Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma

Article (PDF Available)inJournal of immunotherapy (Hagerstown, Md.: 1997) 33(8):817-27 · October 2010with21 Reads
DOI: 10.1097/CJI.0b013e3181ecccad · Source: PubMed
Abstract
High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.
Changes in Dendritic Cell Phenotype After a New
High-dose Weekly Schedule of Interleukin-2
Therapy for Kidney Cancer and Melanoma
Steven E. Finkelstein,*
w
Timothy Carey,* Ingo Fricke,
z
Daohai Yu,
y
Dawn Goetz,JMegan Gratz,J
Mary Dunn,*
z
Patricia Urbas,
z
# Adil Daud,# Ronald DeConti,# Scott Antonia,* **
Dmitry Gabrilovich,*
z
and Mayer Fishman*
ww
Summary: High-dose intravenous interleukin-2 (IL-2) therapy
(14 doses/course, 2 courses/cycle) for metastatic melanoma or
kidney cancer induces infrequent, although major responses. In this
trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h
between doses, 5 doses/course, 4 courses at weekly intervals/cycle)
of high-dose IL-2, in which we inserted more planned breaks while
maintaining high cumulative dose delivery, and investigated the
relationship between dendritic cells (DC) and response to
treatment. Target dose delivery was attained: median IL-2 cum-
ulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1
and 2, respectively). Major responses were observed in patients
with kidney cancer (n=20; 3 complete and 2 partial responses) and
melanoma (n=16; 1 partial response). Adverse events appeared
comparable with those typically associated with high-dose IL-2.
From this data set, we introduce the hypothesis-generating
observation that patients who had more favorable outcomes had
high pretreatment DC-to-myeloid-derived suppressor cell (MDSC)
ratios, similar to the ratio observed in healthy individuals.
However, even in patients with the most favorable outcome, after
treatment, there were IL-2-induced changes in the DC-to-MDSC
ratio, specifically increases in MDSCs. This modified IL-2 schedule
is a feasible option, with a more uniform dose delivery over the
treatment cycle, a similar toxicity profile, and observed complete,
durable response in patients with renal cancer. Pretreatment
assessment of DC phenotypic or maturational status may be a
starting point to predicting response to high-dose IL-2 cytokine
immunotherapy in patients with melanoma and kidney cancer.
Key Words: immunotherapy, dendritic cells, IL-2, weekly
5-in-a-row schedule
(J Immunother 2010;33:817–827)
Interleukin-2 (IL-2) immunotherapy has demonstrated
utility in patients with melanoma and renal cell carci-
noma.
1,2
In patients with renal cell cancer, data from
randomized trials have shown modest therapeutic advan-
tage in favor of high-dose versus low-dose schedules, with
a better frequency of durable, complete responses.
3,4
The
evolving experience with IL-2 is still dominated by the
hallmarks of high intensity of the treatment and low
frequency but high durability of responses. In renal cell
carcinoma, patient selection strategies, incorporating clini-
cal and tumor features are evolving both for targeted drugs
and for IL-2; McDermott provides a contemporary discus-
sion.
5
In melanoma, variations of IL-2 combinations
including biochemotherapy and maintenance therapy repre-
sent different directions than the Food and Drug Adminis-
tration (FDA)-approved schedule described below.
6
With the FDA-approved high-dose IL-2 therapy (a 14-
bolus, 5-d schedule), the later doses are typically associated
with a higher frequency of major and cumbersome side
effects, resulting in intensive care admission, pressor
support, asthenia, capillary leak, and edema.
7
This stan-
dard high-dose bolus schedule also requires hospitalization
for about 6 days at a time.
1,2,7
Key limitations of this
schedule (besides the frequency of major response) include
that most treatment courses are terminated by an adverse
event, and that across a cohort of patients, the cumulative
dose delivery is heterogeneous. These features suggest that
if a combination treatment with IL-2 plus another drug
were developed, it would be hard to discern, for an
individual patient, whether dose-limiting toxicities were
attributable to the new drug. The rationale for initiation of
this trial were to try to maintain the same or better dose
delivery, to have fewer events of courses terminated early
because of toxicity, and to have a high and uniform
percentage of planned dose delivery.
We hypothesized that a schedule that emphasized the
earlier doses and one that provided more frequent planned
breaks would preserve or improve planned dose delivery,
and make a more uniform dose delivery across the treated
group. This could be advantageous for the development of
combination treatment.
For this study, we introduced a modified dose schedule
of a weekly 5-in-a-row course. This format extends over
several weeks, and so resembles some previously published
outpatient low-dose IL-2 treatment regimens, which typically
used a daily dose over a 5-day schedule, and then 2 days
off.
3,4,8
Specifically, our modified high-dose schedule had
5 doses at 8-hour intervals, over 2 days, and then 5 days off,
Copyright r2010 by Lippincott Williams & Wilkins
Received for publication February 9, 2010; accepted May 3, 2010.
From the *Immunotherapy Program; Departments of wRadiation
Oncology; zImmunology; yBiostatistics; wwGenitourinary Onco-
logy; **Thoracic Oncology; JPharmacy; zClinical Research Staff;
#Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research
Institute and; and Department of Oncologic Sciences, University of
South Florida, Tampa, FL.
Present address of Adil Daud is Department of Medicine, University of
California, San Francisco, CA; Timothy Carey is Department of
Oncology, Longstreet Clinic, Gainesville, GA; Megan Gratz is
Department of Pharmacy, All Children’s Hospital, St Petersberg, FL.
All authors have declared there are no financial conflicts of interest in
regards to this work.
Reprints: Steven E. Finkelstein, H. Lee Moffitt Cancer Center and
Research Institute, 12902, Magnolia Drive, Tampa, FL 33612
(e-mail: steven.finkelstein@moffitt.org).
CLINICAL STUDY
J Immunother Volume 33, Number 8, October 2010 www.immunotherapy-journal.com |817
for 4 weeks (Fig. 1). This gives a cumulative, per-course
planned intravenous IL-2 dose [600,000 IU/kg/dose 20
doses = 12 million IU (mIU)/kg] that would compare with
the cumulative dose delivery typically achieved with the
standard high-dose intravenous schedule, as measured by the
dose delivery per course.
3,4
Through this schedule, we explored
the drug delivery and preservation of the good response and
durability associated with the standard high-dose schedule.
Mechanistically, cytokine therapy depends on stimula-
tion of lymphocytes to kill tumors via cell-mediated
cytotoxicity.
9
The pharmacodynamic effect of IL-2 on
myeloid and lymphoid subsets is under active investigation.
IL-2 has been shown to increase T regulatory cells in vivo in
patients with renal cell cancer and metastatic melanoma,
accompanied by a decrease in natural killer cells and
dendritic cells (DCs).
10
However, the increase in T regulatory
cells differed in patients who responded to treatment.
11
Our
group also reported previously that administration of IL-2
acutely then increases the proportion of myeloid-derived
suppressor cells (MDSCs) in patients with renal cell cancer
who were given IL-2 (in a low-dose subcutaneous
schedule).
12
These findings seem to suggest that IL-2 causes
changes in cell subsets that are opposite to the changes that
could be expected to enhance anticancer responses to
cytokine immunotherapy. In a correlative study, we also
analyzed immunophenotypes of DCs and MDSCs from a
group of patients before and after they were given high-
dose IL-2 and the possible relationship of these assays to
clinical response. We considered this immunological testing
to be separate and independent of the introduction of a new
schedule, that is to say directed at the intrinsic features of
the patients, these diagnoses, and the drug IL-2.
METHODS
Patients
This study was approved by the University of South
Florida Institutional Review Board, and informed consent
(HIPPA consent document) was obtained from all subjects.
Patients >18 years old were required to have pathologically
confirmed diagnoses of metastatic nonurothelial renal
cancer or of metastatic melanoma. Additional requirements
were Eastern Cooperative Oncology Group performance
status 0 or 1, creatinine levels of Z2.5 mg/dL, and
creatinine clearance of at least 40 mL/min by the Cock-
roft-Gault formula. Further exclusion criteria included
recent corticosteroid use, active autoimmune disease,
significant coronary artery disease, and seizures in last
2 years (neuroleptic medication allowed). Prior resection of
the primary tumor was not required, nor was RECIST
measurability of the metastatic disease, nor was absence of
central nervous system (CNS) disease history, although
brain imaging within 90 days was required and within 14
days of treatment if imaging previously demonstrated CNS
metastatic disease (which generally must have been stable
for at least 90d).
R
RR
oo
oo
ooo ooo ooo ooo
ooo ooo ooo ooo
R R R RR
*oo ooo R R R R
RRRRR
RR R R R
oo
oo
ooo
ooo
oo ooo ooo ooo ooo
RRR R R R
R
oo
oo
ooo
ooo
CT evaluation *
CT evaluation
R
R R
oo ooo ooo ooo ooo
R R R R R
oo ooo R R R R
R R R R R
R R R RR
oo ooo
oo ooo ooo ooo ooo
RR R R RR
R
oo
oo
ooo
ooo
CT evaluation CT evaluation
FIGURE 1. Calendar schematic representation of the new schedule (right) and standard schedule (left): 1 day=small box; 1 week=1
row; o=1 dose IL-2; R= rest day within a course; and *blood test. Note: depending on the time of day of the hospital admission, some
courses start with 1 dose only on the first day. IL indicates interleukin.
Finkelstein et al J Immunother Volume 33, Number 8, October 2010
818 |www.immunotherapy-journal.com r2010 Lippincott Williams & Wilkins
Dose and Schedule
The initial IL-2 dose level was 600,000 IU/kg rounded
to the nearest 1 million units/dose, fixed per course, with
4 courses (hospital admissions) scheduled at weekly intervals,
with each course having 5 doses at intervals of 8 hours.
Generally, within each course, a dose was omitted and not
reduced if criteria for treatment were not met; reductions to
80%, 60%, or 40% could be used if 2 or more doses were
missed during the previous course or if there were a delay of
>3 days for resolution of toxicities. Each dose was contingent
on the clinical judgment of the treating physician.
Before the start of a weekly course, any adverse event
of grade 3 or higher, as outlined in the Common
Terminology Criteria of Adverse Events version 3.0, had to
be resolved; renal and hepatic functions were monitored for
return to near baseline (creatinine levels within 0.5mg/dL
of the baseline and < 2.5 mg/dL), albumin > 2.0, aspartate
transaminase and alanine transaminase <5upper limit of
normal (ULN), total bilirubin <2ULN (or allowed
<5ULN if patient had Gilbert syndrome). The treating
physician evaluated other side effects to determine whether
the patient could start treatment. During each course of
IL-2, renal function and blood pressure were supported
with up to two 500-mL bags of 0.9% saline per 8 hours; for
hypotension or low urine output, patients were given intra-
venous dopamine at 2 to 5 mg/kg/min. If patients required
dopamine >5 mg/kg/min or other pressor agents, the sub-
sequent doses of IL-2 in that course were omitted. Planned
supportive drugs included potassium phosphate, magne-
sium oxide, proton-pump inhibitor, naproxen or hydromor-
phone for fevers and rigors, diphenoxylate with atropine
for diarrhea, furosemide, and diphenhydramine, certrizine,
or hydroxyzine for pruritis. Antihypertensive drugs were
routinely held; use of corticosteroids was not allowed.
Each treatment cycle was scheduled as 4 consecutive
weeks, usually with each cycle starting on the same day of
the week. The second cycle was after a 2-week to 3-week
break for rest and clinical evaluation after the fourth
treatment week. Radiological evaluation was allowed after
the first cycle and was required during the 2-week to 3-week
break after the second cycle. All patients who received at
least a single IL-2 dose were reported for progression, and
survival was measured from the date of first treatment.
Patients with favorable responses after 2 cycles could be
considered for more at the discretion of the treating
physician; best response is reported.
Correlative Studies
The phenotype of mononuclear cells subsets was
analyzed in 16 patients. Blood samples were collected and
frozen before the first cycle and 2 weeks after the first cycle
had ended. All samples from each patient were analyzed
simultaneously, with the assumption that the single
pretreatment sample was representative. Peripheral blood
mononuclear cells were thawed, cultured overnight in
complete culture medium (RPMI 1640 and 10% fetal calf
serum), and then used for analyses. Cells were labeled with
the antibodies for 40 minutes on ice and analyzed the same
day by flow cytometry. The cocktail of lineage (Lin)-specific
antibodies included phycoerythrin-conjugated antibodies
against CD3, CD19, CD56, and CD14 (all from BD
PharMingen, Franklin Lakes, NJ). In addition, PerCP-
conjugated anti-HLA-DR antibody; APC-conjugated
anti-CD33 and CD11c antibodies; and FITC-conjugated
anti-CD86, CD83, and CD40 antibodies were obtained from
BD PharMingen; FITC-conjugated antibodies against CCR7
and CD123 were obtained from R&D Systems (Minnea-
polis, MN) and Miltenyi (Auburn, CA), respectively. Cell
phenotype was evaluated by multicolor flow cytometry with
a FACSCalibur flow cytometer (BD Biosciences, Mountain
View, CA). The following subsets of cells were evaluated:
(1) MDSC: Lin
()
HLA-DR
()
CD33
+
; (2) DC: Lin
()
H-
LADR
+
; and (3) mature DC: Lin
()
HLA-DR
+
and either
CD86
+
, CD40
+
, CD83
+
, or CCR7
+
. Absolute DC and
MDSC counts are not reported. The ratio of DC:MDSC is
calculated from the percentages of DC and percentages of
MDSC out of the same mononuclear pool.
Tissue specimens were not evaluated.
Statistical Analysis
The primary objective of the study was to investigate
how frequently it was feasible to deliver IL-2 to at least
8.4 mIU/kg during course 1 under our modified schedule
(70% of the planned dose of 540.6 mIU/kg =12 mIU/kg;
also note that 8.4 mIU/kg =0.6 mIU/kg/dose14 doses,
comparable with the median dose delivered in some large
series with 28 planned doses for course 1
3,4
).
With a cohort size of 36 patients, the estimate of the
frequency at which the target dose can be delivered has a
standard error of <10%. There was an intermediate
evaluation for futility at n=15. The clinical response rates
with confidence intervals based on exact binomial distribu-
tions and adverse events are reported descriptively, given
the small sample size and single-arm study design that limit
formal comparisons to other series. Analyses of immuno-
phenotype data were performed with the intent of an
exploratory analysis; test results and Pvalues are provided
in an exploratory fashion. Descriptive summary statistics
on pretreatment and posttreatment measurements and their
differences of the immunophenotype variables were re-
ported; informal comparisons between responders and
nonresponders were made using the normal score test.
The purpose of such informal comparisons was to examine
for evidence whether 1 or more immunophenotype variable
may predict response to the treatment. The Pvalues are
2-sided, P<0.05 was considered statistically significant,
and no multiple comparison adjustments were made. The
sample size and secondary nature of these analyses
markedly limit conclusions about statistical significance
of the findings; nonetheless, they may generate hypotheses
for future study.
RESULTS
Accrual was from April 2004 to March 2005. Forty
patients enrolled: 21 had kidney cancer and 19 had
metastatic melanoma. One patient with renal cell carcino-
ma had metastatic pancreatic cancer and nonmetastatic
kidney cancer at autopsy and was excluded from analyses;
this patient did not meet the dose-delivery target, had
disease-related ascites, and eventual respiratory failure
during IL-2 treatment. Death was attributed to disease
progression with a possible contribution of treatment side
effects. Three patients with metastatic melanoma did not
start because of newly diagnosed brain metastasis.
To evaluate patterns of failure fully, long-term follow-
up was conducted for up to 5 years. The 36 evaluable
patients received at least 1 dose of IL-2 and were followed
for outcome, reported with cut-off date of November 2009.
Patient demographic and disease characteristics are shown
J Immunother Volume 33, Number 8, October 2010 IL-2, Weekly 5-in-a-row Schedule
r2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com |819
TABLE 1. Patient Characteristics and Outcomes: Renal Cell Cancer
Pt
Time From
Diagnosis
to Trial Sex Age (y) Site of Disease No. Metastases
MSKCC
Risk Score
(Ref. 11)
Dose/Cycle 1,
Million Units/kg
Dose/Cycle 2,
Million Units/kg Outcome Survival (mo)
1 4 y 1 mo M 62 Lung 2 0 10.8 7.8 CR 60+
2 8 mo M 71 Lung >5 0 11.4 9.0 PR 59+
3 21 y M 70 Kidney/Pancreas/adrenal 4 1 10.8 9.6 Stable 32
4 4 y M 51 Liver/LN/Sacrum 3 2 4.8 SAE 11
5 2 mo M 50 Lung/brain/bone 5 2 11.4 6.0 CR 50+
6 3 y 8 mo M 49 Lung 4 0 12 12 PR 37
7 4 mo M 44 LN 3 1 10.8 10.2 Stable 44+
8 8 mo M 65 Lung >5 0 6.0 SAE 4
9 2 mo M 52 Lung/LN 5 1 10.8 11.4 CR 63+
10 8 mo M 69 Liver/bone 2 0 10.2 11.4 Progression 20
11 11 mo M 70 Liver 1 1 12.0 Progression 26
12 1 y 6 mo M 58 Lung >5 1 11.4 11.4 Stable 60+
13 11 y M 60 Lung 4 0 9.6 6.6 Stable 62+
14 1 y M 64 Lung 2 0 10.8 10.8 Stable 61+
15 4 y 11 mo M 65 LN 3 0 12.0 10.8 Stable 49+
16 1 m F 71 Bone >5 1 9.0 Progression 3
17 5 y 3 mo F 61 Lung/LN/bone >5 0 7.8 SAE 13
18 2 y 4 mo M 55 Lung/bone >5 2 11.4 4.8 Progression 7
19 7 y M 62 Liver/psoas mass >5 1 12.0 12.0 Stable 54+
20 4 m M 67 Lung >5 1 12.0 12.0 Stable 36+
CR indicates complete response; LN, lymph node; mo, month; MSKCC, Memorial Sloan Kettering Cancer Center; PR, partial response; Pt, patient; SAE, serious adverse event; y, year.
Finkelstein et al J Immunother Volume 33, Number 8, October 2010
820 |www.immunotherapy-journal.com r2010 Lippincott Williams & Wilkins
in Tables 1 and 2, respectively. All renal cell cancer patients
had clear cell carcinoma except for patient 11 (papillary).
The median age was 62 years (range, 44–71 y) for patients
with renal cell carcinoma and 48 years (range, 20–70 y) for
patients with melanoma; there were 30 (83%) men and
6 (17%) women. All but 1 renal cell cancer patient were
postnephrectomy.
The median dose delivered during the first cycle was
11.4 mIU/kg, with a mean of 10.4± 2.47 mIU/kg (SD).
Nineteen patients went on to receive a second cycle, and the
median dose delivered in this cycle was 10.8 mIU/kg (mean
of 9.85±2.42 mIU/kg). The dose delivery per patient by
diagnosis in cycles 1 and 2 is shown in Figures 2A and B,
respectively. As illustrated, the frequency at which a dose of
at least 8.4 mIU IL-2/kg/course was delivered was 86%
[95% confidence interval (71%–95%)]. Of the 17 patients
who did not receive a second cycle, 4 stopped treatment
because of serious adverse events, 2 for general intolerance
of the regimen, and the other 11 for identifiable tumor
progression. One renal cell cancer patient stopped treat-
ment during the second cycle for suspected progression
of a solitary brain metastasis, which was then treated
radiosurgically with no further histological evaluations,
and on subsequent evaluations was shown to have on-
going complete response (regression of somatic disease).
The original treatment of the CNS disease had been
completed 2 weeks before the start of the first course, for
this patient.
Adverse Events
Table 3 shows the serious adverse events in the
evaluable patients; these results are similar to the spectrum
seen in other studies with high-dose IL-2.
1–7,9,12,13
Most
frequent was hypotension, occurring in 34 of 36 patients,
with 14 of 36 patients having grade 3 hypotension or
higher. The second most common was renal dysfunction
(27 of 36 patients), with grade 4 in 1 patient; additionally, 1
patient had progressive elevation of creatinine and eventual
renal failure, managed with dialysis until death, from
metastatic renal cell carcinoma. Supraventricular tachy-
cardia occurred in 3; it was controlled medically and by
withholding IL-2. Three patients had significant CNS
toxicity: 2 had probable seizures (both were known cases
of treated CNS metastasis), and 1 suffered a stroke, from
which he subsequently recovered and remained alive with
disease at last follow-up, having received no further IL-2
treatment (or other anticancer treatment) for about 2 years;
he had had endarterectomy 1 year before. This patient also
suffered a non-ST elevation myocardial infarction (eleva-
tion of troponin-I); both events were attributed to IL-
2-induced hypotension. Other frequent low-grade (Com-
mon Terminology Criteria of Adverse Events version 3.0
grades 1 and 2) adverse events that resolved after a cycle
included nausea, vomiting, diarrhea, thrombocytopenia,
elevated liver tests, and pruritis.
Disease Outcomes
Of the 20 patients with metastatic renal cell carcinoma,
7 (35%) have died as of November 2009 (Table 1). There
were 5 major responses (3 ongoing durable complete
remissions and 2 partial remissions; the 2 patients with
partial response progressed, after May 2007). The response
rate for renal cell cancer patients was 25% [95% confidence
interval (9%–49%)].
TABLE 2. Patient Characteristics and Outcomes: Melanoma
Pt
Time From Diagnosis
to Trial Sex
Age
(y)
Previous
Treatment
Stage of
Disease
No.
Metastases
Dose/Cycle 1,
Million Units/kg
Dose/Cycle 2,
Million Units/kg Outcome
Survival
(mo)
1 6 y 1 mo M 51 IFN M1c 4 12 6.0 Progression 16
2 9 y M 22 None M1c 4 12 12 Progression 13
3 2 y 2 mo F 32 IFN M1b Multiple 12 Progression 6
4 9 y M 56 DTIC M1c 4 10.8 Progression 10
5 1 y 5 mo M 69 IFN M1a 4 12 11.4 PR 53+
6 2 y 2 mo F 35 IFN M1c 4 6.0 Progression 6
7 2 y 3 mo F 62 CVD/Cis Tem M1b Multiple 9.0 Progression 9
8 7 y 7 mo M 48 None M1c Multiple 12 Stable 52+
9 1 y 2 mo M 55 IFN/Tem M1b Multiple 12 Progression 5
10 4 y 11 mo M 70 IFN/CVD Tam/Tem M1b Multiple 1.2 SAE 9
11 11 mo M 47 IFN M1c Multiple 12 Progression 1
12 11 y 1 mo F 48 IFN M1a Multiple 12 Progression 10
13 6 y M 20 IFN/GM-CSF M1a 1 12 12 Progression 7
14 3 mo M 44 IFN M1c Multiple 9.0 Progression 7
15 3 mo M 47 None M1a Multiple 12 Progression 8
16 5 y 7 mo M 58 None M1b 3 12 Progression 41+
Cis indicates cisplatin Tem, temozolomide; CVD, cisplatin, vinblastine, and dacarbazine; DTIC, dacarbizine; GM-CSF, granulocyte-macrophage colony-stimulating factor; INF, interferon alpha; mo, month;
PR, partial response; Pt, patient; SAE, serious adverse event; Tam, tamoxifen; y, year.
J Immunother Volume 33, Number 8, October 2010 IL-2, Weekly 5-in-a-row Schedule
r2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com |821
Thirteen (81%) of the 16 melanoma patients have died
as of November 2009 (Table 2). Ten of these patients had
received prior immunotherapy. Two others had received
cytotoxic chemotherapy. There was 1 response (6%), a
partial response, in a patient with M1a (cutaneous pattern)
metastasis. This remission was durable for 53+ months.
The other 2 surviving patients (41+, 52+ mo) have
received several lines of chemotherapy, including being
included in clinical trials with investigational-targeted
agents.
No formal comparisons of pretreatment clinical prog-
nostic features between the 2 diagnoses were attempted,
although the response frequencies (5/20 vs. 1/16) and
mortality rates (7/20 vs. 13/16) appear different.
FIGURE 2. A, Dose delivery of IL-2 in cycle 1. Waterfall chart shows dose delivered to all 36 patients enrolled on the trial. Broken line
represents 8.4 mIU/kg/cycle, as reported by Yang et al.
3
B, Dose delivery of IL-2 in cycle 2. Waterfall chart shows dose delivered to 19
patients that received a second cycle of IL-2. Broken line represents 8.4 mIU/kg/cycle, as reported by Yang et al.
3
IL indicates interleukin.
TABLE 3. Number of Adverse Events
Category All Grades Grade 3 or Higher (%)
Hypotension 34 (20 required pressors) 14 (38.9)
Cardiac arrhythmia 4 3 (8.3)
CNS (seizure) 3 3 (8.3)
Renal dysfunction 27 1 (2.8)
Liver test elevation 19 1 (2.8)
Nausea 12 1 (2.8)
Thrombocytopenia 12 1 (2.8)
Diarrhea 9 1 (2.8)
Ischemia (stroke, NSTEMI) 1 1 (2.8)
CNS indicates central nervous system; NSTEMI, non-ST elevation myocardial infarction.
Finkelstein et al J Immunother Volume 33, Number 8, October 2010
822 |www.immunotherapy-journal.com r2010 Lippincott Williams & Wilkins
Immunophenotyping
Blood samples before and after IL-2 treatment from
16 patients (10 with renal cell carcinoma and 6 with
melanoma) were available for analyses. In the analyses of
myeloid cells before IL-2 versus after IL-2 treatment,
2 groups became apparent, and our results are presented
according to this retrospective dichotomous division. The
first group consisted of 5 (5/16=31%) patients (4 renal cell
carcinoma, 1 metastatic melanoma) with good response
outcomes and was designated as the “analyzed responder
subset.” Four patients in this group had a major response
to treatment, and the fifth patient had stable disease but did
not meet criteria for major response (renal cell carcinoma,
stable mediastinal lymphadenopathy, regression of cystic
area in the pancreas where previous metastasis had been
resected). The other 11 patients, designated the “remainder
subset,” had no major responses.
The analyzed responder subset presented with a high
ratio of mature DC to MDSC, similar to that shown in
normal, noncancer individuals.
14
The remainder subset had
low DC-to-MDSC ratio, similar to that shown in advanced
cancer patients.
14
The median pretreatment DC-to-MDSC
ratio was significantly elevated in the analyzed responder
group versus the remainder group [88.8 vs. 27.6 or about
3-fold (P=0.001)].
Furthermore, the median pretreatment number of
MDSC per hundred peripheral blood mononuclear cells
was significantly lower in the analyzed responder subset
than in the remainder subset [0.16/100 vs. 0.34/100
(P=0.03), respectively; Table 4 and Fig. 3]. Thus a high
DC-to-MDSC ratio and low MDSC count distinguished
the responder subset in our tested patients.
Measurement of single markers of the immunopheno-
types revealed statistically significant differences, remark-
ably with a converse pattern when the subsets were
compared. The median level of expression of CD40,
CD86, and CCR7 in peripheral blood DC before the start
of treatment was significantly decreased in the analyzed
responder subset when compared with the remainder,
varying from about a 2-fold to 26-fold difference. These
comparisons are listed in Table 4 and graphically illustrated
as box plots in Figure 3 (for the pretreatment comparisons
only). The statistical comparisons between subsets for
individual markers of DC maturity associated the remain-
der group with higher CD86 positivity (P=0.03), higher
CD40 positivity (P=0.02), and higher CCR7 positivity
(P=0.02), with a similar but nonsignificant pattern for
CD83 positivity (P=0.17, a nonsignificant P-value). After
the first 2 cycles of IL-2, the differences between the
2 groups disappeared, consistent with a short-term effect of
IL-2 causing elevation of counts of cells with features of the
MDSC immunophenotype. This was also observed pre-
viously with low-dose IL-2 treatment, as reported by our
group,
12
and by the decreased DC numbers (ratios not
reported) shown by van der Vliet et al.
10
DISCUSSION
Feasibility of the New Schedule
To mediate immunotherapeutic antitumor effects in
vivo, T cells of sufficient avidity for recognition of tumor
antigens must be present in sufficient quantities, traffic to
the tumor site, extravasate from the circulation, and then
mediate effector functions to cause destruction of cancer
cells.
3
IL-2, a cytokine that stimulates T cells and is
approved by the FDA for patients with metastatic
melanoma or renal cancer, can mediate cancer regression
TABLE 4. Comparisons of Pretreatment and Posttreatment Immunophenotypes in the Analyzed Responder SubsetVersus Remainder
Subset
Responder Subset (Highest DC: MDSC) (n=5) Nonresponder Subset (n=11)
Median Lower Q Upper Q Median Lower Q Upper Q P
Dendritic cells
Pretreatment 19.35 14.76 19.59 7.61 5.79 13.46 0.06
Posttreatment 6.61 4.49 10.21 6.17 4.13 10.29 0.76
MDSC
Pretreatment 0.16 0.13 0.22 0.34 0.28 0.58 0.03
Posttreatment 0.35 0.22 0.37 0.43 0.17 0.59 0.68
DC/MDSC
Pretreatment 88.82 67.39 122.5 27.57 18.72 35.92 0.001
Posttreatment 20.12 17.04 29.01 18.88 16.30 35.05 0.97
CD86
+
Pretreatment 14.50 3.64 26.07 47.00 35.87 73.83 0.03
Posttreatment 28.93 8.05 33.57 52.11 22.99 76.15 0.22
CD40
+
Pretreatment 0.45 0.12 1.02 12.32 2.01 40.13 0.02
Posttreatment 1.06 0.61 4.48 7.84 1.36 29.34 0.49
CCR7
+
Pretreatment 0.62 0.15 1.26 4.54 2.53 6.44 0.02
Posttreatment 3.40 0.93 8.57 3.47 0.32 5.47 0.57
CD83
+
Pretreatment 0.73 0.31 1.73 7.11 3.54 8.92 0.17
Posttreatment 4.00 1.29 10.51 6.06 2.34 9.80 0.92
CCR7
+
indicates DC expressing CCR7; CD40
+
, DC expressing CD40; CD83
+
, DC expressing CD83; CD86
+
, DC expressing CD86; DC, dendritic cells;
Lower Q, lower quartile; MDSC, myeloid-derived suppressor cells; Pre- and posttreatment, before and after IL-2 treatment, respectively; Uppe r Q, upper
quartile.
J Immunother Volume 33, Number 8, October 2010 IL-2, Weekly 5-in-a-row Schedule
r2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com |823
in E15% to 20% of these patients.
1
In patients with
metastatic melanoma, the therapeutic arsenal has been
limited
15
and includes high-dose bolus IL-2
1
and dacarbazine
with response rate in the 10% to 20% range, mostly in
good-risk patients,
16,17
and use of carboplatin and pacli-
taxel.
18
In patients with renal cell carcinoma, recently
vascular endothelial growth factor-pathway tyrosine kinase
inhibitors (sorafenib, sunitinib, pazopanib) and vascular
endothelial growth factor chelating drug (bevacizumab)
and mTOR inhibitors (temsirolimus, everolimus) have
demonstrated improved progression-free or overall survival
versus interferon or versus placebo.
15,19–22
Interferon has
been compared with IL-2.
18
Practice patterns emphasizing
use of targeted drugs obviously have changed treatments
for many patients; however, high-dose intravenous IL-2
stands alone in demonstrating routine but infrequent,
durable, unmaintained remissions.
In this trial, we developed a schedule with more
planned breaks and shorter runs of IL-2, which could allow
improved drug delivery and subjectively improved toler-
ability of the hospitalization experience. Our modified
scheduled resulted in 3 complete responses that have been
unmaintained and durable to this point; in addition, the
median overall survival of >44+ months in patients with
FIGURE 3. Box plots of the pretreatment immunophenotypes comparing responders with nonresponders. A to D, comparisons
of the percentage mature dendritic cells [DC; Lin
()
HLA-DR
+
] that express CD83, CD40, CCR7, and CD86, respectively. E, myeloid-
derived suppressor cells (MDSCs): Lin
()
HLA-DR
()
CD33
+
. F, mature DC [Lin
()
HLA-DR
+
]. G, ratio of DC to MDSC. Pvalues are
all 2-sided.
Finkelstein et al J Immunother Volume 33, Number 8, October 2010
824 |www.immunotherapy-journal.com r2010 Lippincott Williams & Wilkins
renal cell carcinoma seems favorable. On the other hand,
frequency of responses in melanoma (0% complete res-
ponse, 6% partial response) does not seem to support the
development of this schedule. Overall response rate was not
distinct from a 14-in-a-row standard schedule.
The trial was not intended to demonstrate an escalated
dose delivery; however, the median dose compares favor-
ably with historical controls of 8.4 to 11.4 mIU/kg per 28
planned doses,
3,4,13
although is not statistically significantly
different.
In terms of toxicities, our modified regimen appears
feasible, in the context of ward with pharmacists and nurses
experienced in administration of IL-2 and pressors at a
tertiary medical center. The pattern of side effects does not
suggest that the new schedule should be used in an inex-
perienced or less-monitored setting. Quality-of-life data were
not collected. The side-effect patterns and frequencies appear
similar to those previously observed, although we conducted
no statistical comparisons. Some severe adverse events occur-
red that may be attributed to the drug or to our schedule but
overall appeared consistent with the known spectrum of side
effects, independent of treatment schedule details.
The response-frequency experiences shown here
should be viewed within the limitation of the group size
and nonstratified patient selection when comparing with
historical experience. Application of risk stratification such
as the Memorial Sloan-Kettering Cancer Center risk score
based on hemoglobin, lactate dehydrogenase, calcium,
performance status, and prior nephrectomy
13
describes
accessible clinical and patient features that relate to renal
cell cancer patient risk. For melanoma, lactate dehydro-
genase, number, and location of metastatic sites also predict
outcome
17
but not response to treatment. With either
diagnosis, location of metastases may influence outcome to
immunotherapy.
2,23–25
The cohort treated here appears
typical in terms of risk; the risk score features are listed in
Tables 1 and 2.
Immunological Versus Tumor-based
Patient Selection
As new targeted agents develop, an imperative remains
to better define patients that may benefit IL-2 therapy.
Besides clinical and pathological features (across a variety
of scoring systems), we conjecture that immunological
features, identifiable before the start of treatment, may
better predict the patient’s response. The accumulation of
MDSC (Gr1+ cells in mice) has been observed in murine
models and in patients with advanced cancer.
14,26–29
The
altered DC-to-MDSC ratio appears to be a consequence of
tumor effect on the host immune system. The choice of the
ratio as the analyzed quantity in the present work coincides
with reports from murine systems and other clinical
data reported by our group.
12,14
Study of the effect of
tumor onto the host immune system as a more direct
consequence of depressed absolute number of DC, or as a
direct consequence of the increased absolute number of
MDSC could be of interest as well. The analysis presented
here was to not meant a priori to be a basis to discern
whether the ratio or the absolute counts are more reflective
of the immune consequence of the tumor burden.
In other work, a patient’s ability to respond to
intravesical immunotherapy of superficial transitional cell
bladder cancer has been proposed to have a relationship to
observable urinary DC.
30
In the exploratory analysis reported here, the best
responses to high-dose cytokine immunotherapy were
observed in the patients who had DC-to-MDSC ratios
that had been effected the least. The data set is too small
to define this as a response predictive factor, but it
is consistent with the view that it is host immune system
features, independent of “tumor features” or “clinical
features,” that can be used to define the capacity for
clinically useful anticancer responses to immunotherapy.
In the analyses presented here, the DC-to-MDSC ratio
appeared to be a key discriminant, although subject to the
limitations of the size of the data set. Single markers, the
frequency of which was conceivably influenced by single-
marker-positive immature cells, did not discriminate in the
expected way. Other investigators have identified other
myeloid markers (CD14
+
HDLA-DR
/lo
in melanoma
31
)
and lymphoid markers,
32
including regulatory T cells,
33
that may govern the capacity for anticancer response.
34
One
may speculate that, ultimately, these derangements could be
a consequence of common tumor biological features.
The plasticity of the DC-to-MDSC ratio in a
contemporaneously treated group of renal cell cancer
patients was previously demonstrated through the use of
all-trans retinoic acid, a drug that induces maturation/
clearance of MDSC and that may also activate DC. The
extent to which patients could be selected for immunother-
apy based on pretreatment assessment of immune compe-
tence or the extent to which the immune system can be
modified or reconstituted so as to provide a better
hypnotherapy context remains an active interest.
We consider that the immunological assays that we
performed are a basis to hypothesize that the DC-to-MDSC
ratio can be prospectively tested to develop in 2 main
directions: One would be selection of patients with immuno-
logical credentials that suggest a higher chance of response to
IL-2 therapy, thereby providing laboratory justification for
exposure to the risk of high-dose IL-2 therapy. Second, these
assays could serve as intermediate laboratory surrogate
markers of the effectiveness of pharmacological maneuvers
directed at the immune context.
Finally, it should be understood that ultimately, the
function of DC (and the pathological functions of MDSC)
occur outside the bloodstream, both in antigen acquisition
in tumor and other locations and in antigen presentation
within the lymph node. Thus, studies of DC and MDSC
from peripheral blood are in this view an indirect vantage
point for understanding the in situ modulation of antigen
presentation occurring in the setting of cancer. An under-
lying assumption of work such as is presented here, is that
phenotypes of the leukocytes of the peripheral blood are a
direct reflection of those in the tumor or the associated
anticancer response developed in the lymph nodes.
In conclusion, our 5-in-a-row/2 days per week 4
schedule appears feasible and delivered an uncompromised
total dose of IL-2 equivalent to the historical median (50%
of patients) dose delivery for high-dose intravenous IL-2
dose in 86% of patients. This schedule still has intensive
management issues but did offer a more uniform dose
delivery over time (Figs. 2A, B) across our cohorts, thus
perhaps accommodating development of future IL-2
combinations. In renal cell carcinoma, the response rate
compared favorably with historical experiences; however,
in patients with metastatic melanoma patients the response
frequency was not encouraging. This may be potentially
mitigated through various immunological approaches.
34–42
J Immunother Volume 33, Number 8, October 2010 IL-2, Weekly 5-in-a-row Schedule
r2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com |825
Finally, the paradoxical “worsening” of the immuno-
phenotype in the short term after IL-2 therapy, as measured
by several cell-surface markers or by the falling DC-
to-MDSC ratio, was observed. This was despite the
eventual excellent, complete, durable response shown in
some of our patients. This may be a starting point from
which to investigate differences of “cancer-induced” MDSC
as opposed to “IL-2-induced or therapy-induced” cells that
otherwise seem to have ex vivo similarity.
REFERENCES
1. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283
consecutive patients with metastatic melanoma or renal cell
cancer using high-dose bolus interleukin-2. J Am Med Assoc.
1994;271:907–913.
2. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose
recombinant interleukin 2 therapy for patients with metastatic
melanoma: analysis of 270 patients treated between 1985 and
1993. J Clin Oncol. 1999;17:2105–2116.
3. Yang JC, Sherry RM, Steinberg SM, et al. Randomized
study of high-dose and low-dose interleukin-2 in patients
with metastatic renal cancer. J Clin Oncol. 2003;21:
3127–3132.
4. McDermott DF, Regan MM, Clark JI, et al. Randomized
phase III trial of high-dose interleukin-2 versus subcutaneous
interleukin-2 and interferon in patients with metastatic renal
cell carcinoma. J Clin Oncol. 2005;23:133–141.
5. McDermott DF. The application of high-dose interleukin-2 for
metastatic renal cell carcinoma. Med Oncol. 2009;26(suppl 1):
13–17.
6. O’Day SJ, Atkins MB, Boasberg P, et al. Phase II multicenter
trial of maintenance biotherapy after induction concurrent
Biochemotherapy for patients with metastatic melanoma.
J Clin Oncol. 2009;27:6207–6212.
7. Dutcher J. Current status of interleukin-2 therapy for
metastatic renal cell carcinoma and metastatic melanoma.
Oncology (Williston Park). 2002;16(suppl 13):4–10.
8. Atzpodien J, Hoffmann R, Franzke M, et al. Thirteen-year,
longterm efficacy of interferon 2alpha and interleukin 2-based
home therapy in patients with advanced renal cell carcinoma.
Cancer. 2002;95:1045–1050.
9. Smith KA. Rational interleukin-2 therapy. Cancer J Sci Am.
1997;3(suppl 1):S137–S140.
10. van der Vliet HJ, Koon HB, Yue SC, et al. Effects of the
administration of high-dose interleukin-2 on immunoregula-
tory cell subsets in patients with advanced melanoma and renal
cell cancer. Clin Cancer Res. 2007;13:2100–2108.
11. Cesana GC, DeRaffele G, Cohen S, et al. Characterization
of CD4+CD25+ regulatory T cells in patients treated with
high-dose interleukin-2 for metastatic melanoma or renal cell
carcinoma. J Clin Oncol. 2006;24:1169–1177.
12. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid
improves differentiation of myeloid cells and immune response
in cancer patients. Cancer Res. 2006;66:9299–9307.
13. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival
update for high-dose recombinant interleukin-2 in patients
with renal cell carcinoma. Cancer J Sci Am. 2000;6(suppl 1):
S55–S57.
14. Almand B, Clark JI, Nikitina E, et al. Increased production
of immature myeloid cells in cancer patients: a mechanism
of immunosuppression in cancer. J Immunol. 2001;166:
678–689.
15. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial.
Temsirolimus, interferon alfa, or both for advanced renal-cell
carcinoma. N Engl J Med. 2007;356:2271–2281.
16. Pantuck AJ, Zisman A, Chao D, et al. A comparison of
interferon versus interleukin-2 following nephrectomy for
metastatic renal cell carcinoma. Proc Am Soc Clin Oncol.
2002;21. Abstract 755.
17. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based
chemotherapy for metastatic melanoma: thirty-year experience
overview. J Exp Clin Cancer Res. 2000;19:21–34.
18. Rao RD, Holtan SG, Ingle JN, et al. Combination
of paclitaxel and carboplatin as second-line therapy for
patients with metastatic melanoma. Cancer. 2006;106:
375–382.
19. Escudier B, Eisen T, Stadler WM, et al; TARGET Study
Group. Sorafenib in advanced clear-cell renal-cell carcinoma.
N Engl J Med. 2007;356:125–134.
20. Escudier B, Pluzanska A, Koralewski P, et al; AVOREN Trial
investigators. Bevacizumab plus interferon alfa-2a for treat-
ment of metastatic renal cell carcinoma: a randomised, double-
blind phase III trial. Lancet. 2007;370:2103–2111.
21. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus
interferon alfa in metastatic renal-cell carcinoma. N Engl J
Med. 2007;356:115–124.
22. Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study
Group. Efficacy of everolimus in advanced renal cell carcino-
ma: a double-blind, randomised, placebo-controlled phase III
trial. Lancet. 2008;372:449–456.
23. Middleton MR, Grob JJ, Aaronson N, et al. Randomized
phase III study of temozolomide versus dacarbazine in the
treatment of patients with advanced metastatic malignant
melanoma. J Clin Oncol. 2000;18:158–166.
24. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and
prognostic stratification of 670 patients with advanced renal
cell carcinoma. J Clin Oncol. 1999;17:2530–2540.
25. Manola J, Atkins M, Ibrahim J, et al. Prognostic factors
in metastatic melanoma: a pooled analysis of Eastern
Cooperative Oncology Group trials. J Clin Oncol. 2000;18:
3782–3793.
26. Gabrilovich DI, Velders MP, Sotomayor EM, et al. Mechan-
ism of immune dysfunction in cancer mediated by immature
Gr-1+ myeloid cells. J Immunol. 2001;166:5398–5406.
27. Melani C, Chiodoni C, Forni G, et al. Myeloid cell expansion
elicited by the progression of spontaneous mammary carcino-
mas in c-erbB-2 transgenic BALB/c mice suppresses immune
reactivity. Blood. 2003;102:2138–2145.
28. Bronte V, Chappell DB, Apolloni E, et al. Unopposed
production of granulocyte-macrophage colony-stimulating
factor by tumors inhibits CD8+ T cell responses by dys-
regulating antigen-presenting cell maturation. J Immunol.
1999;162:5728–5737.
29. Bronte V, Serafini P, Apolloni E, et al. Tumor-induced
immune dysfunctions caused by myeloid suppressor cells.
J Immunother. 2001;24:431–446.
30. Beatty JD, Islam S, North ME, et al. Urine dendritic cells: a
noninvasive probe for immune activity in bladder cancer? BJU
Int. 2004;94:1377–1383.
31. Filipazzi P, Valenti R, Huber V, et al. Identification of a new
subset of myeloid suppressor cells in peripheral blood
of melanoma patients with modulation by a granulocyte-
macrophage colony stimulation factor-based antitumor vac-
cine. J Clin Oncol. 2007;25:2546–2553.
32. Kadagidze ZG, Borunova AA, Zabotina TN. Lymphocyte
subpopulations in melanoma patients treated with dendritic
cell vaccines. Adv Exp Med Biol. 2007;601:381–386.
33. Griffiths RW, Elkord E, Gilham DE, et al. Frequency of
regulatory T cells in renal cell carcinoma patients and
investigation of correlation with survival. Cancer Immunol
Immunother. 2007;56:1743–1753.
34. Rosenberg SA. Overcoming obstacles to the effective immu-
notherapy of human cancer. Proc Natl Acad Sci U S A.
2008;105:12643–12644.
35. Restifo NP, Antony PA, Finkelstein SE, et al. Assumptions of
the tumor “escape” hypothesis. Sem Cancer Biol. 2002;12:
81–86.
36. Overwijk WW, Theoret MR, Finkelstein SE, et al. Tumor
regression and autoimmunity after reversal of a functionally
tolerant state of self-reactive CD8+ T cells. J Exp Med. 2003;
198:569–580.
Finkelstein et al J Immunother Volume 33, Number 8, October 2010
826 |www.immunotherapy-journal.com r2010 Lippincott Williams & Wilkins
37. Nagorsen D, Panelli M, Dudley ME, et al. Biased epitope
selection by recombinant vaccinia-virus (rVV)-infected
mature or immature dendritic cells. Gene Therapy. 2003;10:
1754–1765.
38. Lou Y, Wang G, Lizee G, et al. Dendritic cells strongly boost
the antitumor activity of adoptively transferred T cells in vivo.
Cancer Res. 2004;64:6783–6790.
39. Finkelstein SE, Heimann DM, Klebanoff CA, et al. Bedside to
bench and back again: how animal models are guiding the
development of new immunotherapies for cancer. J Leukocyte
Biol. 2004;76:333–337.
40. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of
homeostatic cytokine sinks by lymphodepletion enhances the
efficacy of adoptively transferred tumor-specific CD8+ T cells.
J Exp Med. 2005;202:907–912.
41. Hinrichs CS, Borman ZA, Cassard L, et al. Adoptively transferred
effector cells derived from naive rather than central memory
CD8+ T cells mediate superior antitumor immunity. Proc Natl
Acad Sci U S A. 2009;106:17469–17474. [Epub 2009 Sep 24].
42. Keilholz U, Conradt C, Legha SS, et al. Results of interleukin-
2-based treatment in advanced melanoma: a case record-based
analysis of 631 patients. J Clin Oncol. 1998;16:2921–2929.
J Immunother Volume 33, Number 8, October 2010 IL-2, Weekly 5-in-a-row Schedule
r2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com |827
    • "MDSCs not only impair T-cell and NK cell function, but also DCvaccine quality as reported in one study, where it was shown that high levels of MDSCs in DC cultures could affect the co-stimulatory molecules CD80 and CD86, and important molecules like CD1a and DC-sign [33]. In another study by other investigators, patients with a high ratio of DCs:MDSCs responded more favorably to highdose IL-2 [34] , indicating the potential general importance of high levels of DCs and low levels of MDSCs. Few studies have focused on the importance of pDCs and their influence on mDCs and vice versa [35][36][37]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Identifying immune markers in blood that are informative for breast cancer patient survival would not only be useful for prognosis but might also provide mechanistic insights into processes facilitating survival. Methods: We phenotyped circulating plasmacytoid dendritic cells (pDCs), myeloid-derived suppressor cells (MDSCs) and regulatory T-cells in relation to T-cell responses to Her-2 in vitro in 75 untreated breast cancer patients 28-87 years of age at diagnosis. Results: Patients with later stage tumors had lower levels of circulating pDCs (p = 0.008). There was a positive association between 5-year survival and higher than median levels of circulating pDCs (p = 0.03). We confirmed that 5-year survival correlated with CD8+ but not CD4+ T-cell responsiveness to Her-2 peptides in this cohort of younger and older patients (p = 0.04). Including pDCs in the analysis of previously-established parameters revealed that patients who had a CD8+ T-cell response to Her-2 together with a low ratio of MDSCs:pDCs had 100 % 5-year survival. High levels of pDCs and the presence of a CD8+ T-cell response to Her-2 were independent positive survival indicators according to multivariate Cox analysis. Conclusions: Our new results suggest that circulating pDCs could be a positive prognostic indicator in breast cancer patients of all ages, together with the previously established CD8+ T-cell reactivity to Her-2 antigens in older patients only. These two prognostic indicators were independent and emphasize the important role of immunity in ensuring breast cancer patient survival, even in those not undergoing immunotherapy.
    Full-text · Article · Dec 2016
    • "The authors agree that peri-treatment mortality can be reduced to less than 1% when guidelines are diligently followed. High priority research includes an exploration of combination therapy wherein IL-2 is used with other immunotherapy agents, stereotactic radiation, or new targeted therapeutics being developed for these diseases [44,59]. Another high priority is the identification and validation of predictive biomarkers to better select potential responders prior to treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient Selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.
    Full-text · Article · Sep 2014
    • "Detailed analysis of the immune status in tumor-bearing mice showed that Ad-USP18 significantly increased the duration of CTL persistence in the spleen and tumor sites of tumor-bearing mice (Figure 7D). As tumor antigens are weakly immunogenic, dendritic cell vaccination and IL-2 treatment are usually used to increase CTL activity clinically [28]. Using our B16 tumor model, we co-administered pmel-1 CTLs, Ad- USP18, IL-2 and dendritic cells into tumor. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown. Method In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. Results Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy. Conclusion These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
    Full-text · Article · May 2014
Show more