Clinical trial NCT03092453
Conditions: Melanoma
Sponsor: University of Pennsylvania
Start date: 2017-05-01; Completion date: 2023-03-31
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate a method of using dendritic cells (a kind of white blood cell) as a vaccine to stimulate your own immune system to react to your melanoma cells.

Detailed description:
This is a single arm open label trial that will assess the safety and tolerability of mature dendritic cell (mDC3/8) vaccine (primer and booster) in subjects with stage III and stage IV melanoma, followed by treatment with pembrolizumab (anti-PD-1 therapy).

Eligible patients that provide written informed consent will undergo apheresis to collect blood mononuclear cells for vaccine production approximately 1 week prior to vaccine infusion. Each study subject will receive cyclophosphamide 300mg/m\^2 intravenously or by mouth 3 to 4 days prior to the vaccine dose, to deplete regulatory T cells. For each vaccine dose, all subjects will receive autologous dendritic cells pulsed with melanoma tumor-specific peptides. On Day 1, the subject will receive the primer vaccine dose; this will be followed by two booster vaccine doses at 6 weeks apart. Peripheral blood will be taken weekly to monitor the immune response to each peptide by tetramer assay. Re-staging will occur after the 3rd vaccine dose, along with tumor biopsy and second apheresis. Anti PD-1 therapy (standard of care) will commence 7-8 weeks after the subject's last dendritic cell vaccine.

Arms: arm 1: Mature DC 7.5-15 million/peptide given day 1, every six weeks for 2 doses followed by standard of care anti PD-1 therapy
Interventions: intervention 1: Mature dendritic cell (DC) vaccine intervention 2: Cyclophosphamide 300mg/m^2 intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Mature DC 7.5-15 million/peptide followed by 2 booster every six weeks of 1-5 million/peptide followed by standard of care anti PD-1 therapy. intervention 2: administered prior to subject's first DC dose intervention 3: administered 7-8 weeks after subject's last DC dose

Protocol documents:
Prot_SAP_000.pdf: 
DC Vaccine for Melanoma 
Protocol Version 9.08-10-2021 
Mature Dendritic Cell Vaccination Against Mutated Antigens 
in Patients with Advanced Melanoma 
Principal Investigator: 
Protocol Numbers: 
IND Number: 
Gerald Linette, MD, PhD 
Division of Hematology Oncology 
University of Penns lvania School of Medicine 
Telephone: 
E-mail:
enn.edu 
cer Immunothera 
Penn IRB# 826433 
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Investigational Product: 
ntigen peptide-pulsed mature dendritic cell 
Cell Manufacturing: 
Next Generation Sequencing 
Related Test 
Conelative Laboratory 
Team: 
Biostatistician: 
Original Protocol Date: 
Amended: 
Vl: November 16, 2016 
V2: January 17, 2017 
V3: February 14, 2017 
V 4: June 5, 2017 
VS: November 10, 2017 
V6: June 27, 2018 
V7: December 7, 2018 
V8: October 13, 2020 
V9: August 10, 2021 
• 
• 
• 
• 
uenza) 
-------I 
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania. Do not disclose or use except as authorized in writing by the study sponsor. 
NCT 03092453


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Schema 
Consent/Screening 
Apheresis (~Day -7) 
CTX 300 mg/m2 IV [Day -3 (+/- 1 day)] 
Day 1: DC Vaccine #1 (Priming vaccine dose) (mature DC 7.5-15 million/peptide) 
Booster vaccine doses (DC Vaccine #2 and DC Vaccine #3) (~q6w) mDC (1-5 million/peptide) 
Re-staging after Last DC Vaccine/Tumor Biopsy/Apheresis 
Anti-PD-1 therapy (standard of care)/Follow-up 
Tumor biopsies/Apheresis 
End of Study 
*Immune monitoring: Beginning on Day 1/Week 1 and collected weekly thereafter through Week 18
(~Day 120), then every third week for 12 additional weeks, for a total of 30 weeks.  Please refer to
Section 8.5 for additional details. 
*Immune Monitoring Sample Collection


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Protocol Version 9.08-10-2021
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TABLE OF CONTENTS 
Schema ......................................................................................................................................................... 2 
1.0 
BACKGROUND AND RATIONALE ......................................................................................... 6 
1.1 
Overview ................................................................................................................................ 6 
1.2 
Chemotherapy for Melanoma ................................................................................................ 6 
1.3 
Cytokines for Melanoma ........................................................................................................ 6 
1.4 
Vaccines for Melanoma ......................................................................................................... 6 
1.4.1 Gp100 Melanoma Antigen Vaccines .......................................................................... 7 
1.4.2 Melanoma Neoantigens .............................................................................................. 7 
1.5 
Dendritic Cells ....................................................................................................................... 7 
1.6 
Regulatory T Cells ................................................................................................................. 8 
1.7 
Study Rationale ...................................................................................................................... 8 
1.8 
Investigational Product Update: September 2016 .................................................................. 8 
1.9 
Major Study Update: November 2017 ................................................................................... 9 
2.0 
OBJECTIVES ................................................................................................................................ 9 
2.1 
Primary Objective .................................................................................................................. 9 
2.2 
Secondary Objectives ............................................................................................................. 9 
3.0 
ELIGIBILITY CRITERIA ......................................................................................................... 10 
3.1 
Inclusion Criteria .................................................................................................................. 10 
3.2 
Exclusion Criteria ................................................................................................................ 10 
4.0 
REGISTRATION ........................................................................................................................ 11 
5.0 
PATIENT RECRUITMENT AND SCREENING .................................................................... 11 
6.0 
CONCOMITANT THERAPY .................................................................................................... 12 
7.0 
INVESTIGATIONAL PRODUCTS .......................................................................................... 13 
7.1 
Dendritic Cell Vaccines (mDC3/8 vaccines with and without influenza) ........................... 13 
7.1.1 Agent Description ..................................................................................................... 13 
7.1.2 Mechanism of Action ............................................................................................... 13 
7.1.3 Pharmacodynamics/Kinetics ..................................................................................... 13 
7.1.4 Formulation .............................................................................................................. 13 
7.1.5 Availability ............................................................................................................... 13 
7.1.6 Preparation ................................................................................................................ 13 
7.1.7 Packaging and Labeling ............................................................................................ 14 
7.1.8 Administration .......................................................................................................... 14 
7.1.9 Potential Toxicities ................................................................................................... 14 
7.1.10 Return or Destruction of Study Drug ........................................................................ 14 
7.2 
Cyclophosphamide ............................................................................................................... 14 
7.2.1 Agent Description ..................................................................................................... 14 
7.2.2 Receipt and Storage .................................................................................................. 15 
7.2.3 Premedication ........................................................................................................... 15 
7.2.4 Administration .......................................................................................................... 15 
7.2.5 Potential Toxicities ................................................................................................... 15 
7.3 
Anti-PD-1 (Pembrolizumab) ................................................................................................ 15 


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8.0 
STUDY PROCEDURES ............................................................................................................. 15 
8.1 
On-study Biopsies ................................................................................................................ 15 
8.2 
Dendritic Cell (mDC3/8) Preparation .................................................................................. 16 
8.3 
Treg Depletion ..................................................................................................................... 16 
8.4 
Administration of Dendritic Cell Vaccines (mDC3/8 vaccines with and without 
influenza) ............................................................................................................................. 16 
8.5 
Immune Monitoring ............................................................................................................. 17 
8.6 
Assessment of Clinical Response ......................................................................................... 17 
8.7 
Anti-PD-1 Administration .................................................................................................... 18 
9.0 
POTENTIAL TOXICITY AND DOSE MODIFICATIONS ................................................... 18 
9.1 
Dose Limiting Toxicity ........................................................................................................ 18 
10.0 
STUDY CALENDAR .................................................................................................................. 19 
11.0 
CRITERIA FOR RESPONSE (RECIST Criteria v1.1) ........................................................... 22 
11.1 Tumor Measurement ............................................................................................................ 22 
11.2 Baseline Documentation of Target and Non-target Lesions ................................................ 22 
11.3 Response Criteria ................................................................................................................. 23 
11.3.1 Evaluation of Target Lesions .................................................................................... 23 
11.3.2 Evaluation of Non-target Lesions ............................................................................. 23 
11.4 Evaluation of Best Overall Response ................................................................................... 23 
11.5 Confirmation ........................................................................................................................ 24 
12.0 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................... 24 
13.0 
SAFETY AND ADVERSE EVENTS ......................................................................................... 25 
13.1 Definitions ............................................................................................................................ 25 
13.2 Recording of Adverse Events ............................................................................................... 27 
13.3 Reporting of Serious Adverse Events .................................................................................. 28 
13.3.1 Investigator Reporting: Local Regulatory Review Committees ............................... 29 
13.4 Pregnancies .......................................................................................................................... 29 
13.5 Protocol Exceptions/Deviations ........................................................................................... 29 
13.6 Medical Monitoring ............................................................................................................. 30 
13.7 Study Stopping Rules ........................................................................................................... 30 
14.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 30 
15.0 
DATA HANDLING AND RECORDKEEPING ....................................................................... 31 
15.1 Confidentiality ..................................................................................................................... 31 
15.2 Source Documents ............................................................................................................... 32 
15.3 Case Report Forms ............................................................................................................... 32 
15.4 Records Retention ................................................................................................................ 32 
16.0 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................... 32 
16.1 Study Monitoring Plan ......................................................................................................... 32 
16.2 Auditing and Inspecting ....................................................................................................... 33 


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17.0 
ETHICAL CONSIDERATIONS ................................................................................................ 33 
18.0 
STUDY FINANCES..................................................................................................................... 33 
18.1 Funding Source .................................................................................................................... 33 
18.2 Conflict of Interest ............................................................................................................... 34 
18.3 Patient Stipends or Payments ............................................................................................... 34 
19.0 
PUBLICATION PLAN ............................................................................................................... 34 
20.0 
REFERENCES ............................................................................................................................. 35 


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1.0 BACKGROUND AND RATIONALE 
1.1 
Overview 
 In 2016, it is estimated that 76,380 new cases of melanoma will be diagnosed in the US (1). 
Although disease will be detected early and cured in many individuals with surgery, approximately 
10,130 patients will die from metastatic melanoma. Patients with metastatic (stage IV) melanoma 
suffer a poor prognosis. Since 2011, two new treatments have become available for patients with 
metastatic melanoma. Checkpoint inhibitors such as Ipilimumab, Nivolumab, and Pembrolizumab 
serve to block negative inhibitory signals during T cell activation and allow tumor-specific T cells 
to recognize and eliminate cancer.  The 3 approved checkpoint inhibitors have all been shown in 
randomized controlled trials to improve overall survival when compared to chemotherapy(2-4). 
The second new treatment targets the BRAF V600E mutation which is present in approximately 
50% of patients with cutaneous melanoma. Vemurafenib is a selective oral inhibitor of the mutated 
(V600E) BRAF kinase. A randomized phase 3 controlled clinical trial demonstrated improved OS 
in patients receiving vemurafenib compared to dacarbazine (5). Vemurafenib was approved in 
August 2011. In addition, the combination of a BRAF inhibitor plus a MEK inhibitor 
(dabrafenib/trametinib, GSK) was granted regulatory approval in 2014 based upon improved ORR 
and overall survival(6,7). Despite approval of these new agents, metastatic melanoma remains an 
incurable malignancy with a median OS estimated at 24 months.   
1.2 
Chemotherapy for Melanoma 
 Chemotherapy has little impact on the natural history of metastatic melanoma. Dacarbazine 
received FDA approval in 1975 and remains a treatment option for patients with stage IV 
melanoma. The response rate to dacarbazine in most studies is 10-15%, primarily partial responses 
that tend to be of short (2-3 months) duration. Few durable complete responses are seen after 
treatment with dacarbazine. A meta-analysis of 74 studies published between 1974-1995 reviewed 
the ineffectiveness of dacarbazine-based chemotherapy as the median survival of enrolled patients 
was 8.8 months (8). Addition of other cytotoxic agents to dacarbazine adds little clinical benefit 
and increases toxicity (9).   
1.3 
Cytokines for Melanoma 
 Interleukin-2 received FDA approval in 1998 as treatment for metastatic melanoma despite 
concerns about toxicities and poor tolerability. In a series of single arm clinical trials (n=270 
patients), the response rate to high dose Interleukin-2 is 16% (6% complete response rate). As 
reported, ten of the 16 patients who achieved a complete response remain disease free at a median 
follow up of 5 years (10). Six deaths occurred due to toxicity. This published experience using high 
dose IL-2 suggests that immunomodulation has a role in the treatment of this disease and in fact, 
may be curative in a small group of patients.  
1.4 
Vaccines for Melanoma 
Since 1970, investigators have pursued the hypothesis that melanoma is inherently immunogenic 
and elicits an immune response that can be, in some instances, protective (11).  As a result, 
therapeutic immunization strategies have evolved over the past decade to develop more 
contemporary approaches based on molecular techniques of antigen identification and immune 
monitoring.  As one example, the molecular cloning of several melanocyte-lineage antigens (MLA) 


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has prompted investigators to identify and isolate immunogenic peptides that can be used in 
vaccination protocols (13). These candidate melanoma tumor antigens include: gp100/pMe117, 
MART-I, Melan-A, tyrosinase as well as antigens from the cancer-testis family (MAGE family) 
which are known to be expressed only in testis and placenta in normal tissues  (14, 15). In normal 
adult tissues, each MLA is expressed at low levels with expression restricted to melanocytes and 
retina pigmented epithelium (16).  
1.4.1 Gp100 Melanoma Antigen Vaccines 
The gp100 antigen has been studied in detail. Three candidate peptides (G154, G209-2M and G280-
9V) that bind HLA-A2 (the most common class I allele expressed by ~50% of the population) have 
been identified and each is known to be immunogenic in patients with melanoma (14)). One peptide 
named (G209-2M (also called gp100:209-217) has been studied extensively and shown to be 
immunogenic when given subcutaneously with adjuvant (17).  In our work, the (G280-9V (also 
called gp100:280-288) peptide was given with autologous dendritic cells (without IL-2 or any other 
cytokine) and shown to be immunogenic in patients with advanced melanoma (18). The third 
peptide epitope named G154 has also been studied in some detail (19). Other gp100 related peptides 
that are restricted to HLA-A3 are known but are less well studied (20).   
1.4.2 Melanoma Neoantigens 
Among cancer genomes, cutaneous melanoma harbors the largest number of non-
synonymous mutations. Ultraviolet light exposure is a major risk factor for cutaneous 
melanoma and whole genome sequencing reveals the high rate of UV light induced 
mutational alterations (21). We have hypothesized that UV light induced non-synonymous 
mutations generate patient-specific neoantigens which could be targeted by vaccination to 
elicit melanoma-specific T cells. Based on our published report  to identify tumor-specific 
neoantigens from melanoma patients samples, we have been able to identify >20 candidate 
peptide neoantigens restricted to the HLA-A*0201 allele with ~50% promoting an immune 
response upon incorporation into a vaccine (22). Thus, inclusion of candidate patient-
specific neoantigen peptides alone or in combination with the gp100 melanoma shared 
peptides into a vaccine is predicted to improve the breadth of the immune response directed 
against the tumor.  
1.5 
Dendritic Cells 
Dendritic cells (DC) serve a critical role in capturing and presenting antigen in the initiation of 
immunity against infectious pathogens and cancer. A variety of technical advances involving the 
isolation of human DC as well as an improved understanding of DC biology have led investigators 
to propose using autologous DC as adjuvant for peptide vaccination in cancer, including melanoma 
(23). The initial clinical reports conclude that DC immunization is safe and well tolerated; serious 
adverse events related to DC vaccination are rare (24). Interestingly, clinical responses have been 
documented by numerous investigators in a variety of malignancies including melanoma (18,25).  


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1.6 
Regulatory T Cells 
Recent advances in immunology confirm the presence of a small population of circulating 
CD4+CD25+ T cells (known as regulatory T cells or Treg) that function to suppress T cell 
immunity toward pathogens and cancer. In healthy adults, approximately 5% of peripheral blood 
CD4+ T cells are Treg based on co-expression of CD25 and the transcription factor FoxP3 (26). 
Depletion of Treg by administration of low dose cyclophosphamide is sufficient to allow tumor 
rejection after peptide vaccination in model systems. This strategy was attempted clinically in the 
1980’s using cyclophosphamide together with a first generation (whole cell, irradiated) vaccine and 
shown to be safe and well tolerated. Several randomized trials later confirmed that vaccine given 
with cyclophosphamide is more immunogenic (27).  Currently, the use of low dose 
cyclophosphamide which can be given either by infusion or orally is an effective strategy to 
eliminate Treg in patients prior to vaccination and is currently being evaluated at multiple centers. 
1.7 
Study Rationale 
Cancer vaccines represent a promising area of clinical investigation in solid tumors based on 
evidence of clinical activity and minimal toxicity (28). Recent progress in immuno-oncology 
supports continued clinical evaluation of cancer vaccines in melanoma patients especially in 
combination with checkpoint inhibitors (29). The central hypothesis is that checkpoint inhibition 
will permit vaccine-elicited T cells to expand and traffic to the tumor microenvironment for more 
efficient elimination of the cancer cells.   
The primary endpoint is immunological response based on tetramer assays performed on 
longitudinal blood samples obtained at multiple time points. Immunological response is based on 
measuring increased numbers of antigen peptide-specific CD8+ T cells as measured by the tetramer 
assay.  In the proposed study, the tetramer assay will be performed at the designated time points. 
The additional laboratory correlative assays such as the 51Cr release assay and functional assays 
will be performed after the third dose. The primary endpoint will also include evaluating the safety 
and tolerability of the mature dendritic cell vaccine.  Secondary study endpoints are described in 
Section 2.2.  
We propose to obtain tumor tissue to evaluate various biomarkers including the expression of PD-
L1 antigens and characterize the tumor infiltrating lymphocytes, and perform exploratory studies 
to discover markers of resistance using tumor biopsy specimens collected at the indicated time 
points. These correlative laboratory studies are viewed as a high priority that will allow scientists 
to better understand the mechanisms of response/resistance to therapy.  
1.8 
Investigational Product Update: September 2016 
Since the IND was open, we have published two reports documenting the safety, tolerability, and 
immunogenicity of the vaccine. Our initial publication reported the initial cohort of patients that 
received the mature DC (mDC) vaccine with the three gp100 peptides restricted to HLA-A*02:01. 
Maturation of DC was performed by activation of cells with CD40-ligand (CD40L) and Interferon-
γ (IFN-γ). Of the seven patients treated, six developed sustained T cell immunity to all 3 melanoma 
peptides (30). Importantly, 3 patients developed a confirmed clinical response by RECIST criteria. 
DC vaccine derived IL-12p70 levels positively correlated with time to progression (TTP) as did 
type-1 immunity as assessed by IFN-γ/IL-13 ratios. A pathway specific defect in IL-12p35 
transcription was identified in clinical non-responder patients and gp100 specific T cells were type-
2 polarized. Incorporation of TLR3 (poly I:C) and TLR8 (R848) agonists into the CD40L/IFN- γ 


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activation protocol for DC maturation corrected the IL-12p70 production defect. 
The second published report involved the incorporation of neoantigen peptides together with 2 
gp100 peptides using autologous DC matured with CD40L/IFN-γ/TLR3/TLR8 agonists (refer to as 
mDC3/8) (22). Our group employed next generation sequencing methods with a novel 
bioinformatics pipeline to identify missense mutations in surgically resected melanoma metastases 
from patients with advanced disease that previously received ipilimumab. The DC vaccine led to 
an increase in the frequency of naturally occurring neoantigen-specific immunity and revealed 
previously undetected HLA class I restricted neoantigens in patients. Vaccination promoted a 
diverse neoantigen-specific T cell receptor repertoire and most importantly, was safe and well 
tolerated.  Please refer to the Investigator Brochure for current toxicity information.  
We have treated two additional patients since this publication using the same vaccine protocol. One 
patient (MEL66) had progression after ipilimumab followed by dabrafenib/trametinib combination 
and the residual disease was surgically resected. She received the vaccine as adjuvant therapy, 
tolerated the treatment well with no adverse events and remains alive with no measurable disease 
18 months later. The other patient (MEL69) had widely metastatic relapsed/refractory disease at 
the start of the vaccine protocol. He received two vaccine doses without side effect or toxicity but 
had documented disease progression and was removed from the study. He died a few weeks later 
due to disease progression.  
We have received funding from NCI and the Parker Institute for Cancer Immunotherapy  to accrue 
additional patients for enrollment into the vaccine protocol. The hypothesis to be tested is that anti-
PD-1 therapy inhibits adaptive immune resistance by enhancing neoantigen-specific T cell 
immunity within the tumor microenvironment leading to more effective tumor regression.  
1.9 
Major Study Update: November 2017 
The results of the BMS 238 clinical trial evaluating nivolumab versus ipilimumab as adjuvant 
therapy for surgically resected stage 3/4 melanoma have been published (31). FDA has accepted 
for priority review its supplemental Biologics License Application for nivolumab to treat patients 
with melanoma in the adjuvant setting and FDA approval is anticipated.  Based on this publication, 
the study has been further amended to allow for subjects without measurable disease (i.e. disease 
that has been completely resected) to enroll on this study.   
2.0 OBJECTIVES 
2.1 
Primary Objective 
1.
To determine the immunological response based on measuring increased numbers of peptide
specific T cells as calculated by the tetramer assay.
2.
To assess the safety and tolerability of the mature dendritic cell vaccine (mDC3/8 vaccines).
2.2 
Secondary Objectives  
1.
To determine the clinical response rate using RECIST 1.1 criteria
2.
To determine the time to progression


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3.
To assess regulatory T cell depletion after cyclophosphamide administration.
4.
To perform exploratory biomarker analysis of accessible tumors
5.
To determine the safety and side effect profile of the dendritic cell vaccine (mDC3/8 vaccines)
administered to patients given after a single dose of cyclophosphamide.
3.0 ELIGIBILITY CRITERIA 
Patients must fulfill the following eligibility requirements: 
3.1 
Inclusion Criteria 
1.
Histologically confirmed stage III and stage IV M1a/M1b/M1c melanoma.  Measurable disease 
is not required for eligibility and patients with completely resected disease are permitted.
2.
Male or female patients age ≥ 18 years
3.
ECOG performance status 0-2
4.
Required initial laboratory values (performed within 14 days prior to eligibility confirmation
by physician-investigator):
a.
WBC >3 THO/µL
b.
Hg ≥ 9.0 g/dL
c.
Platelets >75 THO/µL
d.
Total Bilirubin < 2.0 mg/dl; unless the subject has known or suspected Gilbert syndrome
for which ≤ 3 mg/dl is permitted
e.
Serum Creatinine < 2.0 mg/dl
5.
Subjects of reproductive potential must agree to use a medically accepted birth control method
during the trial and for at least two months following the trial.  Please see Section 5.0 for
additional details.
6.
Provide written informed consent.
3.2 
Exclusion Criteria 
1.
Prior treatment with more than one line of cytotoxic chemotherapy; prior treatment with one
line of cytotoxic chemotherapy is permitted.  Prior treatment with targeted therapy (such as
ipilimumab, anti-PD-1, or BRAF + MEK inhibitor combination) is permitted.
2.
Active untreated CNS metastasis
3.
Active infection
4.
Prior malignancy (except non-melanoma skin cancer) within 3 years


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5.
Pregnant or nursing (lactating) women
6.
Concurrent treatment with high-dose systemic corticosteroids; local (inhaled or topical)
steroids are permitted
7.
Known allergy to eggs
8.
Prior history of uveitis or autoimmune inflammatory eye disease
9.
Known positivity for hepatitis BsAg, hepatitis C antibody, or HIV antibody
4.0 REGISTRATION 
At the time a subject consents to participate in this study, the subject should be registered in the PennCTMS 
(i.e. Velos). Once subject eligibility has been confirmed by a physician-investigator, apheresis collection 
and the manufacturing of the study vaccine may commence. Patients who fail apheresis or who do not 
receive vaccine due to other reasons will be replaced and will not be considered evaluable. 
Each Subject is identified in the study by a Subject Number that is assigned when the subject is first 
consented and is retained as the primary identifier for the subject throughout his/her entire participation in 
the trial. The Subject Number consists of the Protocol Number with a sequential subject number suffixed 
to it, so that each subject is numbered uniquely across the entire database.  Once assigned, the Subject 
Number must not be reused for any other subject and the Subject Number for that individual must not be 
changed, even if the subject is re-screened. If the subject fails screening for any reason, the reason will be 
entered into the End of Study eCRF. 
5.0 PATIENT RECRUITMENT AND SCREENING 
Approximately 12 evaluable subjects will be enrolled in this study.  Patients who fail apheresis or who do 
not receive vaccine due to other reasons will not be considered evaluable and will be replaced. 
Patients will be identified through the clinical practices of the investigator or sub-investigators and through 
referrals from outside hospitals and physicians.  The study will be posted on clinicaltrials.gov, and 
publicized via University of Pennsylvania or Abramson Cancer Center press releases. No direct-to-
patient advertising will be performed. 
Female patients of reproductive potential (women who have reached menarche or women who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 
24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral oophorectomy]) 
must have negative pregnancy test performed at the time of screening and within 30 days of the subject’s 
1st DC vaccine (Day 1). 
Patients must agree not to participate in a conception process while participating in this study (e.g., active 
attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if 
participating in sexual activity that could lead to pregnancy, the study patient must agree to use at least 
one reliable method of contraception during their participation in the study. 


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Acceptable birth control includes one of the following methods: 
•
Total abstinence (no sexual relations)
•
Female sterilization- surgical removal of both ovaries (woman's reproductive system that stores
and releases eggs for fertilization and produces female sex hormones), or tubal ligation (having
your “tubes tied”) at least six weeks prior to signing this consent.
•
Male sterilization (i.e. vasectomy)
•
Condoms (male or female) with or without a spermicidal agent
•
Diaphragm or cervical cap with spermicide
•
Intrauterine device (IUD)
•
Hormonal-based contraception
Patients who are not of reproductive potential (women who have been post-menopausal for at least 24 
consecutive months or have undergone hysterectomy, salpingectomy, and/or bilateral oophorectomy or 
men who have documented azoospermia) do not require the use of contraception.  Acceptable 
documentation of sterilization, azoospermia, and menopause is specified below: 
Written documentation by clinician or clinician’s staff through one of the following: 
1.
Physician report/letter
2.
Operative report or other source documentation in the patient record (a laboratory report of
azoospermia is required to document successful vasectomy)
3.
Discharge summary of sterilization procedure or hysterectomy, and/or salpingectomy,
oophorectomy
4.
Laboratory report of azoospermia
5.
Follicle stimulating hormone measurement elevated into the menopausal range
6.0 CONCOMITANT THERAPY 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by the 
patient within 14 days prior to eligibility confirmation by a physician-investigator will be recorded.  
Concomitant medications will continue to be collected at every visit thereafter, until the subject has 
discontinued participation in the study. Any additions, deletions, or changes of these medications will be 
documented.  
For all subjects, a 28-day washout period for any prior therapy (including adjuvant interferon) is required 
prior to the first vaccine dose.  This does not include adjunctive therapies (i.e. steroids, growth factors, etc); 
just prior therapies for their melanoma. 
High-dose systemic corticosteroids (i.e., prednisone >10 mg daily or equivalent) are prohibited. 
Low-dose systemic corticosteroids (i.e. prednisone ≤10 mg daily or equivalent) are permitted, as well as 
local steroids (inhaled or topical). 


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This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
7.0 INVESTIGATIONAL PRODUCTS 
7.1 
 Dendritic Cell Vaccines (mDC3/8 vaccines with and without influenza) 
7.1.1 Agent Description 
For this study, Dendritic Cell Vaccines (mDC3/8 vaccines) are named as follows: 
•
Priming Vaccine – hereafter identified as DC Vaccine #1
•
Booster Vaccines– hereafter identified as DC Vaccine #2 and DC Vaccine #3
Autologous dendritic cells pulsed with 12 (or fewer) melanoma tumor-specific peptides.  
For DC Vaccine #1 only, inactivated influenza vaccine is added to the DC preparation to 
provide a source of class II antigen to induce CD4+ helper T cells. For patients who are 
not HLA-A2 positive, the gp100 peptides are omitted since they will not bind.  Total 
number of peptides used will remain at a maximum of 12. 
Please refer to the Investigator’s Brochure for additional information. 
7.1.2 Mechanism of Action  
Induction of antigen-specific CD8+ T cells that function to promote tumor regression 
through multiple mechanisms including 1) direct tumor cytolysis requiring cell to cell 
contact; 2) secretion of cytokines such as Interferon-γ and tumor necrosis factor. 
Administration of cyclophosphamide 3-4 days prior to the first immunization will deplete 
regulatory T cells that serve to inhibit the generation of immunity. Multiple immunizations 
are necessary to elicit and sustain CD8+ T cell immunity.  
7.1.3 Pharmacodynamics/Kinetics 
Immunological monitoring is planned to assess the response to DC immunization. 
Regulatory T cell (Treg) counts will be assessed pre-treatment.  
7.1.4 Formulation 
Synthetic peptides (>98% purity) will be obtained commercially.   
7.1.5 Availability 
Cells used to manufacture the DC vaccines will be obtained by apheresis prior to 
administration of cyclophosphamide.  
7.1.6 Preparation 
The manufacture and release testing of the vaccine product will be performed by the 
Clinical Cell and Vaccine Production (CVPF) at the University of Pennsylvania. The 
vaccine product will be manufactured from the patients’ apheresis product. The vaccine 
products are not released from the CVPF until release criteria are met. 
Vaccine will be made starting from fresh peripheral blood mononuclear cells (PBMC) in 


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Protocol Version 9.08-10-2021
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accordance with the Investigator’s Brochure. DC preparations that fail to pass each release 
criteria will be held and not released for patient administration.  
7.1.7 Packaging and Labeling 
The investigational product will be released at room temperature in an infusion bag and 
affixed with a label containing information regarding the dose, the number of cells and 
volume and the following statements “FOR AUTOLOGOUS USE ONLY” and “Caution: 
New Drug-Limited by Federal Law to Investigational Use”.  In addition, the label will have 
at least two unique identifiers. 
7.1.8 Administration 
Dendritic cells (mDC3/8 Vaccine) will be administered intravenously at the following 
doses: 
•
DC Vaccine #1 (Priming Vaccine Dose):  maximum of 7.5-15 million DC per
peptide
•
DC Vaccine #2 and #3 (Booster Vaccine Doses): maximum of 1-5 million DC per
peptide x 2 doses administered ~ q6 weeks apart.
Please see Section 8.4 for additional details. 
7.1.9 Potential Toxicities 
Please refer to the Investigator’s Brochure for toxicity information. 
7.1.10 Return or Destruction of Study Drug 
The investigational product may need to be returned to the manufacturing facility for a 
variety of reasons, including but not limited to: 1) Mislabeled product; 2) Condition of 
patient prohibits infusion/injection, and 3) Subject refuses infusion. Any unused product 
will be returned to CVPF for freezing by CVPF personnel.  Final disposition of the 
investigational product must be documented appropriately.  
7.2 
Cyclophosphamide 
7.2.1 Agent Description 
 Cyclophosphamide is an FDA-approved chemotherapeutic agent. Cyclophosphamide is 
considered an investigational agent on this protocol since it is not the standard of care in 
this patient population and is not being used in accordance with its approved labeling. 
However, while administered for research purposes as part of this study, it will be prepared 
and infused in accordance with its approved package insert. Full details on its mechanisms 
of action and toxicity profiles can be found in the approved package insert. 


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Protocol Version 9.08-10-2021
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7.2.2 Receipt and Storage 
Commercial cyclophosphamide will be obtained through the site-designated research 
pharmacy for research purposes.  It will be stored according to the manufacturing 
instructions in the approved package insert. 
7.2.3 Premedication 
All patients receiving cyclophosphamide may be premedicated with an anti-emetic.  The 
choice of premedication will be left to discretion of the treating physician.  
Cyclophosphamide is associated with moderate to high emetic potential, and antiemetics 
are recommended to prevent nausea and vomiting. Combining NK1R antagonist (e.g. 
aprepitant or fosaprepitant) with 5-HT3 receptor antagonist (e.g. ondansetron) is 
recommended, but may be modified per investigator discretion and institutional standards. 
Glucocorticoids (e.g. dexamethasone) should be avoided as these agents may affect vaccine 
efficacy. 
7.2.4 Administration 
A single dose of 300 mg/m2 cyclophosphamide will be administered via intravenous 
infusion on Day -3 (+/- 1 day) prior to the first dendritic cell vaccine (mDC3/8).   
7.2.5 Potential Toxicities 
Please refer to the cyclophosphamide package insert for toxicity information.  The package 
insert describes the risks of cyclophosphamide when given as part of routine care.  We 
expect similar side effects when administered as part of this study.  
7.3 
Anti-PD-1 (Pembrolizumab) 
Pembrolizumab is FDA approved for the treatment of metastatic melanoma.  Beginning as early as 
14 days after the subjects’ last DC Vaccine, subjects will commence treatment with pembrolizumab 
(anti-PD-1 therapy) as per standard of care.  The timing of pembrolizumab administration will be 
at the discretion of the physician investigator. Treatment will be administered per the FDA 
approved package insert.  As administration and duration of treatment will be driven by routine 
care and not per protocol requirements, these drugs will not be supplied by the study and will be 
obtained commercially through the subjects’ insurance provider.  Please refer to the pembrolizumab 
package insert for toxicity information.  
8.0 STUDY PROCEDURES 
8.1 
On-study Biopsies 
Onstudy biopsies will be performed as follows: 
•
Post DC Vaccine Biopsy #1: Will occur after the subject’s last DC vaccine, and prior to
initiation of treatment with Anti-PD-1 therapy.
•
Post DC Vaccine Biopsy #2: 4 weeks (+/- 5 days) after the subject’s first dose of Anti-PD-
1 therapy.


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•
Post DC Vaccine Biopsy #3: 8 weeks (+/- 1 week) after the subject’s first dose of Anti-
PD-1 therapy.
Onstudy biopsies will only be performed in patients with accessible lesions.  This will be 
determined by the treating investigator.  
8.2 
Dendritic Cell (mDC3/8) Preparation 
After eligibility has been confirmed by a physician-investigator, subjects will undergo a large 
volume apheresis procedure (approximately 15-20 L volume) at the HUP Apheresis Unit according 
to standard procedures for autologous transplantation, to allow for a target of 1.5-2.0 x 1010 
mononuclear cells to be collected. The actual volume apheresis procedure to be performed will be 
at the discretion of the physician-investigator in consultation with transfusion medicine. The 
apheresis product will be transported to the CVPF manufacturing facility and manufactured in 
accordance with the current mDC3/8 Investigator’s Brochure.  
If the initial apheresis collection does not yield an adequate number of cells required for 
manufacturing all required DC Vaccines, the second study apheresis procedure (typically 
performed after the last DC Vaccine and prior to administration of Anti-PD-1 therapy) may be 
moved up to an earlier study timepoint to allow for required manufacturing. An approximate 
15 liter volume procedure will be performed, and the product processed as indicated in the 
Investigator’s Brochure.   
Cells remaining after manufacturing is complete may be banked for research purposes. 
8.3 
Treg Depletion 
Patients will return to the Hospital of the University of Pennsylvania to receive a single dose of IV 
Cyclophosphamide (300 mg/m2)  on Day -3 (+/- 1 day) prior to DC#1 dose, in order to deplete 
circulating Treg prior to Dose #1. Patients may receive premedication at the discretion of the 
treating physician. Only a single dose of cyclophosphamide is given to each patient during the 
initial treatment phase prior to DC vaccine #l.   
8.4 
Administration of Dendritic Cell Vaccines (mDC3/8 vaccines with and 
without influenza) 
A total of 3 DC vaccines will be administered, approximately 6 weeks apart (+/- 2 weeks) beginning 
on Day 1. The timing of the DC Vaccine Infusions will be calculated from the 1st DC Vaccine 
Infusion (i.e. Day 1, also known as Week 1). Thus, the 2nd DC Vaccine Infusion is planned for 6 
full weeks after Day 1/Week 1 at ~Day 43 (i.e. the end of Week 6 and the beginning of Week 7). 
Similarly, the 3rd DC Vaccine Infusion is planned for 12 full weeks after Day 1/Week 1 at ~Day 85 
(i.e. the end of Week 12 and the beginning of Week 13).  Vaccines cannot be administered until all 
toxicities > grade 2 have resolved to baseline.   
All infusions will take place at the Hospital of the University of Pennsylvania by a licensed 
Registered Nurse. Each DC vaccine is administered by intravenous infusion through either a 
peripheral venous line or a central venous line.  A macrodrip intravenous tubing will be used to 
infuse DC vaccine by gravity (i.e. no infusion pump will be used), therefore each infusion will take 
less than 15 minutes.  All subjects will have vital signs (including temperature, respiration rate, 
pulse, blood pressure, oxygen saturation) assessed prior to each infusion.  After the first infusion, 


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Protocol Version 9.08-10-2021
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subjects will be observed for 2 hours after the end of the infusion, with vital signs assessed every 
30 minutes (+/- 5 minutes) from the start of the infusion.  After each subsequent infusion, subjects 
will be observed for 30 minutes after the end of the infusion, with vital signs assessed every 30 
minutes (+/- 5 minutes) from the start of the infusion. If subjects develop temperature greater than 
38ºC, acetaminophen 650mg PO should be given and the PI notified the same day. After the 
required observation period is complete, subjects may be discharged to home from the treatment 
area.  
Administration of the DC Vaccine may be delayed for a number of reasons, including toxicity, 
investigator discretion, etc. Treatment delays of up to 21 days will be allowed. If administration of 
the next planned dose is delayed greater than 21 days, the patient will discontinue the study vaccine 
and will not be eligible to receive additional treatment on this protocol. Treatment delays should 
be to be kept to a minimum and every effort is to be made to maintain a planned schedule.  
8.5 
Immune Monitoring 
Starting on Day 1/Week 1 (DC vaccine #1) and weekly thereafter through Week 18 (~Day 120), 
up to four 10mL green top tubes (BD vacutainer sodium heparin tube, ~ 40 mL) will be obtained 
by venipuncture for immune monitoring analysis. After the Week 18 collection, the frequency of 
peripheral blood draws will shift to q3 weeks for up to12 additional weeks (i.e. at Week 21, Week 
24, Week 27, and Week 30). Sample collection will continue on this schedule, regardless of the 
timing of the 2nd and 3rd DC Vaccinations and any subsequent Anti-PD-L1 therapy.  Any missed 
sample collections must be documented appropriately.  These blood samples will be used for 
tetramer assay and determination of Treg cell counts. The blood samples will be transported to the 
Dr. Carreno’s laboratory (SPE 8-309, bays 305B-307B).  
Patients will also undergo two additional apheresis procedures to collect lymphocytes for functional 
laboratory assays, to determine immunity against the melanoma peptides, at the following 
timepoints:  
•
Apheresis #2:  Collected after the subject’s last DC Vaccine and prior to anti-PD-1 therapy
being administered.  Note: As per Section 8.2 above, this Apheresis Collection may be
moved up to an earlier study timepoint if deemed necessary for manufacturing purposes.
•
Apheresis #3 (Optional): Approximately 4-8 weeks after initiation of anti-PD-1 therapy
(Optional).
The additional apheresis procedures #2 and #3 noted above will be performed at the HUP Apheresis 
Unit according to standard procedures. At each timepoint, an approximate 15 liter volume apheresis 
procedure will be performed.  These cells will then be transported to Dr. Carreno’s laboratory for 
processing.   
Please refer to the Study Calendar in Section 10.0 for additional information related to study 
timepoints.  
8.6 
Assessment of Clinical Response 
Patients will undergo routine clinical monitoring, blood work and  physical examinations. RECIST 
1.1 criteria [56] will be used for tumor response assessment after the subject’s last vaccine dose. 
CT of the chest, abdomen, and pelvis is the preferred imaging modality for assessment. In certain 
instances, MRI scans or other imaging modalities may be performed at physician-investigator 
discretion. For cutaneous lesions, direct measurement is also acceptable and visible lesions should 


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Protocol Version 9.08-10-2021
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be photographed.  After initiation of Anti-PD-1 therapy, subjects will be assessed for clinical 
response according to routine care guidelines. Data from any response evaluations performed while 
the subject remains onstudy will be collected for research purposes. 
Please refer to the Study Calendar in Section 10.0 for complete details.  
8.7 
Anti-PD-1 Administration 
Beginning as early as 14 days after the subjects’ last DC Vaccine, subjects will commence treatment 
with pembrolizumab (anti-PD-1 therapy) as per standard of care.  The timing of pembrolizumab 
administration will be at the discretion of the physician investigator. Treatment with 
pembrolizumab will be administered per the FDA approved package insertand will not be driven 
by protocol requirements.   
During anti-PD-1 administration subjects will continue to have blood samples collected for immune 
monitoring purposes in accordance with Section 8.5, and will undergo apheresis and biopsy 
procedures for research purposes as outlined above.  
If a subject dose not receive pembrolizumab per routine care post-DC Vaccine, either at the 
physician-investigator’s discretion or per subject decision, the subject will complete their End of 
Study Treatment Visit as scheduled and continue to have their immune monitoring samples 
collected per protocol.  However, the subject would not undergo the Post-Anti-PD-1 Therapy Visit 
#1 or Visit #2.  The subject would then complete the End of Study visit once immune monitoring 
sample collection is completed per protocol requirements.  
9.0 POTENTIAL TOXICITY AND DOSE MODIFICATIONS 
Any toxicities of grade 2 or higher, regardless of attribution/expectedness, should be reported immediately 
to the Principal Investigator.  Additional vaccines cannot be administered until all toxicities > grade 2 have 
resolved to baseline.  
9.1 
Dose Limiting Toxicity 
Is defined as any of the below events determined to be at least possibly related to the dendritic cell 
vaccines (mDC3/8 vaccine): 
•
Any Grade 3 or greater hematological and non hematological toxicities
•
Any Grade 3 or greater allergic reaction
•
Any Grade 3 or greater autoimmunity that involves vital organ (heart, kidneys, brain,
eye, liver, colon and adrenal gland).
If a subject experiences a DLT, they will be discontinued from additional study treatment.  
Subjects discontinued from study treatment due to a DLT will continue to be followed per the 
Study Calendar in Section 10.0 until the End of Study visit, and for adverse events per Section 
13.1.  Dose-limited toxicities will be confirmed by the Sponsor Medical Director.  The Medical 
Director will also assess the impact of dose-limiting toxicities on subsequent enrollment/ 
treatment activity.  In the event of a DLT and treatment discontinuation, immune monitoring 
blood samples will continue to be collected until the EOS visit. Please refer to Section 13.7 for 
study stopping rules.   


DC Vaccine for Melanoma 
Protocol Version 9.08-10-2021 
10.0 STUDY CALENDAR 
Tests and 
Observations 
Signed infonned consent 
Tumor Biopsy" 
Medical Histo1y 
Physical Examination 
ECOG Perfonnance 
Status 
Vital Sign Assessment" 
Apheresis 
Cyclophosphamide 
Dendritic Cell 
V a.ccination 
Routine Anti-PD-1 
Thera.ov 
Tumor measurements' 
CBC, CMP1, LDH 
PTIPTT 
Immune monitoringv 
Pregnancy test 
Screening/ 
Enl"Ollment,.. 
X 
Pre-
Treatment 
(C 14 days 
prior to 1st 
DC 
Vacciner 
X-------------------------X 
X 
X 
X 
X 
X 
X 
Xb
xg 
Xh
XU 
X 
X 
X 
Xd 
xe 
xe 
Cyclo-
phosphamide 
Day -3 (+/- 1 
day) 
xi 
Page 19 of 38 
DC Vaccination Visits (Every 6 
Post-DC Vaccine Follow-up 
weeks +I- 2 weeks)" 
End of Study 
Treatment Visit 
Post Anti-PD-
Post Anti-PD-
End of 
DC 
DC 
DC 
(~10-28 
1 Therapy-
1 Therapy-
Study 
Vaccine 
Vaccine 
Vaccine 
Days.After Last 
Visit #1 
Visit #2 
VisitP 
#1 
#2 
#3 
DC Vaccine and 
( 4 weeks after 
(8 weeks afte1· 
(~Week 30 
(Priming 
(Booster 
(Booster 
P1ior to 
initiation of 
initiation of 
Post-DC 
Vaccine) 
Vaccine) 
Vaccine) 
Initiation of 
Anti-PD-I 
Anti-PD-I 
Vaccine 
Anti-PD-I 
Therapy +/- 5 
Therapy +/- 1 
#1) 
Day 1 
~Day 43 
~Day 85 
Therapy)s 
days)t 
week)t 
(Week 1) 
(+/- 14d) 
(+/- 14d) 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk
Xk
Xk
X 
Xb,c
xr
X'1 
xn 
xn 
xo -----------------------------------------------------------------xo
X 
xm ________________________________________ X 
X 
X 
X 
X:! 
Xd 
Q3 weeksd 
XP 
AE assessment i 
X ------------------------------------------------------------------------------------------------------------------------------------ Xi 
Concomitant Medications 
X 
X -------------------------------------------------------------------------------------------------------------------------------------- X 
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania. Do not disclose or use except as authorized in writing by the study sponsor. 


DC Vaccine for Melanoma 
Protocol Version 9.08-10-2021 
Page 20 of38 
DC Vaccination Visits (Every 6 
Post-DC Vaccine Follow-up 
weeks +I- 2 weeks)" 
End of Study 
Pre-
Treatment Visit 
Post Anti-PD-
Post Anti-PD-
Treatment 
Cyclo-
DC 
DC 
DC 
(~10-28 
1 Therapy-
1 Therapy-
Tests and 
Screening/ 
( 14 days 
phosphamide 
Vaccine 
Vaccine 
Vaccine 
Days.After Last 
Visit #1 
Visit #2 
Observations 
Enl"Ollment,.. 
prior to 1st 
Day -3 (+I-1 
#1 
(Priming 
#2 
#3 
DC Vaccine and 
( 4 weeks after 
(8 weeks afte1· 
(Booster 
(Booster 
Survival 
DC 
day) 
P1ior to 
initiation of 
initiation of 
Vacciner 
Vaccine) 
Vaccine) 
Vaccine) 
Initiation of 
Anti-PD-I 
Anti-PD-I 
Anti-PD-I 
Therapy +/-5 
Therapy+/-1 
Dayl 
~Day 43 
~Day 85 
Therapy)s 
days)
t 
week)
t 
(Week 1) 
(+/-14d) 
(+/-14d) 
a. Please refer to Section 8.1 for additional details. Perfonned in patients with accessible lesions as determined by the treating investigator.
b. To obtain mononuclear cells for DC generation. Apheresis #1 will be performed with an approximate volume collection of 15-20 liters ~7 days prior to the
first DC vaccine. If the initial apheresis collection does not yield an adequate number of cells required for manufacturing all required DC Vaccines, the
second study apheresis procedure (typically perfonned after the last DC Vaccine and prior to adrninistration of Anti-PD-1 therapy) may be moved up to an
earlier study timepoint to allow for required manufacturing. An approximate 15 liter volume procedure will be performed, and the product processed as
indicated in the Investigator's Brochure.
c. To obtain mononuclear cells for illllllune monitoring. Apheresis #2 will be performed after DC vaccine #3 and prior to adrninistration of anti-PD-1 therapy at
the End of Study Treatment Visit. Please refer to Section 8.5 for additional details.
d. Immune monitoring studies will be drawn in l0mL green top tubes (BD vacutainer tube). At screening, up to four l0mL green top tubes will be collected.
Starting on Week 1/Day 1 (DC vaccine # 1) and weekly thereafter through Week 18 ( ~Day 120), up to four 1 0mL green top tubes ( ~40 mL total) will be
drawn for immune monitoring analysis. After the Week 18 collection, the frequency of peripheral blood draws will shift to q3 weeks for up to 12 additional
weeks (i.e. at Week 21, Week 24, Week 27, and Week 30). Sample collection will continue on this schedule, regardless of the tirning of the 2nd and 3rd DC
Vaccinations and any subsequent Anti-PD-1 Therapy. Any missed sample collections must be documented appropriately. Please see Section 8.5 for
additional details.
e. Females of childbearing potential. A serum or urine pregnancy test will be accepted. A pregnancy test must be performed within 30 days prior to DC Vaccine
#1 (Day 1).
f.
Apheresis #3 ( optional) will be performed~ 4-8 weeks after initiation of anti-PD-1 therapy. Please refer to Section 8.5 for additional details.
g. Must be completed within 28 days prior to physician-investigator confirmation of eligibility.
h. CT scans do not have to be repeated at pre-treatment as long as screening CT scans were within 28 days of the 1st DC vaccine.
1. Please see Sections 7.2 and 8. 3 for additional details.
j.
Collection of AEs will begin at the time of the first apheresis procedure (Apheresis # 1) and continue until subject discontinuation or the End of Study Visit.
Please refer to Section 13.1 for additional information.
CONFIDENTIAL 
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End of 
Study 
VisitP 
(~Week 3 0
Post-DC 
Vaccine 
#1) 
X 


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k.
Vital sign assessments include temperature, respiration rate, pulse, blood pressure, and oxygen saturation.  Vital signs will be assessed prior to each infusion.
1st DC Vaccine Infusion: Subjects will be observed for 2 hours after the end of the infusion, with vital signs assessed every 30 minutes (+/- 5 minutes) from
the start of the infusion. Subsequent DC Vaccine Infusions: Subjects will be observed for 30 minutes after the end of the infusion, with vital signs assessed
every 30 minutes (+/- 5 minutes) from the start of the infusion.
l.
Comprehensive metabolic panel including Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline
phosphatase, ALT (SGPT), AST (SGOT)
m. Response Follow-up: After initiation of Anti-PD-1 therapy, subjects will be assessed for clinical response according to routine care guidelines.  Patients who
are removed from therapy for reasons other than progressive disease will be followed according to standard of care procedures until disease progression.  Patients
who discontinue study therapy in the absence of progressive disease to pursue alternative therapies will also be followed according to standard of care procedures
until disease progression.  Data from any response evaluations performed while the subject remains onstudy will be collected for research purposes.
n. Please see Section 8.4 for additional details.
o. Beginning as early as 14 days after the subject’s last DC vaccine, subjects will commence treatment with Pembrolizumab (Anti-PD-1) as per standard of care.
The timing of pembrolizumab administration will be at the discretion of the physician investigator.   Treatment will be administered per the FDA approved
package insert and will not be driven by protocol requirements.
p. The end of study visit will occur when the last immune monitoring blood sample is collected ~ 30 weeks after the 1st DC Vaccine (Day 1). If the subject is
prematurely discontinued for any reason (e.g. Investigator discretion, Subject withdrawal of consent, etc), this must be documented appropriately and an End
of Study Visit should be performed at the time of discontinuation.
q. Biopsy to be collected after the last DC vaccine dose and prior to beginning Anti-PD-1 therapy.
r. Please refer to Sections 8.6 and 11 for additional information on response assessments.
s. The End of Treatment Visit will occur ~10-28 days after the last DC Vaccine.  However this visit and associated study procedures must also occur prior to
administration of Anti-PD-1 therapy.  Anti-PD-1 therapy may commence as early as 14 days after the subject’s last DC Vaccine.
t.
If a subject dose not receive pembrolizumab per routine care post-DC Vaccine, either at the physician-investigator’s discretion or per subject decision, the
subject will complete their End of Study Treatment Visit as scheduled and continue to have their immune monitoring samples collected per protocol.  However
the subject would not undergo the Post-Anti-PD-1 Therapy Visit #1 or Visit #2.  The subject would then complete the End of Study visit once immune monitoring
sample collection is completed per protocol requirements.
u. Must be performed within 14 days prior to physician-investigator confirmation of eligibility.
v. Study timepoints will be calculated from the 1st DC Vaccine Infusion (i.e. Day 1, also known as Week 1). Thus, the 2nd DC Vaccine Infusion is planned for 6
full weeks after Day 1/Week 1 at ~Day 43 (i.e. the end of Week 6 and the beginning of Week 7).   Similarly, the 3rd DC Vaccine Infusion is planned for 12
full weeks after Day 1/Week 1 at ~Day 85 (i.e. the end of Week 12 and the beginning of Week 13).  This same principle applies to the timing/identification of
immune monitoring sample collection.
w. Tests/procedures used to evaluate the subject’s eligibility to participate must be performed prior to physician-investigator confirmation of eligibility and
within 28 days prior to physician-investigator confirmation of eligibility unless otherwise specified.  Tests/procedures performed for screening/enrollment
which also fall within the 14 day window required for Pre-Treatment evaluations may be used to fulfill this additional study requirement and do not need to
be repeated unless clinically indicated.


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11.0 CRITERIA FOR RESPONSE (RECIST Criteria v1.1) 
11.1 Tumor Measurement 
Measurable disease:  the presence of at least one measurable lesion.  If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
Measurable lesions: lesions that can be accurately measured in at least one dimension with the 
longest diameter ≥2.0 cm.  With a spiral CT scan, the lesion must be ≥1.0 cm in at least one 
dimension. 
Non-measurable lesions: all other lesions, including small lesions (longest diameter < 2.0 cm with 
conventional techniques or <1.0 cm with spiral CT scans) and other non-measurable lesions. These 
include: bone lesions; leptomeningeal disease; ascites; pleural/pericardial effusion; inflammatory 
breast disease; lymphangitis cutis/pulmonis; abdominal masses that are not confirmed and followed 
by imaging techniques; and cystic lesions. 
All measurements should be recorded in metric notation, using a ruler or calipers.  All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes).  For the case of skin lesions, documentation by color photography including 
a ruler to estimate the size of the lesions is recommended. 
11.2 Baseline Documentation of Target and Non-target Lesions 
All measurable lesions up to a maximum of 10 lesions representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longer diameter) and 
their suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required and these lesions should be followed as 
“present” or “absent.” 


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11.3 Response Criteria 
11.3.1 Evaluation of Target Lesions 
Complete response (CR)−disappearance of all target lesions. 
Partial response (PR)−at least a 30% decrease in the sum of the LD of the target lesions 
taking as reference the baseline sum LD. 
Progression (PD)−at least a 20% increase in the sum of the LD of the target lesions taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions. 
Stable disease (SD)−neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum LD since the treatment started. 
11.3.2 Evaluation of Non-target Lesions 
Complete response (CR)−disappearance of all non-target lesions and normalization of 
tumor marker level. 
Non-complete response (non-CR)/non-progression (non-PD)−persistence of one or more 
non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. 
Progressive disease (PD)−appearance of one or more new lesions.  Unequivocal 
progression of existing non-target lesions.  Although a clear progression of non-target 
lesions only is exceptional, in such circumstances, the opinion of the treating physician 
should prevail and the progression status should be confirmed later on by a review panel 
(or principal investigator). 
11.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general, the patient’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
Target 
lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 


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CONFIDENTIAL 
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deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
11.5 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
studies that should be performed no less than 4 weeks after the criteria for response are first met. 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study 
entry at a minimum interval of 8-12 weeks. 
12.0 EARLY WITHDRAWAL OF SUBJECTS 
Subjects who enroll but do not receive DC Vaccine #1 will be prematurely discontinued from the study, 
will not be followed (with the exception of monitoring of adverse events felt to be related to research 
procedures), and will be replaced in the study.  Reasons for premature discontinuation prior to receipt of 
DC Vaccine #1 may include, but are not limited to the following: 
•
Screen failures
•
The judgment of the principal investigator that the patient is too ill to continue if this occurs
prior to the vaccine dose.
•
Pregnancy
•
Technical difficulties are encountered in the manufacturing process that preclude generation of
a vaccine dose that meets all Quality Control criteria.
•
If a subject develops a condition that precludes treatment after eligibility confirmation by
physician-investigator but before administrative of the vaccine dose. This will be done at the
judgment of the PI, and could include for example, the occurrence of an intercurrent illness,
significant and rapid progression of malignancy requiring alternative treatment, or a serious
adverse event.
•
Patient withdraws consent
•
Termination of the study
Patients may also be discontinued from Protocol Therapy for any of the following reasons: 
•
Patient withdraws consent
•
The PI decides to remove the patient from the study (i.e. for non-compliance with the protocol
or rapid clinical progression requiring urgent therapeutic intervention).
•
Termination of the study
•
Patients who develop DLT (as defined in Section 9.1)
•
Patients who develop an allergic reaction to the dendritic cell vaccine (mDC3/8 vaccines).
•
Pregnancy
If a subject is discontinued from Protocol Therapy for any reason other than withdrawal of consent, they 
will remain in protocol follow-up for 30 days after the last mDC3/8 Vaccine to monitor for any potential 


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CONFIDENTIAL 
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adverse events.  During this 30 day follow-up period, immune monitoring samples will continue to be 
collected and subjects may be treated per routine care at the discretion of their treating physician.  
13.0 SAFETY AND ADVERSE EVENTS 
13.1 Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Intercurrent illnesses or injuries should be 
regarded as adverse events. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
•
fatal
•
life-threatening
•
requires or prolongs hospital stay
•
leads to a persistent or significant disability or incapacity or substantial disruption of the
ability to conduct normal life functions
•
a congenital anomaly or birth defect
•
an important medical event
Note that hospitalizations that meet the following criteria should not be reported as serious 
adverse events: 
•
Routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition, such as preplanned study visits and preplanned hospitalizations
for study procedures or treatment administration
•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent
•
Social reasons and respite care in the absence of any deterioration in the patient’s general
condition
Note: Treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious 
adverse event.   
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.  They may jeopardize the patient, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result-in patient hospitalization, or intensive treatment of bronchospasm in an 
emergency department would typically be considered serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. 


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Unanticipated Adverse Device Effect 
Unanticipated adverse device effect means any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare 
of subjects. 
Unexpected adverse events 
An adverse event is considered unexpected if the event, and the severity (grade) and/or frequency 
of the event, is not described in the investigator brochure or protocol.  Please refer to the 
investigator brochure for additional detail related to severity and/or frequency of a particular 
event. 
Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable 
possibility that an event was caused by an investigational product, intervention, or research-
required procedures.  For the purposes of this study, "reasonable possibility" means there is 
evidence to suggest a causal relationship.  The relationship of the event to the study will be 
classified as possibly related, probably related, and definitely related. 
•
Possibly Related: There is some evidence to suggest a causal relationship; however, other
factors may have contributed to the event.
•
Probably Related: There is evidence to suggest a causal relationship, and the influence of
other factors is unlikely.
•
Definitely Related: There is clear evidence to suggest a causal relationship, and other
possible contributing factors can be ruled out.
Adverse Event Reporting Period 
For this study, collection of AEs will begin at the time of the first apheresis procedure 
(Apheresis #1) and continue until subject discontinuation or the End of Study Visit.  
If a subject is taken off study within 30 days of study treatment, any event that is determined to be 
probably or definitely related regardless to time at which it occurs after infusion(s), will be reported 
to the Sponsor Medical Director for assessment. 
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present at the start of the Adverse Event Reporting Period. 
All clinically significant abnormalities should be recorded as a preexisting condition on the medical 
history eCRF.  During the course of the study, a preexisting condition should be recorded as an 
adverse event if the frequency, intensity, or the character of the condition worsens.  Preexisting 
conditions that improve should also be recorded appropriately. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
•
The laboratory abnormality is not otherwise refuted by a  repeat  test  to  confirm the
abnormality
•
The abnormality suggests a disease and/or organ toxicity
•
The abnormality is of a degree that requires active management; e.g. change of dose,


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CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event, it is 
not necessary to separately record the lab/test result as an additional event. Laboratory 
abnormalities that do not meet the definition of an adverse event, should not be reported as adverse 
events. Whenever possible, a diagnosis, rather than a symptom should be provided (i.e. anemia 
instead of low hemoglobin).   
13.2 Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at each study visit. 
Patients will be monitored by medical histories, physical examinations, and blood studies to detect 
potential toxicities from the treatment.  If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, life-threatening, and death, corresponding to Grades 1-5, will be 
used whenever possible. Subjects will be monitored by medical histories, physical examinations, 
and blood studies to detect potential toxicities from the treatment. 
At each contact with the subject, the investigator must seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events also may be detected 
when they are volunteered by the subject during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments. Information on all adverse events should 
be recorded in the source documentation.  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be grouped 
under one diagnosis. To the extent possible, adverse events should be recorded as a diagnosis and 
symptoms used to make the diagnosis recorded within the diagnosis event.  Do not list symptoms 
separately if a diagnosis can be assigned.  The safety team may require events be reported separately 
if they occur as SAEs (or in the context of a SAE) even if they can also be considered a constituent 
of another AE. 
All adverse events occurring during the adverse event reporting period (defined in Section 13.1 
above) must be recorded.  Adverse events that begin in Primary Follow-up and are ongoing at the 
time the subject enters the Post-DC Vaccine Surveilliance phase of the study will continue to be 
followed until: a) the adverse event resolves; b) the subject discontinues participation (i.e. End of 
Study); or c) there is a change in the adverse event that would normally require the event be 
captured as a new event (i.e. change in attribution). Please refer to the CRF Completion Guidelines 
(CCG) for specific instructions on data entry. 
As much as possible, each adverse event should be evaluated to determine: 
1.
The severity grade (CTCAE Grade 1-5)
2.
Its duration (start and end dates)
3.
Its relationship to the study treatment- [Reasonable possibility that AE is related: No
(unrelated/ not suspected) or Yes (a suspected adverse reaction)].  If yes (suspected)- is the
event possibly, probably or definitely related to the investigational treatment?
4.
Expectedness to study treatment- [Unexpected- if the severity and/or frequency is not
described in the investigator brochure or protocol].


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5.
Action taken with respect to study or investigational treatment (none, dose adjusted,
temporarily interrupted, permanently discontinued, unknown, not applicable)
6.
Whether medication or therapy taken (no concomitant medication/non-drug therapy,
concomitant medication/non-drug therapy)
7.
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 13.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy 
is given, this action should be recorded.  Once an adverse event is detected, it should be followed 
until its resolution or until it is judged to be permanent, and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
study treatment, the interventions required to treat it, and the outcome.   
Adverse events that occur concurrently with the progression of malignancy but that are not related 
to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as an adverse 
event as described above.  Progression of malignancy resulting in death should be reported as a 
serious adverse event.  
Serious adverse events that are still ongoing at the end of the adverse event reporting period must 
be followed to determine the final outcome.  Any serious adverse event that occurs after the adverse 
event reporting period and is considered to be possibly related to the study treatment or study 
participation, should be promptly recorded and reported. 
13.3 Reporting of Serious Adverse Events 
Every SAE and UADE, regardless of suspected causality, occurring during the adverse event 
reporting period defined in Section 13.1 must be reported to the Sponsor Team within 24 hours of 
learning of its occurrence. The original SAE notification may take place by email to meet the 24 
hour reporting window.   
Within 3 business days of initial knowledge of the event, the investigator must submit a complete 
SAE form to the Sponsor along with any other diagnostic information that will assist the 
understanding of the event.  The Investigator will keep a copy of this SAE Form on file at the study 
site.   
New or follow-up information on SAEs should be promptly reported as updates become available. 
At a minimum follow-up SAE Forms should be submitted: 
•
Within 1 week of ICU admission or any life-threatening event
•
Within 2 weeks of hospital discharge
Follow-up information should be submitted as an amendment to the initial SAE form, and should 
include both the follow-up number and report date.  The follow-up information should describe 
whether the event has resolved or continues, if there are any changes in assessment, if and how it 
was treated, and whether the patient continued or withdrew from study participation.    
Report serious adverse events by email to: 
Attention: Clinical Safety Manager or designee 
Center for Cellular Immunotherapies 
University of Pennsylvania 


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Protocol Version 9.08-10-2021
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
At the time of the initial notification, the following information should be provided: 
•
Study identifier
•
Subject number
•
A description of the event
•
Date of onset
•
Current subject status
•
Whether study treatment was
discontinued
•
The reason the event is classified as
serious
•
Investigator assessment of the
association between the event and study
treatment
•
Expectedness relative to investigational
product(s)
13.3.1 Investigator Reporting: Local Regulatory Review Committees 
Report events to local regulatory review committees per institutional requirements. 
13.4 Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to protocol sponsor within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.  If a pregnancy occurs on study, this will be reported as an SAE 
using an SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
13.5 Protocol Exceptions/Deviations 
Exception: 
A one time, intentional action or process that departs from the IRB-approved study protocol, 
intended for one occurrence. If the action disrupts the study progress, such that the study design or 
outcome (endpoints) may be compromised, or the action compromises the safety and welfare of 
study subjects, advance documented approval from the Regulatory Sponsor and local regulatory 
review committees per institutional guidelines is required.  Approval from the Regulatory Sponsor 
must be received prior to submission to local regulatory review committees for approval. 
Deviation: 
A one time, unintentional action or process that departs from the approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on 
the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the 
safety and welfare of the subjects, the deviation must be reported to the Regulatory Sponsor within 
10 business days of PI knowledge, and to local regulatory review committees per institutional 
guidelines. Acknowledgement from the Regulatory Sponsor must be received prior to submission 
to local regulatory review committees.   


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Protocol Version 9.08-10-2021
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Other deviations should be appropriately documented per site policies/procedures (such as a subject 
missing a visit is not an issue unless a critical/important treatment or procedure was missed and 
must have been done at that specific time).  
Include the following information on the Sponsor supplied exception/deviation form:  protocol 
number, subject study number, comprehensive description of the exception/deviation from the 
protocol, rationale, and corrective and preventative action plan (deviations only).  Ensure all 
completed exception/deviation forms are signed by the Principal Investigator (or physician sub-
investigator) and submitted to the Sponsor Project Manager for review.    
Attention: Sponsor Project Manager 
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
Once approval of the exception request or acknowledgement of the deviation has been granted by 
the Regulatory Sponsor, the exception or deviation will be submitted to all applicable committees 
for review and approval/acknowledgement per institutional guidelines.  
13.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at the clinical 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above.  Medical monitoring will include a regular assessment of the number and 
type of serious adverse events. 
13.7 Study Stopping Rules 
This trial will be paused if: 
•
Any death that may be related to the investigational product.
•
DLT is observed in 2 out of the first 2 subjects, 3 out of the first 4 subjects, 4 out of the first 7,
5 out of the first 10, and 6 at any time.
The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other government 
agencies as part of their duties to ensure that research subjects are protected. 
14.0 STATISTICAL CONSIDERATIONS 
Approximately 12 evaluable patients will be enrolled in this study.  Patients who fail apheresis or who do 
not receive vaccine due to other reasons will not be considered evaluable and will be replaced.  
The primary end point of the study is to determine the post-vaccine immune response based on measuring 
increased numbers of peptide-specific CD8 T cells as calculated by the tetramer assay. For each peptide, 
the tetramer assay is performed on blood samples obtained at the indicated time points. Data are presented 
as the percentage of CD8+ T cells positive for tetramer binding based on gating variables set using the 
iMASC reagent kit (Beckman Coulter). The lower limit of detection (LLD) is 0.03% based on the 
acquisition of 100,000 gated events in the lin-CD8+ gate. The HIV gag HLA-A*0201 restricted peptide 
(SLYNTVATL) is used as the non-binding control peptide. Each sample is stained with the HIV gag 
tetramer and the number of HIV gag positive CD8+ T cells is subtracted from each experimental point (ref 
24). The mean and SD at baseline is obtained for each patient. Based on our prior experience, the expected 


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This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
analytical CV (standard deviation/mean) is 10%. A positive tetramer response is defined as an increase 
greater than 3SD above the baseline value. For each gp100 peptide, the proportions of tetramer response 
(positive or negative) and the associated 90% exact confidence intervals (CI) will be reported for each time 
point. With 12 patients, the width of the 90% exact CI will be no more than 25% away from the observed 
proportions. Tetramer counts (percentage of CD8+ T cells positive for tetramer binding) are expected to be 
approximately Gaussian on the original or a transformed scale (e.g., log transformation).  Linear mixed 
models will be used to describe the change in counts by time, dose and the time by dose interaction and 
pattern over time will be examined graphically.  Dose is treated as a fixed effect as the doses to be 
administered cover the range about which conclusions will be drawn.  We will explore whether Time should 
be treated as a random effect, as the time points represent a sample from an ongoing process.  In addition, 
clustered logistic regression will be used to model the probability of tetramer positive versus negative by 
time, dose and time by dose interaction.  These models are intended to be descriptive, and no preliminary 
data exist with which estimate longitudinal trends, so no power calculation is attempted.    
The primary endpoint will also include evaluating the safety and tolerability of the mature dendritic cell 
vaccine using proportions and confidence intervals. Adverse events will be tabulated by grades and body 
system.    
Additional correlative assays will be performed (Elispot and Cr51 release); however, these data will be not 
be used to determine the primary end point but be used as surrogate assays for the tetramer assay to evaluate 
the functionality of gp100 peptide induced CD8+ T cells. These assays will be performed using CD8+ T 
cells from baseline and post-vaccination blood samples. A positive elispot assay is defined as an increase 
greater than 3 SD above the baseline value. A positive Cr51 assay is defined an increase in specific lysis > 
15% above background at effector: target ratio of 5:1.  
For the secondary objective, clinical response rate will be computed with 90% CI. Time to progression 
(TTP) will be described by Kaplan-meier method and median survival time and the associated 90% CI will 
be reported. TTP is defined as time from the first DC dose administration to date of first documented disease 
progression. Patients without disease progression will be censored at time of last disease evaluation. 
Patients who die without evidence of progression will be censored at date of death. Regulatory T cells 
(Treg) are defined as CD4+CD25+foxP3+ (triple positive) cells. At the indicated time points, the percentage 
of Treg cells is determined by 3 color flow cytometry. The depletion of Treg is defined as follows [(Treg 
baseline – Treg nadir)/ Treg baseline x 100= % depletion] and will be analyzed as a continuous variable.    
15.0 DATA HANDLING AND RECORDKEEPING 
15.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following: 
•
What protected health information (PHI) will be collected from subjects in this study
•
Who will have access to that information and why
•
Who will use or disclose that information
•
The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.   For subjects that have revoked authorization to collect or use PHI, attempts 


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should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
15.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents. Examples of these original documents, and data records include: 
hospital  records,  clinical  and  office  charts,  laboratory notes,  memoranda,  patients’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, patient files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
The investigator must maintain source documents for each subject in the study, consisting of case 
and visit notes (hospital or clinical medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
recorded on the eCRFs must be traceable to source documents in the patient’s file. The investigator 
must also keep the original signed informed consent form, and a signed copy must be given to the 
patient. 
15.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All entries will be entered into an electronic 
data capture system (EDC). The Principal Investigator is responsible for assuring that the data 
entered into eCRF is complete, accurate, and that entry and updates are performed in a timely 
manner.  
15.4 Records Retention 
It is the Investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
may be retained for a longer period if required.   
16.0 STUDY MONITORING, AUDITING, AND INSPECTING 
16.1 Study Monitoring Plan 
This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.  
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will 
assure that submitted data are accurate and in agreement with source documentation; verify that 
investigational products are properly stored and accounted for; verify that subject consent for study 
participation has been properly obtained and documented; confirm that research subjects entered 
into the study meet inclusion and exclusion criteria; and assure that all essential documentation 


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required by Good Clinical Practices (GCP) guidelines are approp1iately filed. At the end of the 
study, Monitors will conduct a close-out visit and will advise on storage of study records and 
disposition of unused investigational products. 
The investigator will allocate adequate time for such monitoring activities. The Investigator will 
also ensure that the monitor or other compliance reviewer is given access to all the above noted 
study-related documents and study related facilities (e.g. phrumacy, diagnostic laborato1y, etc.), 
and has adequate space to conduct the monitoring visit. 
16.2 
Auditing and Inspecting 
The investigator will permit study-related monitodng, audits, and inspections by the IRB, the 
Sponsor, government regulato1y bodies, and University compliance groups. The investigator will 
ensure the capability for inspections of applicable study-related facilities ( e.g. phrumacy, diagnostic 
laboratory, etc.). 
Pa1ticipation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance offices. 
The Plincipal Investigator must notify the Sponsor in real-time if an audit/inspection notification 
is received. 
17.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standru·ds of Good Clinical PI·actice (FDA 
Title 21 prut 312 and International Conference on Ha1monization guidelines), applicable government 
regulations and Institutional reseru·ch policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal presc1iptions, for fo1mal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement of this study. 
All subjects for this study will be provided a consent fo1m describing this study and providing sufficient 
info1mation for subjects to make an inf01med decision about their pruticipation in this study. This consent 
fo1m will be submitted with the protocol for review and approval by the IRB for the study. The 
formal consent of a subject, using the !RB-approved consent f01m, must be obtained before that subject is 
submitted to any study procedure. 
The protocol is listed on clinicaltrials.gov. 
18.0 STUDY FINANCES 
18.1 Funding Source 
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania. Do not disclose or use except as authorized in writing by the study sponsor. 


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18.2 
Conflict of Interest 
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All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research. 
18.3 
Patient Stipends or Payments 
There is no patient stipend/payment for pruticipation in this protocol. 
19.0 PUBLICATION PLAN 
Publication of the results ofthis t.Iial will be governed by University of Pennsylvania policies. Neither the 
complete nor any part of the results of the study caITied out under this protocol will be published or passed 
on to any third pruty without the consent of the Sponsor. Any investigator involved with this study is 
obligated to provide the Sponsor with complete test results and all data de1ived from the study. 
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania. Do not disclose or use except as authorized in writing by the study sponsor. 


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Protocol Version 9.08-10-2021
CONFIDENTIAL 
This protocol is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
20.0 REFERENCES 
1: Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 
Jan-Feb;66(1):7-30. doi: 10.3322/caac.21332. Epub 2016 Jan 7. PubMed PMID: 26742998. 
2: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, 
Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, 
Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, 
Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, 
Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma.  
N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 
Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. PubMed PMID: 20525992; 
PubMed Central PMCID: PMC3549297. 
3: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, 
Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann 
KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, 
Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. 
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed 
after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, 
open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. doi: 
10.1016/S1470-2045(15)70076-8. Epub 2035 Mar 18. PubMed PMID: 25795410. 
4: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, 
Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, 
Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, 
Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, 
Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, 
Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice 
chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, 
controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 
10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23. PubMed PMID: 26115796. 
5: Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R,  
Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D,  
Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J,  
Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved 
survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 
2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5. PubMed 
PMID: 21639808; PubMed Central PMCID: PMC3549296. 
6: Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski  
D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, 
Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, 
Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D.  
Improved overall survival in melanoma with combined dabrafenib and trametinib. N  
Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16. 
PubMed PMID: 25399551. 
7: Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, 
Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, 


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Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, 
Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant 
melanoma (coBRIM): updated efficacy results from a randomised, double-blind, 
phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. doi: 
10.1016/S1470-2045(16)30122-X. Epub 2016 Jul 30. PubMed PMID: 27480103. 
8: Huncharek M, Caubet JF, McGarry R. Single-agent DTIC versus combination 
chemotherapy with or without immunotherapy in metastatic melanoma: a 
meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res. 2001 
Feb;11(1):75-81. PubMed PMID: 11254118. 
9: Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, 
Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III 
multicenter randomized trial of the Dartmouth regimen versus dacarbazine in 
patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. PubMed 
PMID: 10561349. 
10: Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, 
Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose 
recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis 
of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 
Jul;17(7):2105-16. PubMed PMID: 10561265. 
11: Morton DL, Eilber FR, Joseph WL, Wood WC, Trahan E, Ketcham AS. Immunological 
factors in human sarcomas and melanomas: a rational basis for immunotherapy. Ann  
Surg. 1970 Oct;172(4):740-9. PubMed PMID: 5272336; PubMed Central PMCID: 
PMC1397284. 
12: Golub SH, Morton DL. Sensitisation of lymphocytes in vitro against human 
melanoma-associated antigens. Nature. 1974 Sep 13;251(5471):161-3. PubMed PMID: 
4421563. 
13: Kawakami Y, Eliyahu S, Jennings C, Sakaguchi K, Kang X, Southwood S, Robbins 
PF, Sette A, Appella E, Rosenberg SA. Recognition of multiple epitopes in the 
human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with  
in vivo tumor regression. J Immunol. 1995 Apr 15;154(8):3961-8. PubMed PMID: 
7706734. 
14: Kawakami Y, Robbins PF, Wang RF, Parkhurst M, Kang X, Rosenberg SA. The use 
of melanosomal proteins in the immunotherapy of melanoma. J Immunother. 1998 
Jul;21(4):237-46. Review. PubMed PMID: 9672845. 
15: Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens 
recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 
2014 Feb;14(2):135-46. doi: 10.1038/nrc3670. Review. PubMed PMID: 24457417. 
16: Marincola FM, Hijazi YM, Fetsch P, Salgaller ML, Rivoltini L, Cormier J, 
Simonis TB, Duray PH, Herlyn M, Kawakami Y, Rosenberg SA. Analysis of expression 
of the melanoma-associated antigens MART-1 and gp100 in metastatic melanoma cell  
lines and in in situ lesions. J Immunother Emphasis Tumor Immunol. 1996 


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May;19(3):192-205. PubMed PMID: 8811494. 
17: Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, 
Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, 
Kawakami Y, Seipp CA, Einhorn JH, White DE. Immunologic and therapeutic 
evaluation of a synthetic peptide vaccine for the treatment of patients with 
metastatic melanoma. Nat Med. 1998 Mar;4(3):321-7. PubMed PMID: 9500606; PubMed 
Central PMCID: PMC2064864. 
18: Linette GP, Zhang D, Hodi FS, Jonasch EP, Longerich S, Stowell CP, Webb IJ, 
Daley H, Soiffer RJ, Cheung AM, Eapen SG, Fee SV, Rubin KM, Sober AJ, Haluska FG. 
Immunization using autologous dendritic cells pulsed with the melanoma-associated 
antigen gp100-derived G280-9V peptide elicits CD8+ immunity. Clin Cancer Res. 
2005 Nov 1;11(21):7692-9. PubMed PMID: 16278389. 
19: Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter 
S, Thompson J, Greenberg PD, Roederer M, Davis MM. Characterization of 
circulating T cells specific for tumor-associated antigens in melanoma patients.  
Nat Med. 1999 Jun;5(6):677-85. PubMed PMID: 10371507. 
20: Skipper JC, Kittlesen DJ, Hendrickson RC, Deacon DD, Harthun NL, Wagner SN, 
Hunt DF, Engelhard VH, Slingluff CL Jr. Shared epitopes for HLA-A3-restricted 
melanoma-reactive human CTL include a naturally processed epitope from 
Pmel-17/gp100. J Immunol. 1996 Dec 1;157(11):5027-33. PubMed PMID: 8943411. 
21: Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, 
Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K,  
Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, 
Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G,  
Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie 
K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner 
SN, Lander ES, Getz G, Chin L, Garraway LA. Melanoma genome sequencing reveals 
frequent PREX2 mutations. Nature. 2012 May 9;485(7399):502-6. doi: 
10.1038/nature11071. PubMed PMID: 22622578; PubMed Central PMCID: PMC3367798. 
22: Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, 
Ly A, Lie WR, Hildebrand WH, Mardis ER, Linette GP. Cancer immunotherapy. A 
dendritic cell vaccine increases the breadth and diversity of melanoma 
neoantigen-specific T cells. Science. 2015 May 15;348(6236):803-8. doi: 
10.1126/science.aaa3828. Epub 2015 Apr 2. PubMed PMID: 25837513; PubMed Central 
PMCID: PMC4549796. 
23: Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen 
processing machines. Cell. 2001 Aug 10;106(3):255-8. Review. PubMed PMID: 
11509172. 
24: Thurner B, Haendle I, Röder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender 
A, Maczek C, Schreiner D, von den Driesch P, Bröcker EB, Steinman RM, Enk A, 
Kämpgen E, Schuler G. Vaccination with mage-3A1 peptide-pulsed mature, 
monocyte-derived dendritic cells expands specific cytotoxic T cells and induces 


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regression of some metastases in advanced stage IV melanoma. J Exp Med. 1999 Dec  
6;190(11):1669-78. PubMed PMID: 10587357; PubMed Central PMCID: PMC2195739. 
25: Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, 
Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J. 
Immune and clinical responses in patients with metastatic melanoma to CD34(+) 
progenitor-derived dendritic cell vaccine. Cancer Res. 2001 Sep 1;61(17):6451-8.  
PubMed PMID: 11522640. 
26: Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr 
Opin Immunol. 2014 Apr;27:1-7. doi: 10.1016/j.coi.2013.12.005. Epub 2014 Jan 14.  
Review. PubMed PMID: 24413387. 
27: Hoon DS, Foshag LJ, Nizze AS, Bohman R, Morton DL. Suppressor cell activity 
in a randomized trial of patients receiving active specific immunotherapy with 
melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res. 1990 Sep 
1;50(17):5358-64. PubMed PMID: 2143687. 
28: Steinman RM. Decisions about dendritic cells: past, present, and future. Annu 
Rev Immunol. 2012;30:1-22. doi: 10.1146/annurev-immunol-100311-102839. Epub 2011 
Nov 17. Review. PubMed PMID: 22136168. 
29: Lesokhin AM, Callahan MK, Postow MA, Wolchok JD. On being less tolerant: 
enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists  
of T cell activation. Sci Transl Med. 2015 Mar 25;7(280):280sr1. doi: 
10.1126/scitranslmed.3010274. Review. PubMed PMID: 25810313. 
30: Carreno BM, Becker-Hapak M, Huang A, Chan M, Alyasiry A, Lie WR, Aft RL, 
Cornelius LA, Trinkaus KM, Linette GP. IL-12p70-producing patient DC vaccine 
elicits Tc1-polarized immunity. J Clin Invest. 2013 Aug;123(8):3383-94. doi: 
10.1172/JCI68395. Epub 2013 Jul 11. PubMed PMID: 23867552; PubMed Central PMCID:  
PMC3726168. 
31: Weber J et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.  N Eng J 
Med 2017; 377: 1824-1835. PubMed PMID: 28891423. 

ICF_001.pdf: 
University of Pennsylvania 
Research Participant 
Informed Consent Form and HIPAA Authorization 
 
 
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DC Vaccine Melanoma 
 
Protocol Title: 
Mature Dendritic Cell Vaccination Against Mutated Antigens in 
Patients With Advanced Melanoma 
Principal 
Investigator: 
Gerald Linette, MD, PhD 
Department of Medicine 
University of Pennsylvania School of Medicine  
Philadelphia, Pennsylvania 19104 
 
Emergency Contact: 
Ask for Oncologist on Call 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you have melanoma that has 
spread (metastatic) beyond its primary biopsy site in the skin. Your participation is voluntary 
which means you can choose whether or not you want to participate.  
 
 
Before agreeing to participate in this research study, it is important that you read the following 
explanation of the proposed procedures and how long you will be in the study. This document 
describes the purpose, procedures, benefits, risks, discomforts and precautions of the study. It 
also describes the alternative procedures that are available to you and your right to withdraw 
from the study at any time.   
 
We are asking that you participate in a research study.  When you take part in a research study, 
you and the study doctor must follow a set plan called the “study protocol.” This is different 
from receiving care outside of the research study.  When you receive medical care from your 
own doctor, he or she develops a plan of care just for you and your individual needs. When 
participating in the research study, the study doctor usually cannot adjust the plan for you as he 
needs to follow the study protocol.  However, this research plan includes steps to follow if you 
are not doing well.  It is important to understand that a clinical trial is an experiment. By its 
nature, that means the answer to the research question is still unknown. 
 
Please take time to read the following information carefully. You may wish to discuss it with 
your family, friends, and your personal doctor (i.e., your family doctor or primary care doctor). If 
you have any questions, you may ask your study doctor and/or the research team for more 
information. Take time to decide whether or not you wish to take part. If you decide to 
participate, you will be asked to sign this form.  If you decide to participate, you can change your 
mind at any time and withdraw from the study without giving a reason.  
 
 
What is the purpose of this study? 
This is a research study designed to evaluate the effects (good and bad) of giving you a vaccine 
against your advanced melanoma. Although there are treatments that can control your disease for 


 
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a period of time, there are no treatments that have been shown to cure melanoma once it has 
spread to distant sites in the body (such as the lung and liver). The purpose of this study is to 
investigate a method of using dendritic cells (a kind of white blood cell) as a vaccine to stimulate 
your own immune system to react to your melanoma cells. 
 
Dendritic cells will be obtained from your blood through apheresis, a process very similar to 
donating blood. The isolated dendritic cells will be grown in the laboratory and exposed to 
proteins that are present on your melanoma tumor cells. After exposure, the dendritic cells will 
be collected and injected back into your body. 
 
You will receive one dendritic cell vaccination through a vein about every 6 weeks for a total of 
3 doses, along with low dose cyclophosphamide before your first vaccine dose only. 
Cyclophosphamide is a drug that may increase the immune response, if given in a low dose, by 
elimination of a certain type of immune cell called a regulatory T cell. 
 
The DC vaccines are experimental and have not been approved by the Food and Drug 
Administration (FDA).  Similar DC vaccines are being tested in other ongoing human studies.  
Cyclophosphamide has been approved by the FDA for other types of cancer, but not for 
treatment of melanoma. It is considered investigational for this study. 
 
After completion of the last vaccine dose, a tumor biopsy will be performed in subjects with 
accessible tumors to assess the T cell infiltration in the tumor. Afterwards, anti-PD-1 therapy 
(pembrolizumab) will be administered as standard of care treatment in order to allow the T cells 
to treat the melanoma. Additional blood studies and tumor biopsies will provide information 
regarding the ability of your immune system to recognize and eliminate the melanoma. 
 
How long will I be in the research study? 
You will be in the study for approximately 8 months.  Every 3 months after your treatment is 
complete, you will return to the clinic for a physical exam, blood tests, and scans.  You will be 
followed for a minimum of 30 days after the last dose of the vaccine that you receive.  
 
How many people will participate? 
It is expected that about 12 adults will participate in this study at the University of Pennsylvania. 
 
What am I being asked to do? 
Procedures 
Prior to taking part in this study, you and your doctor should discuss the current standard 
treatments for your cancer. The study doctor will ask you to read and sign this Informed Consent 
Form after all of your questions have been satisfactorily answered.  
Screening 
Once you decide to participate, you will have to undergo a screening process to determine if you 
are able to join the study.  In order to determine if you are eligible to participate in this study, 


 
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you will be required to undergo the following tests and evaluations: 
   
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
• Research blood to check your immune system (about 2 ¾ tablespoons) 
Yes 
 
• Medical History, physical exam, and vital signs  
• CT scan of your chest, abdomen, and pelvis. If the study doctor thinks it 
is necessary, you may have an MRI of your brain.  
• Baseline routine blood tests (about 1 ½ tablespoons)  
• Blood (about 1 teaspoon) or urine to test for pregnancy if you are female 
and able to bear children 
 
‒ The CAT (computerized axial tomography) scan, also known as the CT (computed 
tomography) scan, is an x-ray technique that produces a film representing a detailed 
cross section of body tissues and structures. The standard CT scan procedure is painless, 
noninvasive, and requires no special preparation. 
‒ An MRI (magnetic resonance imaging) scan uses radio waves and a magnetic field to 
take pictures of your brain or body.  
 
Once you have completed the screening visit, your study doctor will determine whether it is safe 
for you to enter the study or not.   
• Make sure you tell the study staff about any medications you are taking during the 
research study. This includes prescriptions drugs, over-the-counter medicines, natural or 
herbal medicines, alternative medicines and vitamins. This is very important.  
• Tell your study doctor or study staff if you have any unusual symptoms any time, even 
outside the visit period. 
 


 
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Pre-Treatment Phase 
The following procedures will occur prior to your first vaccination: 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
• You will undergo apheresis approximately 1 week prior to your DC 
vaccine infusion.  Apheresis will take place in the apheresis unit and 
is done to collect the cells that will be used to make the DC vaccine. 
‒ If we are unable to collect enough cells from this apheresis 
procedure to make all three vaccine doses, you will be asked to 
undergo another apheresis procedure during the treatment phase 
of this study. This will not require an additional procedure.  The 
post-vaccine apheresis procedure would be performed earlier to 
ensure enough cells are available to make the required doses. If 
there are any cells left over after making the required doses, 
these cells will be banked for research purposes.   
• An apheresis unit is a place where patients who need specific 
components of their blood removed from their bodies go to have this 
procedure performed.   This apheresis visit will take ~5 hours in total 
and the apheresis procedure will take ~ 4 hours to complete.  
• If the veins in your arms are not adequate for the procedure, a special 
apheresis catheter may be inserted into the large vein (intravenously 
or IV) in your neck for the collection. Placement of this IV catheter 
involves putting a small, short plastic tube in your vein. 
Yes 
The following procedures will be done before apheresis: 
• Review of current medical conditions, symptoms/side effects, and list 
of medications 
• Routine blood tests including how fast your blood clots (requires a 
blood draw of about 1 ½ tablespoons) 
• Blood (about 1 teaspoon) or urine to test for pregnancy if you are 
female and able to bear children 
• Vital signs 
• CT scan of your chest, abdomen, and pelvis 
 


 
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Cyclophosphamide 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
Cyclophosphamide (a drug) is given in a low dose one time about 3-4 
days before your first vaccine dose (but not before any other doses).    
Cyclophosphamide is given intravenously (through a vein in your arm) 
and you will receive anti-nausea medications and intravenous fluids 
before and after the cyclophosphamide. The entire visit will last about 4 
hours.  We want to see if the cyclophosphamide is an effective way of 
assisting your immune system in fighting the cancer.  
Yes 
• Review of current medical conditions and list of medications 
• Physical examination and vital signs assessments will be performed 
in accordance with the chemotherapy unit’s standard procedures 
 
Treatment and Primary Follow-up Phase 
 
Vaccination: 
Some of the vaccine infusions listed below may be delayed or canceled.  It is very 
important that you come in for all study-required visits, even if your infusions are missed 
or delayed. Your study doctor will determine whether or not it is appropriate for you to 
make up any missed infusions. 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
Three to four days after you have completed the low dose 
cyclophosphamide treatment, the first dose of your personalized dendritic 
cell vaccine will be given back to you through a vein (intravenously).  
Everyone on the study will receive three vaccine doses 6 weeks apart. Each 
vaccine infusion will take less than 15 minutes. 
 
After your first dose, you will need to remain in the clinic for 2 hours to be 
observed and have your vital signs monitored. After the second and third 
doses, you will need to stay in the clinic for 30 minutes to be observed.  
 
You will be allowed to go home after your infusion if you feel well and 
have not experienced unexpected reactions to the infusion. 
 
You will also be asked to undergo the following procedures: 
• Research blood- collected to check your immune system (about 2 ¾ 
tablespoons) 


 
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Part of Your 
Standard Medical 
Care 
Study Procedures 
Yes 
On the day you receive each vaccine dose, you will undergo the following 
procedures: 
• Review of current medical conditions and list of medications 
• Vital signs (temperature, blood pressure, heart rate, respiratory rate and 
blood oxygen levels)  
• Routine blood tests (about 1 ½ tablespoons)  
 
During Vaccination 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
• Blood for research analysis (including tests for immune responses 
generated by vaccine) will be collected. The maximum amount of 
blood that may be collected from you during any one of these visits 
will be about 4 ¼ tablespoons. Beginning on Day 1 of vaccination, 
blood is drawn weekly for 18 weeks. 
 
Post-Vaccination Visit (After the 3rd DC vaccine infusion and prior to receiving anti-PD-1 
therapy) 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
After your last dendritic cell treatment and prior to receiving anti-PD-1 
therapy as part of your routine care, you will undergo the following 
tests/procedures as part of your End-of-Study treatment visit.  This visit is 
targeted to occur about 10-28 days after your last DC vaccine.  However, 
it will depend on when the study doctor starts your anti-PD-1 therapy 
because it can begin as early as 14 days after your last DC vaccine.   
 
• Apheresis- this procedure will take place in the apheresis unit and is 
done to collect cells that will be used by investigators to determine 
your response to the vaccination.  
‒ This apheresis may be moved up to an earlier time point in the 
event that we are unable to collect enough cells from your first 
apheresis procedure to make all three of your DC vaccine doses. 
If there are any cells left over after making the required doses, 
these cells will be banked for research purposes.   
• CT scan of your chest, abdomen, and pelvis.  


 
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Part of Your 
Standard Medical 
Care 
Study Procedures 
• Tumor biopsy (for patients with accessible tumors) 
• The research blood draws (about 2 ¾ tablespoons) for the detection 
of immune responses will continue weekly for 18 weeks.  After 18 
weeks, these research blood draws (about 2 ¾ tablespoons) for the 
detection of immune responses will continue every three weeks for an 
additional 12 weeks (a combined total of 30 weeks). 
Yes 
• Review of current medical conditions, symptoms/side effects, and list 
of medications 
• Physical examination and vital signs assessments 
 
You will begin treatment with anti-PD-1 therapy (pembrolizumab) as part of your routine care 
as a way to further stimulate the immune response.  You will undergo the following 
tests/procedures: 
 
Part of Your 
Standard Medical 
Care 
Study Procedures 
No 
 
• Research blood (about 2 ¾ tablespoons) for the detection of immune 
responses weekly until 18 weeks after your first DC vaccine.  Then 
this same collection will continue every three weeks for another 12 
weeks (a combined total of 30 weeks).  
• Tumor biopsies (patients with accessible lesions)- approximately 4 
and 8 weeks after beginning anti-PD-1 therapy. 
• Apheresis (optional)- performed approximately 4-8 weeks after 
starting anti-PD-1 therapy. 
 
Yes 
• Routine disease assessments (including CT scans of your chest, 
abdomen and pelvis) 
 
If you and/or your study doctor decide that you will not begin treatment with anti-PD-1 therapy 
(pembrolizumab) as part of your routine care as a way to further stimulate the immune 
response, you will undergo the following procedure: 
 


 
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Part of Your 
Standard Medical 
Care 
Study Procedure 
No 
• Research blood (about 2 ¾ tablespoons) for the detection of immune 
responses weekly until 18 weeks after your first DC vaccine.  Then 
this same collection will continue every three weeks for another 12 
weeks (a combined total of 30 weeks).  
 
End-of-Study Visit  
Your participation in this study will end about 30 weeks after your first DC Vaccine infusion 
after all research blood for the detection of your immune response is complete.   
  
Follow-up 
After your end-of-treatment visit, you will be followed according to routine practice until your 
disease progresses. You may continue on anti-PD-1 therapy (pembrolizumab) as part of your 
standard of care if you and your doctor decide that it is helping your condition. 
 
Additional Research Samples: In the event something unexpected occurs during your 
participation in the protocol (for example a new side effect that has not been experienced by 
other participants), the research team may request additional blood be collected for research 
analysis. This is being done with the intention of evaluating the likely effects from the dendritic 
cells you have received.  The total amount of extra blood that will be collected from you will be 
3½ tablespoons of blood twice in one week.   
 
In addition, if you undergo a biopsy as part of your routine treatment while you are on study, a 
sample of this tumor tissue will be collected for research purposes.  
 
What are the possible risks or discomforts? 
The list of side effects below contains the most common side effects in the small number of 
people that have received the dendritic cells (approximately 17 adults as of August 2020).  This 
research may involve risks that are currently unforeseeable, so tell your doctor if you are 
experiencing any problems.  If you see a doctor other than your study doctor, please let them 
know that you are involved in a research study.   It is very important that you contact your study 
doctor immediately at any signs of fever or other new abnormal symptoms.  Treatment on this 
research study may have risks we do not know about and may require you to go into the hospital 
so the study team can monitor these side effects. 
 
Some risks described in this consent document, if severe, may cause death. 
 


 
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Risks of Melanoma Vaccine:  
Likely: skin rash, fatigue, nausea, pain 
 
Less Likely: rigors/chills, cough, skin changes, abnormal liver function tests which may cause 
jaundice (yellowing of the skin and eyes), diarrhea, anorexia (loss of appetite), headache, 
pruritis/itching, changes in your calcium and glucose (i.e. electrolyte) blood levels, changes in 
your blood counts which may increase your risk of infections 
 
Rare: uveitis (an inflammation of the middle layer of the eye), allergic reaction which can be 
serious. Symptoms may include swelling of the throat and difficulty breathing; rash or hives; 
itching or flushing of the skin. You will be closely monitored in the clinic and provided 
treatment if you develop any signs of allergic reaction. 
 
The decision to include you in this study is based on testing conducted in a research laboratory 
using tests that are not used for standard clinical care and therefore they are considered 
investigational.  
 
Risks of Cyclophosphamide: 
Likely: Nausea 
 
Less Likely: Vomiting, anorexia (loss of appetite), diarrhea, changes in your calcium and 
glucose (i.e. electrolyte) blood levels 
 
Rare: Blood in urine, low blood cell counts which may lead to infection, headache, facial 
flushing, and rash 
 
Risks of anti-PD-1 (pembrolizumab): 
Likely: fatigue, loss of appetite, shortness of breath, cough, itching of skin. 
 
Less Likely: pain in joint, fever, swelling of legs and/or feet, weakness, back pain, rash, stomach 
pain, loose or watery stools, constipation, vomiting, loss of skin color, anemia.  
 
Rare: Inflammation of kidneys leading to decreased urine output (nephritis); inflammation in 
lungs leading to shortness of breath (pneumonitis); inflammation of intestines leading to watery 
or loose stools (colitis); inflammation of pancreas leading to abdominal pain, tiredness, and 
elevated blood sugars (diabetes); inflammation of the thyroid gland leading to anxiety, 
irritability, trembling, weakness, sweating, weight loss (hyperthyroid); inflammation of brain 
including the pituitary gland leading to fatigue, weakness, headache, double vision, dizziness, 
change in menstrual cycles, muscle weakness, change in behavior, rapid heart rate 
(hypophysitis); inflammation of liver leading to fatigue, poor appetite, upset stomach, bleeding 
and bruising more easily, yellow eyes and skin, dark urine (hepatitis); inflammation of the skin 
leading to peeling, itching, and redness of the skin; inflammation of the nerves leading to pain, 
weakness, and tingling in the hands and feet that may spread to the legs, arms, and upper body 
leading to severe muscle weakness (neuropathy); inflammation of the muscles leading to pain or 
cramping (myopathy); inflammation in the eyes leading to redness, blurred or cloudy vision, 


 
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sensitivity to light, eye pain or see floaters (uveitis); infusion reaction leading to fainting or 
dizziness, weakness, low blood pressure, nausea, shortness of breath, cough, tongue swelling, 
rash, hives, itching, feeling cold, fever.  
 
Risks associated with blood draws (uncommon): 
Occasionally there are risks associated with blood draws such as bruising, swelling, black and 
blue marks, fainting and/or infection at the site.   You may also experience a decrease in 
hemoglobin and hematocrit (red blood cell number, called anemia) from having blood drawn 
frequently. Approximately 62 ¼ tablespoons (about 4 cups) of blood will be drawn for research 
purposes during this research study over the period of one year.  
 
Risks associated with intravenous (IV) apheresis catheter:   
Likely: Pain or discomfort at the catheter insertion site. 
 
Less Likely: Bleeding at the site, injury in the blood vessel, entrance of air into the vein 
(airembolus), and injury to the lung (pneumothorax). 
 
Rare: Infection of the blood stream, inflammation of the vein (phlebitis) and development of 
blood clots (thrombosis). 
 
Tumor Biopsy: 
A biopsy is an invasive test in which your cells and/or tissue are collected for examination. It 
involves the surgical removal of a small bit of tissue for examination. Your study doctor will 
explain this procedure to you in more detail, and you will be given a standard hospital consent 
form to sign detailing your specific type of biopsy prior to the procedure. 
 
Likely: 
• Pain 
• Discomfort 
• Soreness 
• Minor bleeding 
• Bruising 
 
Less likely: 
• Redness 
• Swelling 
• Bleeding 
 
Rare: 
• Bleeding, life threatening 
• Possible damage to adjacent organs 
• Drainage from the biopsy site 
• Abnormal wound healing 
• Fever 


 
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• Infection 
• Allergic reaction to the medication used to numb the skin over the biopsy site 
 
The collection of previously obtained tumor tissue, for research purposes, may result in using up 
or depleting all available tumor tissue.  This means that should you need the tissue for a future 
treatment decision, tissue may no longer be available and a biopsy may be needed. 
 
Risks associated with Apheresis (uncommon): 
Side effects that can occur during peripheral mononuclear cell collection include nausea, 
vomiting, fainting or dizziness, seizures, skin rash, hives, flushing (redness and warmness of the 
skin, usually the face), blood loss, and infection. Tingling of the lips, muscle cramping and, very 
rarely, changes in the heart rhythm can occur. These can be prevented or made milder by giving 
calcium supplements, either by mouth or in the vein, also called intravenous (IV). Very rarely, 
(less than 1 in 1,000 procedures), clotting may occur in the apheresis machine or in a patient and 
is potentially life-threatening. To reduce the risk of clotting, you will be given a drug called ACD 
(acid-citrate-dextrose). This drug may increase the risk of bleeding and may cause temporary 
tingling of the lips and limbs, muscle cramping, seizures, or changes in the heart rhythm. After 
the apheresis procedure you may experience temporary discomfort, including irritation, swelling 
or bruising at the place where the needle was inserted into your vein to collect the blood. 
Apheresis can also occasionally cause: nausea, vomiting, fainting, seizures, blood loss, infection, 
skin rash, flushing, hives, numbness and tingling, or swelling of your feet and ankles. 
 
Risks associated with radiation exposure: 
This research study involves exposure to radiation from CT scans.  Therefore, you will receive a 
radiation dose.  Some of these procedures may not be necessary for your medical care and will 
only occur as a result of your participation in the study.  At doses much higher than you will 
receive, radiation is known to increase the risk of developing cancer after many years.  At the 
dose you will receive, it is very likely that you will see no effects at all. 
 
Risks of Genetic Testing: 
Additional research performed using your blood and tissue samples may include genetic testing. 
Even without your name or other identifiers, your genetic information is unique to you. The 
researchers believe the chance that someone will identify you is very small, but the risk may 
change in the future as people come up with new ways of tracing information. 
 
There can be a risk in knowing genetic information. New health information about inherited 
traits that might affect you or your blood relatives could be found during a research study. Even 
though your genes are unique, you share some of the same genes with your blood relatives. 
Although we are not able to know all of the risks from taking part in research on inherited traits, 
we believe that the risks to you and your family are very low, because your samples will be 
coded. Research results will not be returned to you or your doctor.  
 
Very rarely health or genetic information could be misused by employers, insurance companies, 
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insurance companies may charge a higher rate based on this information. We believe the chance 
these things will happen is very small, but we cannot make guarantees. 
 
A federal law (Genetic Information Non-Discrimination Act, GINA) helps reduce the risk from 
health insurance or employment discrimination. The law does not include other types of misuse 
by life insurance or long-term care insurance. If you want to learn more about GINA, you can 
find information about it on the internet or ask the study staff. 
 
Reproductive Risks: 
The effects of dendritic cells on pregnancy and child development are unknown. Therefore, there 
could be serious harm to unborn children (or children who are breastfeeding) and it could also 
jeopardize the health of the mother.   
 
If you are capable of becoming pregnant, you will undergo a serum pregnancy test prior to entry 
into the research study and a urine or serum pregnancy test prior to the dendritic cell infusion. If 
you are found to be pregnant or breastfeeding at that time you will not be allowed to participate 
in the research study. 
 
If you are a female participant in the study and are capable of becoming pregnant, you MUST 
use at least one method of birth control during the entire time you participate in the study, 
including long-term follow-up. If you are male, you MUST use at least one method of birth 
control during the entire time you participate in order to avoid impregnating a female.   
 
Examples of medically acceptable birth control methods include any of the following:  
 
Female Birth Control Methods 
• Total abstinence (no sexual relations) 
• Female sterilization- surgical removal of both ovaries (woman's reproductive system that 
stores and releases eggs for fertilization and produces female sex hormones), or tubal 
ligation (having your “tubes tied”) at least six weeks prior to signing this consent.  
• Condoms with or without a spermicidal agent 
• Diaphragm or cervical cap with spermicide 
• A hormonal or non-hormonal intrauterine device (IUD) 
• Hormonal based contraception (including the birth control pill, vaginal rings, etc.) 
 
Male Birth Control Methods 
• Total abstinence (no sexual relations) 
• Male sterilization (i.e. vasectomy) 
• Condoms with or without a spermicidal agent 
 
If you do become pregnant or suspect you may be pregnant, you must tell the study doctor 
immediately and consult an obstetrician or maternal-fetal specialist. If you become pregnant 
while you are on this research study you will be taken off the research study. Your study doctor 
will follow your pregnancy until outcome to monitor your safety.   


 
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If you are a male participant and your partner becomes pregnant, you must tell the study doctor 
as soon as possible. Your partner will be asked to provide consent to follow their pregnancy until 
outcome for safety purposes. 
 
What are the benefits of this study? 
You may or may not benefit from being in this study. However, we hope that information 
learned from this study will help patients with melanoma in the future. 
 
What other treatment options are there? 
Before you decide whether or not to be in this study, your doctor will discuss the other options 
that are available to you. Instead of being in this study, you could: 
• get treatment or care for your cancer without being in a research study 
• take part in another research study 
• get no treatment 
• get comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not 
treat the cancer directly, but instead tries to improve how you feel. Comfort care 
tries to keep you as active and comfortable as possible. 
 
Will I have to pay for anything? 
The research study will cover the cost of research related tests, procedures and study visits. 
There is no cost for the investigational DC vaccines that you will receive during your 
participation. There will also be no cost to you for IV cyclophosphamide or its administration.  
 
As part of this study you will receive tests and procedures that are similar to what you would 
receive during routine clinical care of your condition. Your health plan/insurance company will 
be billed for some or all of these costs, and you will be responsible for any co-pays and 
deductibles that are normally required by your health plan/insurance. Not all insurance plans 
cover the costs associated with being in a study. Even if they do, you may be responsible for 
more out-of-pocket expenses, such as co-pays and deductibles, when there are more tests and 
procedures or more expensive tests and procedures involved in the study than if you were to 
receive routine clinical care outside the study. 
 
If you wish to know whether there are more tests and procedures or more expensive tests and 
procedures in the study, you should ask your study doctor. 
 
If you wish to know whether your insurance will pay, you should contact them directly, or 
request that a financial pre-certification be done before enrolling in this study. 
 
Will I be paid for participating? 
You will not be paid for being in this research study. 
 


 
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Who is funding this study? 
The National Cancer Institute (NCI) and the Parker Institute for Cancer Immunotherapy (PICI) 
are funding this research study. This means that the University of Pennsylvania is receiving 
payments from the NCI and PICI to support the activities that are required to conduct the study. 
No one on the research team will receive a direct payment or increase in salary from the NCI and 
PICI for conducting this study. 
 
What happens if I am injured or hurt during the research study? 
If you have a medical emergency during your participation on this study, you should go to the 
nearest emergency room.  You should contact the Principal Investigator or Emergency contact 
listed on page one of this form. You may also contact your own doctor, or seek treatment outside 
of the University of Pennsylvania.  Be sure to tell the doctor or his/her staff that you are in a 
research study being conducted at the University of Pennsylvania. Ask them to call the telephone 
numbers on the first page of this consent form for further instructions or information about your 
care. 
 
We will offer you the care needed to treat injuries directly resulting from taking part in this 
research.  We may bill your insurance company or other third parties, if appropriate, for the costs 
of the care you get for the injury, but you may also be responsible for some of them.  There are 
no plans for the University of Pennsylvania to pay you or give you other compensation for the 
injury.   
 
Financial compensation for such things as traveling, parking, lost wages, disability or discomfort 
due to injury is not available.   
 
You will not lose any of your legal rights when you sign this form. 
 
When is the research Study over? Can I leave the Research Study 
before it ends? 
This research study is expected to end after all participants have completed all visits, and all 
information has been collected.  Your participation in this research study may also be stopped at 
any time by your physician, the study Sponsor, study Funder or the Food and Drug 
Administration (FDA) without your consent because: 
• The Primary Investigator feels it is necessary for your health or safety.  Such an action 
would not require your consent, but you will be informed if such a decision is made and 
the reason for this decision.  
• You have not followed study instructions. 
• The Sponsor, Study Funder, the study Principal Investigator, or the Food and Drug 
Administration (FDA) has decided to stop the study. 
 
If you decide not to participate, you are free to leave the research study at any time.  Withdrawal 
will not interfere with your future care. 
 
 


 
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Who can see or use my information? How will my personal 
information be protected? 
We will do our best to make sure that the personal information obtained during the course of this 
research study will be kept private.  However, we cannot guarantee total privacy.  Your personal 
information may be given out if required by law.  Only the minimum necessary data will be 
provided to the people/entities named below and when possible participants will be identified 
with a unique study identification number. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. This 
study is being overseen by the Food and Drug Administration (FDA), who may also review your 
research records. 
 
Electronic Medical Records and Release of Study Related Information 
An Electronic Medical Record (EMR) is an electronic version of your medical chart within a 
health system. An EMR is simply a computerized version of a paper medical record. 
 
If you  have  never  received  care  within  Penn Medicine and  are  participating  in  a  
University  of Pennsylvania research study that uses Penn Medicine healthcare-related services, 
an EMR will be created for you for the purpose of maintaining any information produced for 
your participation in this research study.  The creation of this EMR is a requirement of your 
participation in this research study. In order to create your EMR, the study team will need to 
obtain basic information about you that would be similar to the information you would provide 
the first time you visit a hospital or medical facility (i.e. your name, the name of your primary 
doctor, the type of insurance you have). If you have been a patient at Penn Medicine in the past, 
information from your research participation will be added to your existing medical record. 
 
What may be placed in the EMR? 
Information related to your participation in the research (e.g., laboratory tests, notes from your 
physician, imaging studies, and clinical procedures, etc.) may be placed in your EMR maintained 
by Penn Medicine. 
 
Once placed in your EMR, your information may be accessible to appropriate Penn Medicine 
workforce members that are not part of the research team.  Information within your EMR may 
also be shared with others who are determined by Penn Medicine to be appropriate to have 
access to your EMR (e.g. health insurance company, disability provider, etc.). 
 
Penn Medicine also participates in automated information sharing through Health Information 
Exchanges (HIEs). HIEs securely share parts of your electronic health record, including research 
information, with other healthcare organizations involved in your care. This information is 
shared to improve the quality, safety and efficiency of your healthcare. To request that your 
health information not be shared through HIEs, please call 215-662-4484. 
 


 
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Will I, as a subject, have access to research related information within 
the EMR? 
The 21st Century Cures Act requires healthcare institutions to allow patients increased access to 
their electronic medical record. As part of your participation in this research, you will have 
access to research related information within your EMR through Penn Medicine’s patient portal 
– called MyPennMedicine (MPM). 
 
Results that may be placed in the medical record 
Your medical record may include results from laboratory tests, imaging studies, and clinical 
procedures, etc. (or any results that would have been placed in the medical record, regardless of 
research participation). Results placed in the medical record are part of the designated record set 
and you have a right to review these results per HIPAA regulations. 
 
Results that may not be placed in the medical record 
Results from biospecimen testing conducted in a laboratory that is not part of the HIPAA 
covered entity OR results from testing conducted in a non-CLIA certified laboratory (i.e., the 
results would not have been placed in the medical record as part of clinical care). 
 
Some information specific to this clinical research study may be shared with you in a delayed 
manner, shared with you at the end of the study, or not shared with you. Not sharing or delaying 
certain research information within your EMR may be necessary to protect the integrity of the 
trial results or for other reasons. 
 
Will I receive the results of research testing? 
Most tests done in research studies are only for research and have no clear meaning for your 
routine medical care. Research results will not be returned to you because they would not be 
relevant to your routine medical care. 
 
Will information about this study be available to the public? 
A description of this clinical trial will be available on http://www.clinicaltrials.gov. This website 
will not include information that can identify you. 
 
What information about me may be collected, used or shared with 
others? 
The following personal health information will be collected, used for research, and may be 
disclosed during your involvement with this research study: 
 


 
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• Name, address, telephone number, 
e-mail address, date of birth 
• Personal and family medical history, 
allergies; prior hospital 
admission/discharge information 
• Current and past medications or 
therapies 
• Medical record number 
• Information from a physical 
examination that generally also 
includes blood pressure reading, heart 
rate, breathing rate and temperature 
• Results of tests and procedures you will 
undergo during this research study as 
described in this informed consent form 
 
Why is my information being used? 
Your information is used by the research team to contact you during the research study. Your 
information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• evaluate and manage research functions. 
 
Where may my information be stored? 
Information related to your participation in clinical research will be contained in a clinical trial 
management system (CTMS). A clinical trial management system (CTMS) is used to register 
your information as a participant in a study. This allows for your research data to be entered and 
stored for the purposes of study operational and financial applications and other activities 
required as part of the conduct of the research. Once placed in the CTMS your information may 
be accessible to other authorized personnel at Penn Medicine that support research operations. 
Your information may be held in other research databases. 
 
Who may use and share information about me? 
The following individuals may use or share your information for this research study: 
• The Principal Investigator and the study team 
• Other authorized personnel at Penn Medicine and the University of Pennsylvania, 
including offices that support research operations. 
• Other research personnel with access to the databases for research and/or study 
coordination and as otherwise approved by the IRB. 
 
As part of your participation in this study, we may need to contact you via email to facilitate 
scheduling, send you appointment notes or send you information about your participation in the 
study.  Email communications are often not secure and may be seen by others as a result.  By 
agreeing to participate in this study, you accept this potential risk.  If you wish for us to use a 
different means to communicate with you during the course of the trial, please discuss this with 
the research team and alternative methods can be arranged. 
 


 
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Who, outside of Penn Medicine, might receive my information? 
• The funding sponsors, National Cancer Institute (NCI) and the Parker Institute for 
Cancer Immunotherapy (PICI), and its authorized agents  
• ExamOne – a company that may be used to provide in-home laboratory services as part 
of your participation in this study.   
 
Regulatory and safety oversight organizations 
• Government  representatives (including the Office for Human Research Protections) to 
complete federal or state responsibilities 
• The U.S. Food and Drug Administration 
• Your primary care physician if a medical condition that needs urgent attention is 
discovered 
• Information about your participation in this study may be documented in your health 
care records and be available to your health care providers who are not part of the 
research team. 
• The last four digits of your social security number may be used in hospital or University 
systems to track billing information for research procedures 
 
Once your personal health information is disclosed to others outside of Penn Medicine, it may no 
longer be covered by federal privacy protection regulations. 
 
The Principal Investigator or study staff will inform you if there are any additions to the list 
above during your active participation in the trial. Any additions will be subject to Penn 
Medicine procedures developed to protect your privacy. 
 
How long may Penn Medicine use or disclose my personal health 
information? 
Your authorization for use of your personal health information for this specific research study 
does not expire.  Your information may be held in a research database.  However, the School of 
Medicine may not re-use or re-disclose information collected in this research study for a purpose 
other than this research study unless: 
• You have given written authorization 
• The University of Pennsylvania’s Institutional Review Board grants permission 
• As permitted by law 
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the investigator for the research 
study. If you withdraw your permission, you will not be able to stay in this research study. 
 


 
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What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
What if new information becomes available about the study? 
During the course of this research study, we may find more information that could be important 
to you. This includes information that, once learned, might cause you to change your mind about 
being in the research study.  We will notify you as soon as possible if such information becomes 
available. In order to provide this information to you, you must provide your current address and 
telephone number to the study doctor and must update this information so that the research staff 
will be able to contact you to give you any new information learned from this research study in 
the future. 
 
What may happen to my information and samples collected on this 
study? 
As outlined above, you will have research samples (or specimens) collected as part of your 
participation in this study.    Depending on the type of specimen, these samples may be labeled 
with identifiable information. It is possible that your specimens may be used to establish 
products that could be patented, licensed, or sold, which could make money for others.  If this 
happens, there are no plans to tell you or provide financial compensation to you or your family.  
Most uses of biospecimens do not lead to commercial products or profit to anyone. 
 
Whole genome sequencing may be conducted on your samples as part of the planned study 
analysis. Whole genome sequencing involves analyzing your entire personal genetic code. Please 
refer to the risks section of the consent for the risks of genetic testing.   
 
Future Use of Data and Specimens 
Blood, remaining unmanufactured cells (from your apheresis collections), unused manufactured 
CAR T cells or other samples obtained from you while you are participating in this study will be 
stored indefinitely and used for research purposes by researchers/collaborators at the University 
of Pennsylvania. These samples may be used for future research, to conduct new laboratory 
studies, or be sent to other researchers for collaborative studies, including researchers at for-
profit agencies.  There are no plans to tell you about any of the specific testing that will be done.  
This future research may include genetic testing and/or whole genome sequencing. Whole 
genome sequencing involves analyzing your entire personal genetic code. It is possible that you 
may have chosen not to participate in these future research studies, if you had been approached 
for participation. Please refer to the risks section of the consent for the risks of genetic testing.   
 
You will not be given the results of any future testing performed on your samples.   
 
You will also not directly benefit from any future research with your specimens. However, it is 
possible this research may help others by improving our understanding of your disease and 
possible treatments. 


 
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There is also a risk of breach of confidentiality (unintentional release of your information). We 
will do our best to make sure that this does not happen. However, we cannot guarantee total 
privacy. We will protect your confidentiality during storage and sharing by using coded 
specimens.  Coded means that all direct identifiers (name, initials, medical record numbers) have 
been removed.  However, your samples will still include your unique subject identification 
number and may be linked back to information/data that was collected from you as part of this 
study (i.e., disease response, safety, diagnosis, etc).  However, the information shared with other 
researchers will also be coded.  It will not be possible for future researchers to identify you.  The 
future use of your samples only applies to the samples collected on this study. 
 
As part of your consent to participate in this study, you are agreeing to the use of your samples as 
outlined above.  If you have any questions about the storage of your samples, or would like to 
withdraw your permission to use and store these samples at any time, please contact the study 
doctor, Dr. Gerald Linette at 
.  However, any samples that have already been 
used for research purposes will be retained.  After all research analysis on these samples is 
complete, these samples may be destroyed at any time without notice. 
 
Genomic Data Sharing 
Genomic studies examine genetic differences in the entire human genome (the complete set of 
human genes) and the association between these genetic differences and health conditions.  As 
this is an NIH-funded study, we are required to send this data to a NIH designated data 
repository that includes all kinds of genomic data from studies funded by the NIH.  
 
The aim of collecting this information is to look for genetic connections that may: 
• Increase the likelihood of getting a certain disease (such as asthma, cancer, diabetes, heart 
disease or mental illness) or a condition (such as high blood pressure or obesity) 
• Affect the progress of a certain disease or condition 
• Affect treatments (medicines, etc) that work for certain diseases in some people, but not 
others 
 
The data that is shared will not include any direct identifiers (such as your name), and will be 
coded.  The key to this code, which links your data back to your identifiers, will not be shared.  
The repository is a controlled-access repository.  Controlled-access data is only available to 
researchers and companies who apply to the NIH. The NIH will review data requests for 
scientific merit and for methods to protect data and methods to ensure data will be used for the 
approved purpose.  We will not know what types of health-related research will be done with the 
data that are sent to the repository.  
 
There may be risks to your privacy and the privacy of your relatives from storing your 
information in the repository.  Although the NIH takes measures to protect privacy, we do not 
know how likely it is that your identity could be re-connected with your genetic and health 
information. If your genetic information were re-identified, personal information about you, your 
health and your disease could become known to others.  This could present unknown risks.  


 
Informed Consent Form and HIPAA Authorization 
Mature Dendritic Cell Vaccination Against Mutated Antigens in Patients With Advanced Melanoma 
 
 
UPCC 17616 Main ICF V13.08-10-2021 
21 of 22 
 
Current federal law will help protect you from genetic discrimination in health insurance and 
employment. Please also refer to the risks of the consent for the risks of genetic testing for 
additional information.  
 
There is no direct benefit to you from placing your genetic information in the repository.  
However, allowing researchers to study your genetic information may lead to a better 
understanding of how genes affect health, therefore may help other people in the future.   
We may also be required to share the results of genetic research, known as genomic summary 
results (GSR), at the time of publication or presentation.  If required, these results will be placed 
in a special database.  Depending on the publication/presentation, this database may be restricted 
to limited individuals who receive appropriate permissions to view the data, but this may also 
become publicly available.  The data that is shared will not include any direct identifiers (such as 
your name), and will be coded.  The key to this code, which links your data back to your 
identifiers, will not be shared.   
 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research participant? 
If you have questions, concerns or complaints regarding your participation in this research study 
or if you have any questions about your rights as a research participant, you should speak with 
the Principal Investigator listed on page one of this form.   If a member of the research team 
cannot be reached, or you want to talk to someone other than those working on the research 
study, you may contact the Office of Regulatory Affairs with any concerns or complaints at the 
University of Pennsylvania by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. This means that you 
have read the consent form, your questions have been answered, and you have decided to 
volunteer.  Your signature also means that you are permitting Penn Medicine and the University 
of Pennsylvania to use your personal health information collected about you for research 
purposes within our institution. You are also allowing Penn Medicine and the University of 
Pennsylvania to disclose that personal health information to outside organizations or people 
involved with the operations of this research study. 
 


 
Informed Consent Form and HIPAA Authorization 
Mature Dendritic Cell Vaccination Against Mutated Antigens in Patients With Advanced Melanoma 
 
 
UPCC 17616 Main ICF V13.08-10-2021 
22 of 22 
 
A copy of this consent form and Research Participant HIPAA Authorization describing your 
confidentiality and privacy rights for this research study will be given to you. By signing this 
document you are permitting the School of Medicine to use and disclose personal health 
information collected about you for research purposes as described above. 
 
 
 
 
Name of Participant 
 Signature of Participant 
 Date 
 
 
 
 
 
  
 
 
Name of Person Obtaining 
Consent 
 Signature of Person Obtaining 
Consent  
 
Date