
pulmonary function assessment 
• Allowed for patients to have undergone prior irradiation to persistent lesions 
• Allowed for washout period of current treatment to begin closer to treatment rather than 
from tumor harvest 
• Multiple clarifications around study assessments and procedures to be performed and 
timing for the assessments and procedures 
• Updated the description of the production and expansion of TIL for clarity 
• Changed the cutoff for obese BMI from > 30.0 kg/m2 to > 35.0 kg/m2 

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Version 2.0, Dated 30 August 2017 
• Clarified the sample size calculation and revised the statistical analyses to align with the 
revised study objectives and endpoints 
• Revised the timing of evaluations to be performed by the DSMB 
• Clarified permitted and prohibited concomitant medications 
• Clarified prophylaxis therapies to be administered 
• Added guidance on management of LN-145, NMA-LD, and IL-2 toxicities  
• Clarified definitions for study treatment completion and study completion 
• Numerous clarifications for safety monitoring 
• Added special situations reporting 
• Updated the key sponsor and designee contact information  
The minor changes and purposes for revising the C-145-03 protocol are the following: 
• Revised protocol title for clarity 
• Updated Table of Contents and Introduction 
• Revised the study flow chart to reflect the current study design 
• Numerous typographical changes were made for clarity and consistency 
• Minor administrative changes and additions to clarify operational issues 
• Formatting, including additions to the List of Abbreviations and adding hyperlinks for 
Sections, Tables, Figures, Appendices, and References 
A separate Summary of Changes document outlines the noteworthy changes from Version 1.0 to 
Version 2.0, and includes rationales for the changes.