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Originally published as JCO Early Release 10.1200/JCO.2005.01.109 on October 3 2005 © 2005 American Society of Clinical Oncology. Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT Address reprint requests to Luis H. Camacho, MD, MPH, Phase I Program/Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 422, Houston, TX 77030; e-mail: lhcamacho{at}mdanderson.org.
PURPOSE: Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206. PATIENTS AND METHODS: Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose. RESULTS: Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response. CONCLUSION: CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.
Evidence from experimental carcinogenesis models demonstrates that tumors develop more frequently in immune-suppressed hosts, incriminating a central role of immune surveillance in the pathogenesis of cancer.1 Likewise, human subjects with congenital or acquired immune suppression have an increased frequency of cancer (for review, see Dunn et al2). However, these antitumor immune protective mechanisms ultimately fail to control tumor growth adequately in patients with progressive cancer. Immune failure may be due to tumor-induced immune escape or immune system homeostatic negative regulatory pathways. Blockade of mechanisms of immune system negative regulation may result in tumor regression by boosting the natural immune response against cancer.3 CTLA4 (CD152) is an activation-induced, type I transmembrane protein expressed by T lymphocytes and monocytes3-5 that functions as an inhibitory receptor for the costimulatory molecules B7.1 (CD80) and B7.2 (CD86). In resting T lymphocytes, B7 molecules are recognized by the activating receptor CD28, a molecule constitutively expressed on the surface of T lymphocytes. B7/CD28 interactions provide the second signal for T-cell activation, after antigen recognition has taken place through the interaction of major histocompatibility complex (MHC) and T-cell receptors (TCRs). After activation, T cells upregulate CTLA4, which successfully competes for binding to B7 molecules, due to a much higher binding affinity. Cross linking of CTLA4 by B7 in the context of TCR engagement inhibits TCR signaling, IL-2 gene transcription and T-cell proliferation.3,4 In addition, CD4+ CD25+ T-regulatory (T-reg) cells constitutively expressing CTLA4 provide reverse signaling through B7 costimulatory molecules directly to T cells,6 or indirectly through dendritic cells (DCs).7,8 CTLA4/B7 interaction results in the induction of indolamine 2,3 dioxygenase (IDO) in a subset of DCs, a rate-limiting enzyme on tryptophan catabolism.7 IDO-expressing DCs acquire potent and dominant T cell–suppressive properties.9 The critical inhibitory role of CTLA4 on T-cell homeostasis and maintenance of peripheral self-tolerance is clearly exemplified by the lethal lymphoproliferation and autoimmunity in CTLA4 gene knock-out mice.10,11 CP-675,206 is a fully human IgG2 monoclonal antibody with high CTLA4 specificity. CP-675,206 antagonizes the binding of CTLA4 to B7 ligands resulting in enhanced T-cell activation, as demonstrated by increased cytokine production tested in in vitro assays.12 Original work conducted primarily by Allison's group demonstrated that CTLA4 blocking antibodies induced rejection of established tumors and immunologic memory in murine models.3,4 In nonhuman primates, anti-CTLA4 antibodies enhanced T-cell and antibody responses to an infectious-disease vaccine and a whole tumor cell vaccine.13 Three prior studies testing the safety and antitumor activity of a different anti-CTLA4 monoclonal antibody have been published.14-16 These studies attest to the biologic and clinical activity of this class of agents. We herein present the results of a single intravenous (IV) infusion, dose-escalation, phase I clinical trial demonstrating that CP-675,206 can be administered safely at doses that result in immune activation against self-tissues and objective antitumor responses in patients with melanoma.
Trial Objectives Thirty-nine patients with solid malignancies were enrolled between January 2002 and August 2003 at the University of California, Los Angeles (Los Angeles, CA) and M.D. Anderson Cancer Center (Houston, TX). This was the first-in-human, open label, phase I dose-escalation study of a single, IV infusion of CP-675,206. The protocol and consent forms, and all modifications, were approved by the local institutional review boards (IRBs). The M.D. Anderson Cancer Center IRB allowed only patients with advanced and measurable disease to participate; all other parameters were common to both study sites. The primary objective was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose. Secondary objectives were to evaluate safety, tolerability, pharmacokinetics (PK), and antitumor activity of CP-675,206.
Study Design and Drug Administration
Redosing
Eligibility Criteria
Study Procedures
Criteria for Tumor Response
Statistical Analysis
Patient Characteristics Thirty-nine patients were enrolled between January 2002 and August 2003. This trial had broad subject eligibility, allowing inclusion of patients with resected tumors at high risk of relapse and patients with metastatic disease regardless of prior therapy (see Patients and Methods). The rationale was that the assessment of the trial primary end points (ie, toxicity and immune activation) could be fulfilled with patients regardless of the presence of measurable disease. As the trial progressed, the study investigators focused on enrolling patients with measurable metastatic melanoma, which was hypothesized to be a tumor type more likely to show demonstrable benefit from this immunologic intervention. CP-675,206 was administered to four patients (10%) in the adjuvant setting, to 11 (28%) as front-line therapy for metastatic disease, and to 24 (62%) as second or greater line of therapy for metastatic disease (Table 1). Most had melanoma (34 patients, 87%). Twenty-eight (80%) of 35 patients with metastatic disease had visceral metastasis.
Toxicity Three of six patients at 15 mg/kg experienced DLTs (Table 2). Therefore, the immediately lower dose level, 10 mg/kg, was considered the MTD. The DLTs were dermatitis and diarrhea. Dermatitis presented most often as a pruriginous maculopapular erythema, typically developing within 2 weeks from dosing and lasting for less than 1 month (Figs 1A and 1B). In one patient, biopsy of active skin lesions revealed a perivascular lymphocytic and eosinophilic infiltrate. Diarrhea was watery without blood or leukocytes, and also typically presented within 2 weeks and lasted 2 to 3 weeks. Two patients with grade 3 diarrhea (patient 115 at 6 mg/kg, and patient 12 at 15 mg/kg) underwent colonic biopsies, one of them revealing intraepithelial lymphocytic infiltrates consistent with lymphocytic colitis (Fig 1C) and the other without evidence of these infiltrates. A patient dosed at 1.0 mg/kg had reactivation of Clostridium difficile colitis in the setting of a prior history of relapsing infectious colitis triggered by antibiotic therapy, but no prior events for more than 6 months before CP-675,206 dosing. This patient was eligible for redosing, and the diarrhea reappeared after redosing at 6 mg/kg, this second time being C difficile negative. All other cases of diarrhea were C difficile negative. Several patients at the highest dose cohorts developed asymptomatic elevations of amylase, lipase, and liver enzymes. Two patients had worsening of pre-existing vitiligo and one developed de novo vitiligo. One patient developed panhypopituitarism, which spontaneously resolved over the next 3 months (Fig 1D). One patient developed asymptomatic autoimmune thyroiditis with elevated antithyroglobin and anti–thyroid peroxidase antibodies, which normalized within 1 month. The patient later developed hypothyroidism requiring chronic replacement therapy. With the exception of hypothyroidism and vitiligo, toxicities resolved within weeks without corticosteroids or other immune suppressants. Neither the cytokine release syndrome nor hypersensitivity reactions were observed.
Clinical Outcome Four patients with melanoma experienced objective antitumor responses (Table 3). Patient 113 (3 mg/kg) had residual (biopsy-proven) melanoma metastatic to the lungs after therapy with a MART-1 peptide-pulsed DC vaccine approximately 1 year earlier, and two doses of another CTLA4 blocking monoclonal antibody, the last one 6 months before receiving CP-675,206. This patient has been recently reported within a cohort of 10 patients receiving a MART-1 peptide–ulsed DC vaccine.24 The patient underwent an open–lung biopsy before participating in the current trial, which revealed the presence of a lung mass with active melanoma. She attained a complete response (CR) after dosing with CP-675,206, and is currently receiving maintenance with CP-675,206. Patient 125 (10 mg/kg) had progressive malignant melanoma to the skin, lung, liver and peritoneum after biochemotherapy and attained a partial response (PR; Fig 2A). He is currently receiving CP-675,206 maintenance with residual small lung lesions at 26+ months. Patient 12 (15 mg/kg) had decrease in size in lung metastasis labeled as stable disease (SD) at the end of study (day +90), and eventually evolved to have criteria of a PR at 18 months from dosing. This patient continues in PR at 25+ months with two subsequent doses of CP-675,206. Patient 13 (15 mg/kg) had metastatic disease in the lung and experienced a CR. He remains free of disease at 25+ months without further therapy (Fig 2B).
Four patients were classified as having SD as best overall response (patient 102/119, 0.01 mg/kg and 3 mg/kg redosing; patient 110, 3 mg/kg; patient 120, 6 mg/kg; patient 128, 10 mg/kg). Two of these patients had stabilization of lung metastases and two of soft tissue disease (lymph node and subcutaneous tissue) ranging from 4 to 16 months (Table 3). In addition, patient 126 (15 mg/kg) entered the study after surgical resection of a large thoracic tumor, with positive margins of resection and residual bilateral pulmonary subcentimeter nodularities. This patient did not meet criteria of measurable disease and her tumor response could not be assessed, but she did experience 16 months without apparent disease progression. She has since developed brain metastases, treated with irradiation and temozolomide plus thalidomide. Five patients classified as having SD or progressive disease (PD) at end of study evaluation underwent surgical resection of residual lesions, which was followed with long periods of disease-free survival. Patient 108, originally dosed at 1.0 mg/kg, had metastatic mucosal melanoma to the bone and received redosing at 6.0 mg/kg. This patient developed a submandibular nodal tumor recurrence. After complete resection of this node, the patient continues to be alive and currently without evidence of disease after complete resolution of bone lesions (evaluated by bone scan, positron emission tomography and magnetic resonance imaging) at 36+ months. Patient 110 (3 mg/kg) had a history of resected brain and lung metastasis, and entered the trial with progressive subcutaneous metastasis. This patient had progression after CP-675,206 and a subsequent DC-based vaccine trial. The two metastatic sites were later resected and the patient continues to be alive with no evidence of disease (NED) at 35+ months. Patient 11 (15 mg/kg) had progression of liver metastasis and underwent complete surgical resection followed by a multipeptide vaccine, and remains without relapse at 26+ months. Patient 127 (15 mg/kg) had a solitary liver lesion and developed progressive small bowel metastasis after dosing. The bowel metastases were resected and the liver lesion underwent radiofrequency ablation; the patient remains without relapse at 24+ months. Patient 14 had regression of multiple lung metastases but increase in the size of a single chest wall lesion, which was resected at the end of study follow-up (Fig 2C). Surgical resection of the residual mass demonstrated an extensive infiltrate of macrophages within and around areas of tumor necrosis. This was labeled as PD by radiologic size criteria, but may very well reflect a misclassification of the response based on imaging of an ongoing inflammatory response. This patient continues without relapse at 23+ months.
PK
Logistic modeling of the data from patients with melanoma indicates that there is a statistically significant relationship between efficacy measured as clinical benefit response (CR, PR, or SD, and patient 14) and systemic exposure to CP-675,206 measured both as the AUC (P = .015) and the plasma concentration of CP-675,206 4 weeks postdosing (P = .006, Fig 3B). The predicted probability of experiencing a clinical benefit response without exposure to CP-675,206 is 0.077 (90% CI, 0.020 to 0.247). In contrast, the predicted probability of clinical benefit response at the highest value of AUC seen in this study is 0.843 (90% CI, 0.184 to 0.992). Based on preclinical models of T-cell immunostimulation, the target plasma concentration of CP-675,206 4 weeks postdosing was 30 µg/mL.12 Almost all of the patients who experienced clinical benefit response had a plasma concentration of CP-675,206 4 weeks postdosing greater than this target value (Fig 3C).
This single-dose, dose-escalation, phase I trial demonstrates that CP-675,206 can be administered safely to patients. CP-675,206 administration resulted in breaking peripheral tolerance to self-tissues, with the development of autoimmune thyroiditis, colitis, and vitiligo in a subset of patients. Although it was not specifically designed to detect tumor responses, this study also provided evidence of antitumor activity in melanoma. The clinical tumor behavior after therapy, with evidence of delayed responses after apparent disease progression, may limit the immediate application of standard tumor measurement criteria for this agent. We also observed unusually favorable courses among several patients without objective response after dosing, which may be reflective of a less aggressive natural course of their disease or a more difficult to predict positive impact of CP-675,206 on their disease. Despite these caveats, it is remarkable that CP-675,206 induced long-lasting objective tumor responses in a subset of patients. The outcome of patients entered onto the 15 mg/kg cohort is particularly striking. Two of five patients with measurable disease had objective responses (one CR and one PR). One patient was conservatively labeled as having PD despite the regression of most lesions but increase in size in a single lesion (found to have a marked inflammatory response). Together with two other patients who had PD in this cohort, no relapses have been noted after local treatment during a mean follow-up time of 24+ months (Table 3). The sixth patient had regression of subcentimeter (considered nonmeasurable) nodular metastases in the lung, and relapsed with brain metastasis 18 months after the single CP-675,206 dose. The protocol prospectively defined the MTD as the dose immediately below the cohort in which two of six patients developed grade 3 to 4 toxicities. On the basis of this criterion, dose-escalation was halted at 15 mg/kg, and 10 mg/kg was declared the MTD. However, we believe that higher dose levels warrant further exploration, since higher plasma levels correlated with antitumor responses and toxicities resolved without using immunosuppressant therapy. Furthermore, DLT in this trial were defined in the absence of specific supportive interventions, and more aggressive management of the observed toxicities may certainly allow further dose escalation. When the toxicity, response rate, and duration of antitumor response at the high-dose cohorts is compared with standard US Food and Drug Administration–approved therapies, it is evident that the therapeutic window of CP-675,206 can be further explored. All patients treated with high-dose IL-2 routinely experience grade 3 to 4 toxicities, with an overall median survival of 1 year and 5% to 10% of long-term survivors.26,27 The only other US Food and Drug Administration–approved therapy for melanoma, dacarbazine (DTIC), has an 6% to 12% response rate and a median survival less than 8 months in randomized, controlled trials.28,29 In randomized trials, combination chemotherapy does not improve survival compared to DTIC alone,30 and biochemotherapy is not superior to combination chemotherapy.29 Based on all these considerations, we believe that the current study does not fully define the optimal dose of CP-675,206 for phase II-III testing, and further exploration of dose and schedule is ongoing. The ability of CTLA4 blockade to impact the natural history of patients with cancer is further suggested by three prior reports of human studies with the CTLA4 blocking antibody MDX-010.14-16 A single-dose study of 3 mg/kg therapy demonstrated biologic activity,14 and repeated dosing together with a peptide vaccine led to objective long-lasting responses in three of 14 patients.15 CTLA4 polymorphisms were suggested to be involved in autoimmune phenomena after administration in the adjuvant setting in patients with resected stage III or IV melanoma, and induced expression of the gut-homing chemokines CCR9 may correlate with the frequent gastrointestinal findings in this study.16 The combination of a vaccine and CTLA4 blockade is supported by preclinical studies in murine models, where a vaccine, or another form of immune activation like T-reg cell depletion, is required in addition to CTLA-4 blockade to induce regressions in nonimmunogenic tumors31,32 (most human cancers should be considered nonimmunogenic, since they grow progressively despite an intact immune system). Additionally, it is conceptually appealing that an immune intervention aimed at avoiding that the immune system is turned off may benefit from a prior turning on of the immune system against the cancer with a vaccine. Several of our patients received prior vaccines (Tables 1 and 3), but in the limited set of patients with objective responses, it is not clearly evident that prior vaccination is required to receive clinical benefit from CP-675,206. Two of the four patients with objective responses in the current study had not received prior vaccination, one had not received prior systemic therapy for metastatic disease, and one entered after progression to biochemotherapy with no prior vaccination. Therefore, contrary to prior clinical experiences with MDX010,14,15 the results of our study suggest that a single dose of CTLA4-blocking antibody can induce clinical responses in patients with melanoma without prior vaccination. Most patients in this series received a single dose of CP-675,206, and response was assessed after this dose. Some patients were eligible for redosing at a higher dose level if they had been entered in the first three cohorts, which were deemed to achieve plasma levels of circulating CP-675,206 below the target of 30 µg/mL. The only patient with change in the response assessment after redosing was patient 120, who had SD for 7 months at redosing at 6 mg/kg, while had disease progression when initially dosed at 1 mg/kg. This patient had small volume and slow-growing lung metastasis throughout this period, and it is unclear whether CP-675,206 had any impact on the disease progression or the disease stabilization after redosing was a reflection of the natural course of his disease. Other patients received redosing with CP-675,206 after documenting clinical benefit after the initial dose. However, this study cannot provide evidence that redosing contributed to their response or duration of response. It is notable that patient 13 in this series had a CR after a single dose, and has not received any further therapy while being on continued CR for over 2 years. In conclusion, CP-675,206 is an IgG2 human monoclonal antibody with encouraging antitumor activity in patients with advanced melanoma and an acceptable safety profile. Clinical efficacy increased with systemic exposure, and most cases of clinical benefit were noted above the predicted therapeutic plasma concentration of 30 µg/mL. Further evaluation of the antitumor activity of CP-675,206 is being pursued in malignant melanoma.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C)
We thank Deborah Porter; Ann Alcasid; Candida L. Lionetti; Judy Bresserer; Doug Hansen, PhD; Kelly Page; John Cuzmano; Karen Ferrante, MD; Huong T. Vu; Maribel Ontiveros; Rosalinda Rivera; Marily Elopre, RN; Clement Nzegwu; Brigitte Englahner, RN; Denise Oseguera, RN; Shawn Bachelor; and Victoria A. Dwyer for their dedication and excellent contribution to the conduction of this study. We also thank Victor Prieto, MD, and Hafeez Diwan, MD, from M.D. Anderson Cancer Center, for pathologic analysis of biopsies.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Grohmann U, Orabona C, Fallarino F, et al: CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097-1101, 2002[CrossRef][Medline] 8. Munn DH, Sharma MD, Hou D, et al: Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114:280-290, 2004[CrossRef][Medline] 9. Mellor AL, Chandler P, Baban B, et al: Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 16:1391-1401, 2004 10. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985-988, 1995 11. Tivol EA, Borriello F, Schweitzer AN, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541-547, 1995[CrossRef][Medline] 12. Hansen D, Canniff P, Primiano M, et al: Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206. Proc Am Assoc Cancer Res, 2004 (abstr 3802) 13. Keler T, Halk E, Vitale L, et al: Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol 171:6251-6259, 2003 14. Hodi FS, Mihm MC, Soiffer RJ, et al: Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100:4712-4717, 2003 15. Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372-8377, 2003 16. Sanderson K, Scotland R, Lee P, et al: Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741-750, 2005 17. Chatenoud L, Ferran C, Legendre C, et al: In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation 49:697-702, 1990[Medline] 18. Wing MG, Moreau T, Greenwood J, et al: Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest 98:2819-2826, 1996[Medline] 19. Byrd JC, Waselenko JK, Maneatis TJ, et al: Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 17:791-795, 1999 20. Criteria NCT: The revised Common Toxicity Criteria version 2.0. http://ctep.info.nih.gov/reporting/ctc.html 21. Lee SY, Lee YH, Shin C, et al: Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 122:171-176, 2002 22. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 23. MathSoft: S-PLUS 2000 Guide to Statistics, Vol 1. Data Analysis Products Division, Seattle, WA, 1999, p 301 24. Ribas A, Glaspy JA, Lee Y, et al: Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27:354-367, 2004 25. Morell A, Terry WD, Waldmann TA: Metabolic properties of IgG subclasses in man. J Clin Invest 49:673-680, 1970 26. 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 27. Chang E, Rosenberg SA: Patients with melanoma metastases at cutaneous and subcutaneous sites are highly susceptible to interleukin-2-based therapy. J Immunother 24:88-90, 2001 28. 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 18:158-66 29. Eigentler TK, Caroli UM, Radny P, et al: Palliative therapy of disseminated malignant melanoma: A systematic review of 41 randomised clinical trials. Lancet Oncol 4:748-759, 2003[CrossRef][Medline] 30. Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 16:1743-1751, 1998[Abstract] 31. McCoy KD, Hermans IF, Fraser JH, et al: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can regulate dendritic cell-induced activation and cytotoxicity of CD8(+) T cells independently of CD4(+) T cell help. J Exp Med 189:1157-1162, 1999 32. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al: Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823-832, 2001 Submitted March 8, 2005; accepted May 26, 2005. Related Editorial
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ABSTRACT
INTRODUCTION
grade 3 according to the National Cancer Institute Common Toxicity Criteria version 2.0.
