| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
in Progressive Metastatic Melanoma and Renal Cell Carcinoma
Division of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
in patients with progressive metastatic melanoma or renal cell
carcinoma (RCC). In addition, the activation and expansion of effector
cells were measured. Cohorts of three patients were treated with
increasing doses of IL-2 (1, 4, and 8 MIU/m2) and GM-CSF
(2.5 and 5 µg/kg) with a constant dose of IFN (5 million
units) s.c. for 12 days every 3 weeks. An additional six
patients were treated at the MTD. Immune activation was monitored
during the first cycle. Response was evaluated after two cycles. The
MTD was found to be 2.5 µg/kg GM-CSF, 4 MIU/m2 IL-2, and
5 mega units of IFN. DLT was grade 4 fever, chills with hypotension,
grade 3 fatigue/malaise, and fluid retention. Dose reduction of
IL-2 to 2 MIU/m2 was necessary in three of nine patients
who initially received the MTD. Treatment was initiated in the hospital
but could be continued at home after 3–4 days. Significant increases
in lymphocytes, (activated) T cells (CD4+ and CD8+), NK cells,
monocyte DR expression, neutrophils, and eosinophils were found.
CD8+ T-cell activation (sCD8) and NK cell expansion was mainly
present in patients receiving 2 or 4 MIU/m2 IL-2. Of eight
patients with progressive metastatic RCC after nephrectomy, three
achieved a complete remission, and 1 of 7 patients with metastatic
melanoma achieved a partial remission. In our study, the MTD of
combined immunotherapy with GM-CSF, IL-2, and IFN was established;
DLT was: (a) grade 4 fever with hypotension needing i.v.
fluid support; and (b) grade 3 fluid retention and/or
fatigue/malaise. The scheme resulted in considerable expansion
and/or activation of various effector cells. The complete responses in
RCC patients are promising but need to be confirmed in Phase II
studies. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
and the combination have shown responses in metastatic melanoma
and RCC (3
, 4)
. High-dose IL-2 i.v. can result in
long-term survivors in about 10% of cases but at the cost of
considerable toxicity (3
, 5, 6, 7, 8)
. The addition of
chemotherapy to immunotherapy has resulted in a higher number of
responders in metastatic melanoma but not in a better long-term
survival rate (9, 10, 11, 12)
.To develop a more effective
immunotherapy than IL-2 + IFN and to avoid the toxicity of high-dose
IL-2, we performed a Phase I trial of the combination of GM-CSF, IL-2,
and IFN given s.c. for 12 days. We started with a dose of 2.5
µg/kg GM-CSF, 1 MIU/m2 IL-2, and 5 MU of IFN
regardless of body weight, as this was well tolerated without serious
(grade 3 or 4, common toxicity criteria) toxicity in an
outpatient setting in a Phase II study in metastatic
melanoma.3
In that trial, no clear
CD8+ T- or NK-cell activation was found. The present
trial was conceived to find out whether such cells, thought to be
important for antitumor activity, could be activated by increases in
IL-2 and/or GM-CSF. Therefore, the rationale of the combination was to
induce nonspecifically the activation and expansion of all of the
putative effector cells without serious toxicity and to maintain such
activation for a longer time than previously achieved. Experimental
data have shown that GM-CSF and low-dose IL-2 induce T-LAK
without inducing NK-LAK and its inherent toxicity of vascular-leak
syndrome, as seen with high-dose IL-2 i.v. (13, 14, 15, 16)
.
However, little is known about the toxicity of this combination and the
immunological effects in humans. |
PATIENTS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
2b (Intron-A) in yeast
expression vectors, using recombinant techniques (Schering-Plough,
Maarssen, the Netherlands).
Clinical Protocol
Patients.
Eighteen patients were enrolled in this Phase I trial (Netherlands
Cancer Institute, protocol N98IRM), which was approved by the local
Ethics committee. All of the patients had progressive metastatic RCC
(n = 11), chemotherapy (Dacarbazine)-resistant
skin melanoma (n = 5), or uveal melanoma
(n = 2). Three patients with metastatic RCC had their
primary tumor in situ. Patients had a WHO performance status
of 0–2 and a life expectancy of at least 12 weeks.
Eligibility criteria included: (a) adequate hematological parameters (hemoglobin, >6.0 mmol/liter; WBC, >4.0/nl; and platelets, >100/nl); (b) adequate liver function (total serum bilirubin and serum glutamic oxalacetic transaminase, <3 times the upper limit of normal); (c) adequate renal function (serum creatinine, <180 µmol/liter); and (d) written informed consent. Exclusion criteria included: (a) major surgery; (b) cytotoxic chemotherapy or radiation therapy within 4 weeks of entry into this clinical trial; and (c) past or present autoimmune disease and HIV antibodies. Patients with clinically significant cardiac, pulmonary, or metabolic disease were ineligible, as well as patients with symptomatic central nervous system disease, serious recent infections, or requirement of systemic steroids or nonsteroidal anti-inflammatory agents.
Treatment Program.
Patients were scheduled to receive simultaneously s.c. injections of
GM-CSF (2.5 or 5 µg/kg), low-dose IL-2 (1, 4, or 8
MIU/m2) and IFN (5 MU regardless of body
weight). Saline (500 ml) was given the first day at the start of the
injections as a prophylactic measure against hypotension during fever.
Acetaminophen (up to 4 g/day) was given prophylactically 1 h after
the injections (1 g) and at the start of chills (1 g) and later on,
therapeutically, to mitigate fever and chills. Patients were entered in
groups of three. During the first 3–4 days, the s.c. injections were
given in the hospital to monitor toxicity and to instruct the patients
or family members to prepare and administer the s.c. injections, which
were given in different places (GM-CSF, upper left leg; IFN, upper
right leg; IL-2, abdomen). The cycle was continued at home for a total
of 12 days. A second cycle of 12 days was given at home after 9 days of
rest if no dose-limiting toxicity or PD disease was present.
Response was evaluated after two cycles; patients with response or with
SD were eligible for another two cycles.
Toxicity Grading and Dose Modifications.
The common toxicity criteria (CTC version 2.0) were used for
grading toxicity. In case of grade 4 fever (>40°C) with hypotension
requiring i.v. fluids, the patient received parenteral fluid per
continuous infusion, and treatment was withheld until the toxic
reaction improved to grade 1 or symptoms returned to baseline.
Subsequently, dose reduction was applied, which allowed patients to be
discharged and safely continue treatment at home. Other grade 3
toxicities were managed accordingly with symptomatic treatment.
Patients were discharged from hospital if 
grade 2 toxicity was
achieved with the exception of grade 3 fever and chills. If GM-CSF
induced leucocytosis of >30/nl, GM-CSF was stopped for the remainder
of the cycle.
Response Criteria.
A CR was defined as a complete disappearance of all of the known
measurable disease for at least 1 month; a PR, as a 50% or greater
decrease in the sum of the products of the largest diameters of all
evaluable disease, lasting 1 month; SD as <50% decrease or <25%
increase in evaluable lesions without new lesions, lasting 1 month; and
PD as >25% increase of known disease or appearance of new lesions.
|
Immunological Monitoring |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
Flow Cytometry.
To detect cellular differentiation markers on peripheral blood cell
samples taken before, during and after immunotherapy, WBCs were
collected from heparinized peripheral blood by lysis of red cells with
ammonium chloride. Triple staining was performed by the incubation of
cell samples in a mixture of fluorescein (FITC)-, R-PE-, and
PE-cychrome (Cy5)-conjugated mouse monoclonal antibodies,
directed to cellular differentiation markers, for 20 min at room
temperature followed by washing in PBS containing 0.2% BSA and 0.02%
azide. FITC and PE conjugates were obtained from Becton & Dickinson
Immunocytometry Systems (San Jose, CA) and cychrome-conjugates
from Coulter Immunotech (Mijdrecht, the Netherlands.) To prevent
aspecific binding via Fc-receptors, incubation was carried out
in the presence of 1% normal mouse serum (Central Laboratory of the
Netherlands Red Cross Blood Transfusion Service, Amsterdam, the
Netherlands). Fluorochrome-labeled isotype control antibodies were
included in each assay to determine background staining. Lymphocyte
(CD3+, CD19+, and CD16+56+) and monocyte (CD14+) populations were gated
according to their differential forward and side scatter, which was
confirmed by back-gating. Fluorescence was measured on a FACScan flow
cytometer (Becton & Dickinson, Mountain View, CA), and data were
analyzed using Cellquest software (Becton & Dickinson).
Cytokine Assays.
Cytokine levels were determined in plasma derived from EDTA-treated
blood that had been kept directly on ice after collection and promptly
centrifuged and frozen at -20°C, according to the manufacturer’s
instructions. The following cytokines were assayed by ELISA: sIL-2R
(Eurogenetics, Tesserderlo, Belgium) and soluble CD8/sCD8 (T cell
Diagnostics, Cambridge, MA). The measurable threshold levels were 100
units/ml for sIL-2R and 100 units/ml for sCD8.
Statistics.
Levels of circulating cells in peripheral blood and of cytokines at
various time points were compared by Student’s t test.
Ps < 0.05 were considered significant.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
. Performance score was 0 or 1, except
in one melanoma patient (patient 2). All of the patients received at
least one cycle of immunotherapy and were evaluable for toxicity and
response. Mean number of cycles was 3.0 (range, 1–6).
|
, only 1 of 3
patients at dose level 1 developed grade 3 fever. At dose level 2, 3 of
3 had grade 3 fever and chills, but no other grade 3 toxicity except
fatigue and malaise with a decrease in performance status to WHO
grade 3. At dose levels 3 and 4, all of the patients developed
grade 4 fever with chills and hypotension the first day, which could be
corrected by i.v. fluids within 12 h. In all of the patients the
dose of GM was reduced to 2.5 µg/kg (level 3) and the dose of IL-2 to
4 MIU/m2 (level 4). A further dose reduction of
IL-2 was necessary in three patients (in one patient, to 2
MIU/m2; in two, to 1
MIU/m2) to maintain systolic blood pressure at
>100 mm Hg without i.v. fluids (see Table 1
). These results defined
dose level 2 as the MTD. Six additional patients were entered at this
dose level to clearly establish the MTD. In 1 of 6 patients, dose
reduction of IL-2 to 2 MIU/m2 was necessary
because of grade 4 fever with hypotension. In two other patients, a
similar dose reduction of IL-2 was necessary because of fluid retention
that was not responsive to diuretics. Thus, in 3 of 9 patients starting
at the MTD, dose reduction of IL-2 to 2 MIU/m2
was necessary. No further toxicity requiring dose reduction was seen
during subsequent cycles at home. Dose-limiting toxicity was mainly
grade 4 fever with chills and hypotension on the first day and fluid
retention or severe malaise/fatigue with anorexia after 7–10 days. One
patient (patient 7) had angioedema at the start of the second cycle,
which was relieved rapidly by clemastine. A rechallenge with IL-2 and
IFN did not produce similar complaints, identifying GM-CSF as the
probable cause of this serious adverse event. Another patient (patient
16) experienced a CVA at the end of the third cycle with coma
and right-sided hemiplegia. A brain magnetic resonance image
showed bilateral infarction in the region of the medial cerebral
artery, without evidence of metastasis. Blood analysis showed mild
leukocytosis (16.0/nl). A relationship with immunotherapy was
considered possible. All of the therapy was stopped, and i.v. fluids
were given. The hemiplegia resolved, but the patient remained in a coma
and died 5 days later. He had no prior history of transient ischemic
attack or CVA; thus, a relationship with the treatment
is possible.
|
, of the seven patients with metastatic
melanoma, two showed PD, four showed SD, and one showed
PR. Additional cycles of immunotherapy in the patient with PR
did not result in further regression, and progression occurred 4 months
after achieving PR. Three patients had RCC with metastases; two showed
PD (one after one cycle, and one after two cycles). In the patient with
SD after two cycles, the primary tumor and LN metastases in the abdomen
were removed surgically. This patient received another two cycles of
immunotherapy but then showed PD. Of eight patients with progressive
RCC metastases who had previously undergone nephrectomy (in four of
eight patients, metastases were present at diagnosis) three showed
CR, four had SD, and one progressed. Patient 4 (with
mediastinal LN, lung, and bone metastases) achieved PR after two cycles
and CR after four cycles; patient 14 with lung metastases had a CR
after two cycles; and patient 15 with lung and pleural metastases and
abdominal relapse also had a CR after two cycles. Patients with CR
received two additional cycles of immunotherapy as consolidation. CRs
are maintained for 15+, 15+, and 8 months. Of the four patients with
RCC who achieved SD, one had a CVA at the third cycle, and three showed
progression after 3, 7, and 8 months. Median survival of all of the
patients was 11 months. After 1 year follow-up, 8 patients were alive
(five RCC, three melanoma). |
Effector Cell Numbers (Fluorescence-activated Cell-sorting) and Cytokines |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
. Increases of at least 3-fold or more were
found for NK cells in 10 of 18 patients as follows: in 4 of 4 patients
with a response, in 6 of 10 patients with SD, and in 0 of 4 patients
with PD; for CD3/DR, increases of at least 3-fold or more were found in
12 of 18 patients: in 3 of 4 with a response, in 8 of 10 with SD, and
in 1 of 4 with PD.
As tabulated in Table 3
, for the whole
group, a significant rise in absolute numbers of lymphocytes, T cells,
activated T cells (CD3/DR, comprising both activated CD4+ and CD8+T
cells), NK cells, neutrophils, and eosinophils was found when baseline
values were compared with day 12 of immunotherapy. Monocytes (CD14+)
did not increase. However, mean DR expression on monocytes was
already increased significantly at day 8, remained increased at day 12,
and returned to pretreatment levels after stopping (data not shown).
|
|
Effect of IL-2 Dose on Immunological Parameters |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
dose was kept constant and the GM-CSF dose had
to be reduced immediately from 5 µg/kg to 2.5 µg/kg after the first
day at dose level 3, the effect of the different IL-2 doses could be
studied; 1 MIU/m2 was used as the final dose in
five patients, 2 MIU/m2 in four patients, and 4
MIU/m2 in nine patients (Tables 1
and 4)
.
|
The increase in the number of NK cells and sCD8 seemed proportional to the IL-2 dose. Patients receiving 4 MIU IL-2/m2 reached significantly higher sCD8 and NK values than those receiving 1 MIU/m2 (P = 0.02).
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
given s.c. for 12 days. Dose-limiting toxicity was grade 4 fever
with hypotension requiring i.v. fluids and grade 3 fluid retention with
weight gain and severe fatigue and malaise.
Most IL-2-induced toxicities seem to be dose-related, with the highest
doses frequently requiring intensive-care-unit support
(17, 18, 19, 20, 21)
. s.c. IL-2 gives lower peak levels and less
toxicity, even with the same doses (21, 22, 23, 24, 25)
. Low-dose IL-2
s.c. can induce T cell activation without NK cell activation because
activated T cells have a high affinity for IL-2R in contrast to
NK cells, which have an IL-2R of intermediate affinity
(26, 27, 28)
. There has been only one report on the
combination of GM-CSF s.c. and IL-2 i.v. (15)
, in which
the MTD was 2.5 µg/kg GM-CSF and 4.5 MIU/m2 IL-2.
Dose-limiting toxicity in that study of concurrent GM-CSF and IL-2 were
primarily neurological and cardiovascular, apart from fever. In our
study, we also observed one patient with a fatal CVA, which is a
serious concern. Because of the data, we stopped GM-CSF when leukocytes
rose above 30/nl; this was seldom necessary, perhaps because we
combined it with IFN. It is not clear whether a high number of
leukocytes, especially eosinophils, is responsible for CVAs. In an
ongoing Phase II studies in RCC (30 patients) and melanoma (40
patients), no CVAs have been observed.3
Most of the
toxicities associated with s.c. administration of GM-CSF, low-dose
IL-2, and IFN seemed to be manageable. Treatment could be continued
at home after the first days in hospital. The combination of GM-CSF and
low-dose IL-2 seemed powerful in T cell activation and the induction of
T-LAK without NK-LAK, which may explain the limited toxicity due to
vascular leak syndrome (13
, 20)
.
Immunological Effects.
An important aspect of this study was in monitoring the response to
document which effector cells were expanded and activated. A
significant increase in circulating (activated) T cells (both CD4 and
CD8), NK cells, neutrophils, and eosinophils were found after 12 days
of treatment. Circulating monocyte numbers did not increase, but we did
find an increase of monocyte DR expression, probably due to GM-CSF. We
assume that DR expression is increased as well on dendritic cells,
because GM-CSF promotes differentiation of DC (29)
. The
increases in activated CD3 T cells (both CD4+ and CD8+) and NK cells
are probably relevant for the antitumor effect, but differences between
patients and the correlation with response should be studied in a
larger series. The role of eosinophils, which are clearly produced and
activated by GM-CSF and IL-2, is unclear, but they are often found as
infiltrating cells in tumor sites. In the study with GM-CSF and IL-2,
eosinophilia seemed to correlate with response (15)
.
Eosinophils may be important in view of the production of IL-12 and
histamine. They can produce similar amounts of IL-12 as macrophages
(30)
, which can skew T cell differentiation to the TH-1
and TC-1 direction, thought to be important for antitumor response
(31)
. Histamine has been shown to counteract the
depression of cytotoxicity of NK cells and T cells due to
O2 radicals and
H2O2 production by local
macrophages (32)
. sIL-2R and sCD8 both increased
significantly during combined immunotherapy and probably reflect not
only activation of CD4-T and CD8-T in the circulation, but also in
LNs and tumor. Similar increases in sIL-2R and sCD8 have been
described in patients with malignant lymphoma treated with GM-CSF alone
after intensive chemotherapy (33)
.
Relationship of Immunological Effects and IL-2 Dose.
IFN was kept constant; GM-CSF was doubled in dose level 3 (with 4
MIU/m2 IL-2) but had to be reduced immediately
from 5 µg/kg to 2.5 µg/kg because of grade 4 fever with
hypotension. Therefore, the effect of the IL-2 dose could be studied in
patients receiving 1 MIU/m2 (n =
5; in three patients as starting dose, in two patients after reduction
because of grade 4 fever with hypotension), 2
MIU/m2 (n = 4; patients started
with 8 or 4 MIU/m2 but reduced to 2
MIU/m2), and 4 MIU/m2
(n = 9; starting with that dose or reduced from 8
MIU/m2). Combined immunotherapy with 1
MIU/m2 did induce T cell activation (CD3/DR and
sIL-2R increases) but it remained restricted to CD4+T. Neither CD8+T
cells nor NK cells were significantly expanded or activated. The higher
dose of IL-2 (2 or 4 MIU/m2) resulted not only in
CD4+T, but also in CD8+T and NK cell expansion and activation. A larger
series and longer follow-up is necessary to determine whether there are
significant differences between 2 and 4 MIU/m2
IL-2. Prolonged administration of low-dose IL-2 can indeed induce an
increase in NK cell number and cytotoxic activity (34)
.
Remarkably, three of eight patients with progressive metastatic RCC after nephrectomy achieved CR. Efficacy is now being tested in Phase II trials in progressive metastatic RCC and in therapy-naïve metastatic melanoma patients (in the last category combined with chemotherapy). It seems feasible to give combined immunotherapy with these cytokines at home after hospitalization during the first days to establish the tolerated dose of IL-2.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be
addressed, at Division of Medical Oncology, Netherlands Cancer
Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone:
31-20-5122570; Fax: 31-20-5122572; E-mail: irene{at}nki.nl 
2 The abbreviations used are: RCC, renal cell
carcinoma; IL, interleukin; GM-CSF, granulocyte macrophage
colony-stimulating factor; PD, progressive disease; SD, stable disease;
PR, partial response; CR, complete response; IL-2R, IL-2 receptor;
sIL-2R, soluble IL-2R; CVA, cerebrovascular accident; LN, lymph node;
MTD, maximal tolerated dose; sCD8, soluble CD8; PE, phycoerytrin; LAK,
lymphokine-activated killer.
3 G. Groenewegen and G. C. de Gast. Sequential
chemoimmunotherapy (SCIT) for metastatic melanoma: outpatient treatment
with dacarbazine, molgramostim, interleukin-2, and interferon-,
submitted for publication.
Received 4/28/99; revised 12/ 1/99; accepted 1/19/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunological MonitoringRESULTSEffector Cell Numbers...Effect of IL-2 Dose...DISCUSSIONREFERENCES |
|---|
-interferon for the treatment of patients with advanced cancer. J. Clin. Oncol., 7: 1863-1874, 1989.[Abstract]
-2a and interleukin-2 for the treatment of metastatic cancer. J. Clin. Oncol., 13: 1110-1122, 1995.[Abstract]
-2a for metastatic melanoma. J. Clin. Oncol., 11: 2173-2180, 1993., and interleukin-2 for patients with metastatic melanoma. J. Clin. Oncol., 16: 1752-1759, 1998.[Abstract]
2b in advanced human malignancies. Lancet, 335: 1509-1512, 1990.[CrossRef][Medline]
molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytotoxicity. Eur. J. Immunol., 26: 1308-1313, 1996.[Medline]
This article has been cited by other articles:
|
|
 |
|
  P.-H. Zahl, J. Maehlen, and H. G. Welch The Natural History of Invasive Breast Cancers Detected by Screening Mammography Arch Intern Med, November 24, 2008; 168(21): 2311 - 2316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Luiten, E. W.M. Kueter, W. Mooi, M. P.W. Gallee, E. M. Rankin, W. R. Gerritsen, S. M. Clift, W. J. Nooijen, P. Weder, W. F. van de Kasteele, et al. Immunogenicity, Including Vitiligo, and Feasibility of Vaccination With Autologous GM-CSF-Transduced Tumor Cells in Metastatic Melanoma Patients J. Clin. Oncol., December 10, 2005; 23(35): 8978 - 8991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Weber, S. O'Day, M. Rose, R. Deck, P. Ames, J. Good, J. Meyer, R. Allen, S. Trautvetter, M. Timmerman, et al. Low-Dose Outpatient Chemobiotherapy With Temozolomide, Granulocyte-Macrophage Colony Stimulating Factor, Interferon-{alpha}2b, and Recombinant Interleukin-2 for the Treatment of Metastatic Melanoma J. Clin. Oncol., December 10, 2005; 23(35): 8992 - 9000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. van Oijen, A. Bins, S. Elias, J. Sein, P. Weder, G. de Gast, H. Mallo, M. Gallee, H. van Tinteren, T. Schumacher, et al. On the Role of Melanoma-Specific CD8+ T-Cell Immunity in Disease Progression of Advanced-Stage Melanoma Patients Clin. Cancer Res., July 15, 2004; 10(14): 4754 - 4760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. O'Day, P. D. Boasberg, L. Piro, T. S. Kristedja, H.-J. Wang, M. Martin, R. Deck, P. Ames, K. Shinn, H. Kim, et al. Maintenance Biotherapy for Metastatic Melanoma with Interleukin-2 and Granulocyte Macrophage-Colony Stimulating Factor Improves Survival for Patients Responding to Induction Concurrent Biochemotherapy Clin. Cancer Res., September 1, 2002; 8(9): 2775 - 2781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Crul, G. J. de Klerk, M. Swart, L. J. van't Veer, D. de Jong, L. Boerrigter, P. A. Palmer, C. J. Bol, H. Tan, G. C. de Gast, et al. Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer J. Clin. Oncol., June 1, 2002; 20(11): 2726 - 2735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. de Gast, F. A. Vyth-Dreese, W. Nooijen, C. J.C. van den Bogaard, J. Sein, M. M.J. Holtkamp, G. A.M. Linthorst, J. W. Baars, J. H. Schornagel, and S. Rodenhuis Reinfusion of Autologous Lymphocytes With Granulocyte-Macrophage Colony-Stimulating Factor Induces Rapid Recovery of CD4+ and CD8+ T Cells After High-Dose Chemotherapy for Metastatic Breast Cancer J. Clin. Oncol., January 1, 2002; 20(1): 58 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-L. H. Skog, M. Wadhwa, M. Hassan, B. Gharizadeh, C. Bird, P. Ragnhammar, R. Thorpe, and H. Mellstedt Alteration of Interleukin 2 (IL-2) Pharmacokinetics and Function by IL-2 Antibodies Induced after Treatment of Colorectal Carcinoma Patients with a Combination of Monoclonal Antibody 17-1A, Granulocyte Macrophage Colony-Stimulating Factor, and IL-2 Clin. Cancer Res., May 1, 2001; 7(5): 1163 - 1170. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
