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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2292-2298 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3165 Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma
From the Vanderbilt University Medical Center, Nashville, TN; Earle A. Chiles Research Institute, Portland, OR; Wayne State University, Detroit, MI; Beth Israel Deaconess Medical Center, Boston, MA; Loyola University Medical Center, Maywood, IL; Our Lady of Mercy Medical Center, Bronx, NY; City of Hope Medical Center, Duarte, CA; University of Pittsburgh Medical Center, Pittsburgh, PA; and Dartmouth Hitchcock Medical Center, Lebanon, NH Corresponding author: Jeffrey A. Sosman, MD, Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307; e-mail: jeff.sosman{at}vanderbilt.edu
Purpose High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. Patients and Methods In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.
Results From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at Conclusion The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.
The median survival time for patients with advanced melanoma remains dismal at 6 to 10 months.1 Chemotherapy with dacarbazine has a response rate (RR) of only 5% to 20%, with most responses being short lived. Chemotherapy combined with biologic agents provides no survival benefit.1-3 In a report on 270 patients with melanoma, high-dose bolus interleukin-2 (IL-2) therapy produced a 16% objective RR with long-lasting responses in select patients (5% to 8%); thus, the US Food and Drug Administration approved high-dose IL-2 in patients with melanoma. Previous attempts to enhance high-dose IL-2 efficacy in patients with melanoma have been largely unsuccessful.4-9 A number of immunogenic peptides derived from tissue (lineage) -restricted antigens, cancer-testis antigens, and rarely mutated cancer-specific antigens have been identified in melanoma, and many have the ability to induce antimelanoma T-cell responses.10-16 A peptide derived from gp100 (a lineage-restricted antigen) has been synthesized in a mutated (heteroclitic) form for the purpose of enhancing HLA-A2.1 binding. This peptide, gp100:209-217(210M) binds with a higher affinity to HLA-A2 than the native peptide and induces better T-cell stimulation in vitro and in vivo.17 Initial clinical trials at the National Cancer Institute (NCI) with 210M demonstrated induction in peripheral blood of peptide- and tumor-specific cytotoxic T-lymphocyte responses in 10 of 11 patients with HLA-A2.1–positive melanoma, although no definitive antitumor activity was observed.18,19 However, clinical experience combining 210M followed by IL-2 (high-dose bolus) demonstrated tumor responses in 13 (42%) of 31 patients.18 Patients were treated with different schedules of peptide vaccines and IL-2. In responding patients receiving IL-2 early in their course of treatment, circulating tumor-specific T cells were not generated, questioning their role as a biomarker of clinical activity. We evaluated different schedules of peptide vaccine plus high-dose IL-2 in three separate, single-arm, and single-stage phase II trials to define which schedule was most promising. The three schedules were chosen based on our discussion with the investigators at the NCI-Surgery Branch and the similarity to the regimens used by them, as previously reported.18 Our primary intent was to determine whether more extensive testing of any of the schedules was justified.
Patient Eligibility Patients with advanced melanoma were HLA-A2 positive by serology, flow cytometry, or molecular techniques (HLA-A2.1). Patients had an Eastern Cooperative Oncology Group performance status of 0 to 1 and adequate organ function for high-dose IL-2 therapy. Normal exercise stress test and forced expiratory volume in 1 second more than 2.0 L or 75% predicted were required. Patients with brain metastases or prior IL-2 therapy were ineligible. The protocol was approved by the institutional review boards at each of the participating centers, and written informed consent was required.
Therapeutic Agents Montanide ISA-51 adjuvant. Montanide ISA-51 (NSC 675756) is an oil-based adjuvant similar to incomplete Freund's. The product is manufactured by Seppic, Inc (Fairfield, NJ) and was provided by CTEP. IL-2. Commercial recombinant human IL-2 (Proleukin; Chiron, Emeryville, CA), lyophilized in vials containing 22 million U (approximately 1.3 mg), was reconstituted with 1.2 mL of sterile water for injection.
Treatment Plan
Patients underwent tumor response assessments at week 12 by WHO criteria.20 Patients with stable disease, partial response (PR), or complete response (CR) could receive another course of treatment, whereas patients with disease progression were removed from protocol. All responses were confirmed at 3 months, and the RR was based on best response any time after treatment had been initiated. Patients could receive up to three 12-week courses of IL-2 and 36 weeks of vaccine. Vaccine alone could be administered without further IL-2. Progression-free survival (PFS) was defined as the time from trial entry to the time of documented objective disease progression or death. Overall survival (OS) was defined as the time from trial entry until death. Treatment modifications were made by withholding doses of IL-2 for life-threatening toxicities including refractory hypotension, hypoxia, anuria, acidosis, and mental status changes. Toxicity was managed based on guidelines of the Cytokine Working Group (CWG).21 No dose modifications were required for the vaccinations because there were no systemic or severe local skin reactions.
Immunologic Assessments
Flow Cytometry Analysis
Surface staining of PBMC with CD14-FITC, CD11b-PE, CD15-PC5, and CD15-isotype control was at 4°C, and staining of CD8PerCP, gp100 PE, Flu PE, and CD15-isotype control was at room temperature. Cells were washed and then analyzed on FC500 cytometer (Beckman Coulter). Lymphocytes were first stained using CD4-FITC and CD25-APC (eBioscience, San Diego, CA). After fixation and permeabilization, FoxP3-PE was added. Cells were washed and fixed with 1% formaldehyde in phosphate-buffered saline. For analysis, CD4+ and CD25+ cells were gated and analyzed for FoxP3. Isotype controls for all antibodies were included.
Statistical Analysis To examine immune cell populations and clinical efficacy (CR, PR, or PFS > 12 months), repeated measures analysis of variance methods were used for paired (pre- and post-treatment) data within each subject. These methods take the paired nature of the data into account, resulting in a test statistic that is equivalent to a paired t test. The data are assumed to be normally distributed because the immune cells are measured as percentage of cells expressing the phenotype. The data are interval data (eg, bounded by 0 to 100), and not discrete samples from Poisson, Bernoulli, or binomial distributions. These tests were used to compare data both within response groups (before and after treatment) and between response groups (pretreatment and post-treatment responders and nonresponders). We tested time (before and after treatment), response, and the time by response interaction in these models. We used the log-rank test statistic to examine the difference in survival between the cohorts. Rather than show all of the pair-wise CIs, we chose to show them within response group differences along with the actual data. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC).
Patients With Melanoma A total of 131 patients were enrolled from September 1998 to November 2003 at eight institutions. Clinical data were available for 121 patients. One patient did not have melanoma, and nine patients were lost to follow-up and excluded from the analysis. The characteristics of the 121 patients are listed in Table 1. More than 65% of patients had M1c disease. All three cohorts were similar in patient characteristics, except that trial 2 enrolled fewer patients who had received adjuvant interferon and more patients with lactate dehydrogenase (LDH) elevations. Neither of these differences was statistically significant.
Treatment Administration and Toxicities Toxicity of high-dose IL-2 was primarily assessed by reduction in the number of IL-2 doses administered. Toxicity was not affected by the 210M peptide administration.21,22 Vascular leak syndrome and mental status changes were the primary reasons for withholding doses of IL-2. Three patients died of progressive melanoma during the initial 12 weeks of the study. Fourteen patients did not receive IL-2 therapy (12 patients on trial 2), many as a result of a decline in performance status from disease progression during the initial weeks of vaccination, which prevented IL-2 administration. These patients were included in the analysis. Of patients who received  one dose of IL-2, those on trial 3 received the most doses, with a median of 35 of 56 possible doses (range, eight to 51 doses) for the 12 weeks. Patients receiving one dose of IL-2 in both trials 1 and 2 received a median of 20 of 28 IL-2 doses. The number of doses ranged from nine to 27 in trial 2 and from 11 to 27 in trial 1. The only direct toxicities caused by the peptide vaccine were local swelling and discomfort. No episodes of uveitis, thyroiditis, or other autoimmune sequelae were recorded, and vitiligo was observed in some responders but not systematically collected.23 The number of patients who received additional 12-week courses of vaccine and/or IL-2 is presented in Table 2.
Tumor Responses, Durability of Responses, OS, and PFS With a median follow-up time of 60 months (range, 30 to 74 months), there were 20 clinical responses (16%) among 121 assessable patients (Table 3). Trial 1 had the highest RR of 23.8% (10 of 42 patients), trial 2 had an RR of 12.5% (five of 40 patients), and trial 3 had an RR of 12.8% (five of 39 patients). None of the schedules (trials) reached the 30% RR targeted in the trial. Overall, nine of the responses (7%) were PRs, and 11 (9%) were CRs. Nine of the 11 patients who achieved CR remain progression free (PF) at 30+ to 73+ months (30+, 30+, 38+, 40+, 42+, 46+, 46+, 46+, and 73+ months), whereas two patients experienced progression at 17 and 51 months. Only one of the nine patients who achieved PR remains PF at 30+ months. Five of the patients with PR experienced disease progression in less than 12 months.
The median PFS time was 3 months (time of initial tumor evaluation) for each of the three trials (log-rank test for difference in PFS between trials, P = .165; Appendix Fig A1, online only). Eleven patients (9%) remain PF with more than 30 months follow-up. Patients who are PF include seven patients in trial 1, three in trial 2, and one in trial 3. At the time of this analysis, there were 18 patients (15%) who remained alive for 30+ to 70+ months. The median OS time of the entire group was similar in each trial (range, 13.7 to 15.4 months) or slightly under 15 months combined (log-rank test for difference in OS between trials, P = .723; Appendix Fig A2, online only).
Immunologic Studies and Clinical Correlations
In advanced melanoma, high-dose IL-2 has an RR of 16%, with a 5-year PFS rate of more than 5% (14 of 270 patients).3 In 1998, Rosenberg et al18 reported on 31 patients with melanoma receiving both 210M and high-dose IL-2, with an RR of 42% (13 of 31 patients). We report the clinical results of three separate phase II trials with 210M peptide vaccine and high-dose IL-2 against melanoma. None of the three trials reached the target clinical activity (30% RR) to proceed to an adequately powered phase III trial. Why do our results differ from the NCI trial?18 Patient characteristics such as performance status, LDH level, prior chemotherapy, and disease organ sites may have significantly differed in the two studies and are not available for the NCI-SB trial.30 The NCI-SB has shown that certain characteristics are associated with responses to IL-2, such as subcutaneous or cutaneous disease.31 The CWG administered smaller doses of IL-2 (600,000 U/kg in CWG study v 720,000 U/kg in NCI-SB study), but the number of doses administered was greater in the CWG trial, with 20 doses over a 3-week period versus 13 to 14 doses for the NCI-SB. This more than compensated for the difference per dose. Finally, patients who travel to the NCI are a self-selected group of patients, which could impact on patient characteristics.
The overall RR of 16.5% was similar to HD IL-2 alone.3 Ten patients remain PF with
Unfortunately, our attempts to define immune correlates of response were unsuccessful in the 53 patients for whom pre- and post-treatment specimens were available. Ten of these patients had objective clinical responses. The populations of immune cells assessed were chosen because all four populations play a potential role in an antitumor immune response. The gp100-specific CD8 T cells represent the vaccine-induced effector T cells, whereas the CD4+/CD25+/FoxP3+ Tregs suppress effective T-cell responses by effector T cells, and the MDSCs (CD11b+/CD15+/CD14–) represent a population that also suppresses T-cell responses. Finally, low CD3- The main limitation in the immune testing is the amount of intrasubject variation inherent in the assays. Using pre- and post-treatment paired samples is generally an analytic approach for data with this type of variation. The results have limitations because the trials are not randomized and each cohort was relatively small. This set of phase II trials cannot definitively establish whether or not vaccine adds to the benefit of IL-2, but we did not reach the 30% RR that was targeted a priori. Powering this type of study effectively is difficult. Serum LDH levels were elevated in only 18 of those patients tested and do not explain the variability of the groups. A great need exists to learn whether any biomarker might predict clinical outcome.32 Our results should not deter others from pursuing biomarkers that can predict response to immunotherapy. Functional studies were not feasible because of the number of cells collected and concern for loss of function with processing.33 The timing of the sample collections may be critical, and although samples were all obtained at week 12, the time after IL-2 dosing was variable. Two different approaches might have made the immune assays more informative. Most important is the need to examine the tumor site, not the peripheral blood, for immunologic changes. Changes in the blood may not reflect changes in tumor. Also, assays that include T-cell function may have been more useful, such as enzyme-linked immunosorbent spot assays for cytokine release or flow cytometry for intracellular cytokine expression. Given our results, the combination of 210M peptide vaccine and high-dose IL-2 does not seem to represent a significant advance. This does not substitute for a phase III trial of high-dose IL-2 with or without peptide vaccination, which is ongoing and will accrue 160 patients. On the basis of our results (trial 1), this phase III trial could be underpowered to detect a difference. We must find better treatments for patients with melanoma. Peptide vaccines alone are likely not going to be the answer. Advances in immunization methods, understanding mechanisms of escape from immunotherapy, and improved assays for immune activation have all taken place since this trial.24-29 Presently, attempts to overcome host immune suppression induced by tumor is a major target of tumor immunology. Attempts include elimination of Tregs, induction of the differentiation of MDSCs, and utilization of ex vivo autologous tumor-specific T cells (adoptive cellular therapy) with nonmyeloablative chemotherapy and cell infusion with high-dose IL-2.33-37 These approaches are under investigation and will hopefully fulfill their promise to improve therapy of patients with advanced melanoma.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Michael B. Atkins, Novartis/Chiron (C); Janet Dutcher, Novartis/Chiron (C); Marc S. Ernstoff, Novartis/Chiron (C) Stock Ownership: None Honoraria: Lawrence Flaherty, Novartis/Chiron; Michael B. Atkins, Novartis/Chiron; Joseph I. Clark, Novartis/Chiron; Janet Dutcher, Novartis/Chiron; Kim A. Margolin, Novartis/Chiron; Jarod Gollob, Novartis/Chiron; Marc S. Ernstoff, Novartis/Chiron Research Funding: Jeffrey A. Sosman, Novartis; Lawrence Flaherty, Novartis/Chiron; Michael B. Atkins, Novartis/Chiron; Joseph I. Clark, Novartis/Chiron; Janet Dutcher, Novartis/Chiron; Kim A. Margolin, Novartis/Chiron; Jarod Gollob, Novartis/Chiron; Marc S. Ernstoff, Novartis/Chiron Expert Testimony: None Other Remuneration: None
Conception and design: Jeffrey A. Sosman Provision of study materials or patients: Jeffrey A. Sosman, Walter J. Urba, Lawrence Flaherty, Michael B. Atkins, Joseph I. Clark, Janet Dutcher, Kim A. Margolin, James Mier, Jarod Gollob, John M. Kirkwood, David J. Panka, Nancy A. Crosby, Kevin O'Boyle, Marc S. Ernstoff Collection and assembly of data: Jeffrey A. Sosman, Carole Carrillo, David J. Panka Data analysis and interpretation: Jeffrey A. Sosman, Bonnie LaFleur Manuscript writing: Jeffrey A. Sosman, Walter J. Urba, Michael B. Atkins, Kim A. Margolin, Bonnie LaFleur, David J. Panka, Marc S. Ernstoff Final approval of manuscript: Jeffrey A. Sosman, Carole Carrillo, Walter J. Urba, Lawrence Flaherty, Joseph I. Clark, Janet Dutcher, Kim A. Margolin, James Mier, Jarod Gollob, David J. Panka, Nancy A. Crosby, Kevin O'Boyle, Bonnie LaFleur, Marc S. Ernstoff
Supported by a research grant from Chiron Pharmaceuticals (Emeryville, CA); support from Cancer Therapy Evaluation Program–National Cancer Institute, which held the Investigation New Drug Applications for gp100:209-217(210M) (NSC 683472) and Montanide ISA-51 (NSC 675756); and K24 Grant No. 5K24-CA097588 (J.A.S.). Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Eggermont AM, Kirkwood JM: Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years? Eur J Cancer 40:1825-1836, 2004[CrossRef][Medline] 2. Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 351:998-1012, 2004 3. 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 17:2105-2116, 1999: 4. Sosman JA, Weiss GR, Margolin KA, et al: Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: Clinical and immunologic effects. J Clin Oncol 11:1496-1505, 1993 5. Whitehead RP, Friedman KD, Clark DA, et al: Phase I trial of simultaneous administration of interleukin 2 and interleukin 4 subcutaneously. Clin Cancer Res 1:1145-1152, 1995[Abstract] 6. Sosman JA, Fisher SG, Kefer C, et al: A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Ann Oncol 5:447-452, 1994 7. Sparano JA, Fisher RI, Sunderland M, et al: Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11:1969-1977, 1993 8. Rosenberg SA, Lotze MT, Yang JC, et al: Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85:622-632, 1993 9. Rosenberg SA, Aebersold P, Cornetta K, et al: Gene transfer into humans: Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323:570-578, 1990[Abstract] 10. Boon T: Tumor antigens recognized by cytolytic T lymphocytes: Present perspectives for specific immunotherapy. Int J Cancer 54:177-180, 1993[Medline] 11. Kawakami Y, Eliyahu S, Delgado CH, et al: Identification of a human melanoma antigen recognized by tumor infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A 91:6458-6462, 1994 12. Kawakami Y, Eliyahu S, Delgado CH, et al: Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A 91:3515-3519, 1994 13. Kawakami Y, Eliyahu S, Sakaguchi K, et al: Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2 restricted tumor infiltrating lymphocytes. J Exp Med 180:347-352, 1994 14. Kawakami Y, Eliyahu S, Jennings C, et al: Recognition of multiple epitopes in the human melanoma antigen gp 100 by tumor infiltrating T-lymphocytes associated with in vivo tumor regression. J Immunol 154:3461-3968, 1995[Abstract] 15. Rivoltini L, Loftus DJ, Barracchini K, et al: Binding and presentation of peptides derived from melanoma antigens MART-1 and glycoprotein-100 by HLA-A2 subtypes: Implications for peptide-based immunotherapy. J Immunol 156:3882-3891, 1996[Abstract] 16. Rosenberg SA: Progress in human tumor immunology and immunotherapy. Nature 411:380-384, 2001[CrossRef][Medline] 17. Parkhurst MR, Salgaller ML, Southwood S, et al: Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. J Immunol 157:2539-2548, 1996[Abstract] 18. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321-327, 1998[CrossRef][Medline] 19. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 20. Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: Moving beyond current vaccines. Nat Med 10:909-915, 1998 21. Margolin KA, Rayner AA, Hawkins MJ, et al: Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: Analysis of toxicity and management guidelines. J Clin Oncol 7:486-498, 1989[Abstract] 22. Rosenberg SA, Yang JC, Topalian SL: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 271:907-913, 1994 23. Rosenberg SA, White DE: Vitiligo in patients with melanoma: Normal tissue antigens can be targets for cancer immunotherapy. J Immunother Emphasis Tumor Immunol 19:81-84, 1996[Medline] 24. Mizoguchi H, O'Shea JJ, Longo DL, et al: Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795-1798, 1992 25. Ochoa AC, Longo DL: Alteration of signal transduction in T cells from cancer patients. Important Adv Oncol 55:43-54, 1995 26. Zou W: Regulatory T cells, tumor immunity, and immunotherapy. Nat Rev Immunol 6:295-307, 2006[CrossRef][Medline] 27. Fehervari Z, Sakaguchi S: CD4+ Tregs and immune control. J Clin Invest 114:1209-1217, 2004[CrossRef][Medline] 28. Kusmartsev S, Gabrilovich DI: Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55:237-245, 2006[CrossRef][Medline] 29. 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 166:678-689, 2001 30. 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 18:3782-3793, 2000 31. Phan GQ, Attia P, Steinberg SM, et al: Factors associated with response to high-dose Interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477-3482, 2001 32. Roberts JD, Niedzwiecki D, Carson WE, et al: Phase 2 study of the g209-2M melanoma peptide vaccine and low-dose interleukin-2 in advanced melanoma: Cancer and Leukemia Group B 509901. J Immunother 29:95-101, 2006[CrossRef][Medline] 33. Keilholz U, Weber J, Finke JH, et al: Immunologic monitoring of cancer vaccine therapy: Results of a workshop sponsored by the Society for Biological Therapy. J Immunother 25:97-138, 2002[Medline] 34. Dannull J, Su Z, Rizzieri D, et al: Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623-3633, 2005[CrossRef][Medline] 35. Gabrilovich DI, Ishida T, Nadaf S, et al: Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5:2963-2970, 1999 36. Kusmartsev S, Cheng F, Yu B, et al: All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63:4441-4449, 2003 37. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002 Submitted July 16, 2007; accepted January 25, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14– immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. 
