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Melanoma: HELP
Articles by Brendan D. Curti
Based on 17 articles published since 2009
(Why 17 articles?)

Between 2009 and 2019, Brendan Curti wrote the following 17 articles about Melanoma.
+ Citations + Abstracts
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

2 Editorial Rapid evolution of combination therapy in melanoma. 2014

Curti, Brendan D. ·From the Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR. ·N Engl J Med · Pubmed #25390744.

ABSTRACT: -- No abstract --

3 Review Clinical deployment of antibodies for treatment of melanoma. 2015

Curti, Brendan D / Urba, Walter J. ·Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan St. 2N35, Portland, OR 97213, United States. Electronic address: brendan.curti@providence.org. · Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan St. 2N35, Portland, OR 97213, United States. Electronic address: walter.urba@providence.org. ·Mol Immunol · Pubmed #25746916.

ABSTRACT: The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described.

4 Review Integrating new therapies in the treatment of advanced melanoma. 2012

Curti, Brendan D / Urba, Walter J. ·Providence Cancer Center, Portland, OR 97213, USA. brendan.curti@providence.org ·Curr Treat Options Oncol · Pubmed #22743761.

ABSTRACT: Treatments for advanced melanoma have evolved rapidly based on improved understanding of the pathways that determine T-cell responses and knowledge of growth-related mutations, which can be targeted with new classes of pharmacologic agents. The FDA approved ipilimumab and vemurafenib for advanced melanoma in 2011. Our practice is to evaluate all tumors from patients with metastatic disease for the presence of a BRAF mutation (Fig. 1). More than 20 years of follow-up show that responders to IL-2 can be cured of their melanoma. Therefore, we recommend high-dose IL-2 as first line therapy for patients with excellent functional status and normal cardiopulmonary reserve regardless of their BRAF mutation status. We use ipilimumab, which can induce durable tumor regressions and improved survival, as initial therapy for patients who refuse or are not candidates for IL-2, also regardless of their BRAF mutation status. Ipilimumab can be used as salvage therapy for patients with advanced disease after IL-2 or vemurafenib. Targeted therapies such as vemurafenib or imatinib can be offered to patients whose melanomas express the BRAF V600E or C-Kit mutations. Vemurafenib is particularly useful for patients whose disease is progressing rapidly, as clinical improvement can be obtained within days of starting therapy and response rates may be as high as 70 %. The major reason we do not recommend vemurafenib as first line treatment in all patients whose tumors have BRAF mutations is the short median duration of response of approximately 7 months. Enrollment in a clinical trial should always be considered for patients with metastatic melanoma. The clinical trial focus has changed from finding any agent with activity in melanoma, to overcoming mechanisms of resistance and enhancing the immunomodulatory activity of these new agents that confer therapeutic benefit. Selected patients can benefit from surgical resection or radiation to manage oligometastatic disease.

5 Clinical Trial Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma. 2018

Chesney, Jason / Awasthi, Sanjay / Curti, Brendan / Hutchins, Laura / Linette, Gerald / Triozzi, Pierre / Tan, Marcus C B / Brown, Russell E / Nemunaitis, John / Whitman, Eric / Windham, Christopher / Lutzky, Jose / Downey, Gerald F / Batty, Nicolas / Amatruda, Thomas. ·Department of Medicine, University of Louisville, Louisville, Kentucky. · Department of Medical Oncology, City of Hope, Duarte. · Earle A Chiles Research Institute, Providence Cancer Center, Portland, Oregon. · Department of Internal Medicine, Division of Hematology Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. · Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem. · Division of Surgical Oncology, University of South Alabama, Mobile, Alabama. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Medical Hematology and Oncology, Mary Crowley Cancer Research Center, Dallas, Texas. · Department of Endocrine and Oncologic Surgery, Atlantic Melanoma Center, Atlantic Health System Cancer Care, Morristown, New Jersey. · Department of Oncology, Cone Health, Greensboro, North Carolina. · Division of Hematology and Oncology, Mount Sinai Medical Center, Miami Beach, Florida. · Center for Design and Analysis, Amgen Limited, Cambridge, UK. · Department of Clinical Research, Amgen Inc., Thousand Oaks, California. · Department of Hematology and Oncology, Minnesota Oncology, Fridley, Minnesota. ·Melanoma Res · Pubmed #29176501.

ABSTRACT: Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

6 Clinical Trial Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIM 2017

Curti, Brendan / Daniels, Gregory A / McDermott, David F / Clark, Joseph I / Kaufman, Howard L / Logan, Theodore F / Singh, Jatinder / Kaur, Meenu / Luna, Theresa L / Gregory, Nancy / Morse, Michael A / Wong, Michael K K / Dutcher, Janice P. ·Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR, 97213, USA. · Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Loyola University Medical Center, 2160 S First Avenue, Maywood, IL, 60153, USA. · Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. · Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, 46202, USA. · Primary Biostatistical Solutions, 2042 Carnarvon Ct, Victoria, BC, V8R2V3, Canada. · Prometheus Laboratories, 9410 Carroll Park Drive, San Diego, CA, 92121, USA. · Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27705, USA. · MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Cancer Research Foundation of NY, 43 Longview Lane, Chappaqua, NY, 10514, USA. jpd4401@aol.com. ·J Immunother Cancer · Pubmed #29254506.

ABSTRACT: BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIM CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

7 Clinical Trial Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab. 2015

Koguchi, Yoshinobu / Hoen, Helena M / Bambina, Shelly A / Rynning, Michael D / Fuerstenberg, Richard K / Curti, Brendan D / Urba, Walter J / Milburn, Christina / Bahjat, Frances Rena / Korman, Alan J / Bahjat, Keith S. ·Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon. · R&D Systems, Minneapolis, Minnesota. · Bristol-Myers Squibb, Redwood City, California. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon. keith.bahjat@providence.org. ·Cancer Res · Pubmed #26627641.

ABSTRACT: Treatment with ipilimumab improves overall survival (OS) in patients with metastatic melanoma. Because ipilimumab targets T lymphocytes and not the tumor itself, efficacy may be uniquely sensitive to immunomodulatory factors present at the time of treatment. We analyzed serum from patients with metastatic melanoma (247 of 273, 90.4%) randomly assigned to receive ipilimumab or gp100 peptide vaccine. We quantified candidate biomarkers at baseline and assessed the association of each using multivariate analyses. Results were confirmed in an independent cohort of similar patients (48 of 52, 92.3%) treated with ipilimumab. After controlling for baseline covariates, elevated chemokine (C-X-C motif) ligand 11 (CXCL11) and soluble MHC class I polypeptide-related chain A (sMICA) were associated with poor OS in ipilimumab-treated patients [log10 CXCL11: HR, 1.88; 95% confidence interval (CI), 1.14-3.12; P = 0.014; and log10 sMICA quadratic effect P = 0.066; sMICA (≥ 247 vs. 247): HR, 1.75; 95% CI, 1.02-3.01]. Multivariate analysis of an independent ipilimumab-treated cohort confirmed the association between log10 CXCL11 and OS (HR, 3.18; 95% CI, 1.13-8.95; P = 0.029), whereas sMICA was less strongly associated with OS [log10 sMICA quadratic effect P = 0.16; sMICA (≥ 247 vs. 247): HR, 1.48; 95% CI, 0.67-3.27]. High baseline CXCL11 and sMICA were associated with poor OS in patients with metastatic melanoma after ipilimumab treatment but not vaccine treatment. Thus, pretreatment CXCL11 and sMICA may represent predictors of survival benefit after ipilimumab treatment as well as therapeutic targets.

8 Clinical Trial Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. 2015

Andtbacka, Robert H I / Kaufman, Howard L / Collichio, Frances / Amatruda, Thomas / Senzer, Neil / Chesney, Jason / Delman, Keith A / Spitler, Lynn E / Puzanov, Igor / Agarwala, Sanjiv S / Milhem, Mohammed / Cranmer, Lee / Curti, Brendan / Lewis, Karl / Ross, Merrick / Guthrie, Troy / Linette, Gerald P / Daniels, Gregory A / Harrington, Kevin / Middleton, Mark R / Miller, Wilson H / Zager, Jonathan S / Ye, Yining / Yao, Bin / Li, Ai / Doleman, Susan / VanderWalde, Ari / Gansert, Jennifer / Coffin, Robert S. ·Robert H.I. Andtbacka, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT · Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ · Frances Collichio, University of North Carolina Medical Center, Chapel Hill, NC · Thomas Amatruda, Minnesota Oncology, Fridley, MN · Neil Senzer, Mary Crowley Cancer Research Center, Dallas · Merrick Ross, University of Texas MD Anderson Cancer Center, Houston, TX · Jason Chesney, University of Louisville, Louisville, KY · Keith A. Delman, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA · Lynn E. Spitler, Northern California Melanoma Center, San Francisco · Gregory A. Daniels, University of California San Diego Medical Center, Moores Cancer Center, La Jolla · Yining Ye, Bin Yao, Ai Li, Ari Vander Walde, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Igor Puzanov, Vanderbilt University, Nashville, TN · Sanjiv S. Agarwala, St Luke's University Hospital and Health Network, Bethlehem, and Temple University School of Medicine, Philadelphia, PA · Mohammed Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · Lee Cranmer, University of Arizona, Tucson, AZ · Brendan Curti, Earle A. Chiles Research Institute, Portland, OR · Karl Lewis, University of Colorado Cancer Center, Aurora, CO · Troy Guthrie, Baptist Cancer Institute, Jacksonville · Jonathan S. Zager, Moffitt Cancer Center, Tampa, FL · Gerald P. Linette, Washington University School of Medicine, St Louis, MO · Kevin Harrington, Institute of Cancer Research, Royal Marsden Hospital, London · Mark R. Middleton, National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom · Wilson H. Miller Jr, McGill University, Montreal, Quebec, Canada · and Susan Doleman and Robert S. Coffin, Amgen, Woburn, MA. ·J Clin Oncol · Pubmed #26014293.

ABSTRACT: PURPOSE: Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. PATIENTS AND METHODS: Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. RESULTS: Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred. CONCLUSION: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.

9 Clinical Trial A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. 2014

Flaherty, Lawrence / Hamid, Omid / Linette, Gerald / Schuchter, Lynn / Hallmeyer, Sigrun / Gonzalez, Rene / Cowey, C Lance / Pavlick, Anna / Kudrik, Fred / Curti, Brendan / Lawson, David / Chapman, Paul B / Margolin, Kim / Ribas, Antoni / McDermott, David / Flaherty, Keith / Cranmer, Lee / Hodi, F Stephen / Day, Bann-Mo / Linke, Rolf / Hainsworth, John. ·From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN. ·Cancer J · Pubmed #24445759.

ABSTRACT: PURPOSE: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). PATIENTS AND METHODS: Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. RESULTS: Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. DISCUSSION: This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

10 Clinical Trial Phase 1 study of stereotactic body radiotherapy and interleukin-2--tumor and immunological responses. 2012

Seung, Steven K / Curti, Brendan D / Crittenden, Marka / Walker, Edwin / Coffey, Todd / Siebert, Janet C / Miller, William / Payne, Roxanne / Glenn, Lyn / Bageac, Alexandru / Urba, Walter J. ·Earle A. Chiles Research Institute, Portland, OR 97213, USA. ·Sci Transl Med · Pubmed #22674552.

ABSTRACT: Preclinical models suggest that focal high-dose radiation can make tumors more immunogenic. We performed a pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) to assess safety and tumor response rate and perform exploratory immune monitoring studies. Patients with metastatic melanoma or renal cell carcinoma (RCC) who had received no previous medical therapy for metastatic disease were eligible. Patients received one, two, or three doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting IL-2. IL-2 (600,000 IU per kilogram by means of intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Patients with regressing disease received up to six IL-2 cycles. Twelve patients were included in the intent-to-treat analysis, and 11 completed treatment per the study design. Response Evaluation Criteria in Solid Tumors criteria were used to assess overall response in nonirradiated target lesions. Eight of 12 patients (66.6%) achieved a complete (CR) or partial response (PR) (1 CR and 7 PR). Six of the patients with PR on computed tomography had a CR by positron emission tomography imaging. Five of seven (71.4%) patients with melanoma had a PR or CR, and three of five (60%) with RCC had a PR. Immune monitoring showed a statistically significantly greater frequency of proliferating CD4(+) T cells with an early activated effector memory phenotype (CD3(+)CD4(+)Ki67(+)CD25(+)FoxP3(-)CCR7(-)CD45RA(-)CD27(+)CD28(+/-)) in the peripheral blood of responding patients. SBRT and IL-2 can be administered safely. Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data, we believe that the combination and investigation of CD4(+) effector memory T cells as a predictor of response warrant further study.

11 Clinical Trial gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. 2011

Schwartzentruber, Douglas J / Lawson, David H / Richards, Jon M / Conry, Robert M / Miller, Donald M / Treisman, Jonathan / Gailani, Fawaz / Riley, Lee / Conlon, Kevin / Pockaj, Barbara / Kendra, Kari L / White, Richard L / Gonzalez, Rene / Kuzel, Timothy M / Curti, Brendan / Leming, Phillip D / Whitman, Eric D / Balkissoon, Jai / Reintgen, Douglas S / Kaufman, Howard / Marincola, Francesco M / Merino, Maria J / Rosenberg, Steven A / Choyke, Peter / Vena, Don / Hwu, Patrick. ·Indiana University Health Goshen Center for Cancer Care, Goshen, IN 46526, USA. dschwart@iuhealth.org ·N Engl J Med · Pubmed #21631324.

ABSTRACT: BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

12 Article Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. 2016

Alva, Ajjai / Daniels, Gregory A / Wong, Michael K K / Kaufman, Howard L / Morse, Michael A / McDermott, David F / Clark, Joseph I / Agarwala, Sanjiv S / Miletello, Gerald / Logan, Theodore F / Hauke, Ralph J / Curti, Brendan / Kirkwood, John M / Gonzalez, Rene / Amin, Asim / Fishman, Mayer / Agarwal, Neeraj / Lowder, James N / Hua, Hong / Aung, Sandra / Dutcher, Janice P. ·University of Michigan, Ann Arbor, MI, USA. · Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. · University of Southern California, Los Angeles, CA, USA. · M.D. Anderson Cancer Center, Houston, TX, USA. · Rutgers Cancer Center Institute of New Jersey, New Brunswick, NJ, USA. · Duke University Medical Center, Durham, NC, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Loyola University Medical Center, Maywood, IL, USA. · St. Luke's University Health Network and Temple University, Bethlehem, PA, USA. · Hematology/Oncology Clinic, Baton Rouge, LA, USA. · Indiana University Simon Cancer Center, Indianapolis, IN, USA. · Nebraska Cancer Specialists, Omaha, NE, USA. · Providence Portland Medical Center, Portland, OR, USA. · Hillman Cancer Center Research, University of Pittsburgh Cancer Institute, Pavillion L1 32c, Pittsburgh, PA, USA. · University of Colorado Cancer Center, Aurora, CO, USA. · Levine Cancer Institute, Charlotte, NC, USA. · Moffitt Cancer Center, Tampa, FL, USA. · Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. · Astex Pharmaceuticals, Pleasanton, CA, USA. · Prometheus Laboratories Inc., San Diego, CA, USA. · Nektar Therapeutics, San Francisco, CA, USA. · Cancer Research Foundation, Chappaqua, NY, USA. jpd4401@aol.com. ·Cancer Immunol Immunother · Pubmed #27714434.

ABSTRACT: High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIM

13 Article Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity. 2015

Sckisel, Gail D / Bouchlaka, Myriam N / Monjazeb, Arta M / Crittenden, Marka / Curti, Brendan D / Wilkins, Danice E C / Alderson, Kory A / Sungur, Can M / Ames, Erik / Mirsoian, Annie / Reddy, Abhinav / Alexander, Warren / Soulika, Athena / Blazar, Bruce R / Longo, Dan L / Wiltrout, Robert H / Murphy, William J. ·Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA. · Department of Radiation-Oncology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA. · Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR 97213, USA; The Oregon Clinic, Portland, OR 97220, USA. · Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA. · The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia. · Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriner's Hospitals for Children - Northern California, Sacramento, CA 95817, USA. · Department of Pediatrics, Division of Blood and Marrow Transplantation and the University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. · Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA. · Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA. · Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA. Electronic address: wmjmurphy@ucdavis.edu. ·Immunity · Pubmed #26231116.

ABSTRACT: Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions.

14 Article Clinical impact of sentinel lymph node biopsy in patients with thick (>4 mm) melanomas. 2014

White, Ian / Fortino, Jeanine / Curti, Brendan / Vetto, John. ·Division of Surgical Oncology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA. · Providence Cancer Center, Providence Portland Medical Center, Portland, OR, USA. · Division of Surgical Oncology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: vettoj@ohsu.edu. ·Am J Surg · Pubmed #24791630.

ABSTRACT: BACKGROUND: The role of sentinel lymph node status (SLNS) in thick melanoma is evolving. The purpose of this study was to determine the prognostic value of SLNS in thick melanoma. METHODS: A retrospective analysis of 120 prospectively collected clinically node-negative thick melanomas over 5 years was performed. Patient (age/sex) and tumor (thickness, ulceration, SLNS, mitoses, metastases, and recurrence) features were collected. Multivariate analysis was performed using Cox proportional hazard model. RESULTS: Factors predictive of positive SLN included male sex, ulceration, and high mitoses. Factors associated with positive SLN had higher local-regional recurrence and metastases than negative SLN. SLNS and tumor thickness impacted 5-year disease-free survival (DFS) and overall survival (OS). Positive SLN, ulceration, age, and mitoses were independent predictors of DFS/OS. CONCLUSIONS: Nonulcerated/lower mitoses thick melanomas had lower positive SLN rates. Positive SLN develop recurrence and metastases and have worse OS/DFS. SLNS is an important prognosticator for OS/DFS. Sentinel lymph node biopsy delineates prognostic groups in thick melanomas and can impact management.

15 Article Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG. 2012

Triplett, Todd A / Curti, Brendan D / Bonafede, Peter R / Miller, William L / Walker, Edwin B / Weinberg, Andrew D. ·Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA. ·Eur J Immunol · Pubmed #22585674.

ABSTRACT: Surface expression of the IL-2 receptor α-chain (CD25) has been used to discriminate between CD4(+) CD25(HI) FOXP3(+) regulatory T (Treg) cells and CD4(+) CD25(NEG) FOXP3(-) non-Treg cells. However, this study reports that the majority of resting human memory CD4(+) FOXP3(-) T cells expresses intermediate levels of CD25 and that CD25 expression can be used to delineate a functionally distinct memory subpopulation. The CD25(NEG) memory T-cell population contains the vast majority of late differentiated cells that respond to antigens associated with chronic immune responses and are increased in patients with systemic lupus erythematosus (SLE). In contrast, the CD25(INT) memory T cells respond to antigens associated with recall responses, produce a greater array of cytokines, and are less dependent on costimulation for effector responses due to their expression of CD25. Lastly, compared to the CD25(NEG) and Treg-cell populations, the CD25(INT) memory population is lost to a greater degree from the blood of cancer patients treated with IL-2. Collectively, these results show that in humans, a large proportion of CD4(+) memory T cells express intermediate levels of CD25, and this CD25(INT) FOXP3(-) subset is a functionally distinct memory population that is uniquely affected by IL-2.

16 Article Characterization of the class I-restricted gp100 melanoma peptide-stimulated primary immune response in tumor-free vaccine-draining lymph nodes and peripheral blood. 2009

Walker, Edwin B / Miller, William / Haley, Daniel / Floyd, Kevin / Curti, Brendan / Urba, Walter J. ·Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon 97213, USA. Edwin.Walker@providence.org ·Clin Cancer Res · Pubmed #19318471.

ABSTRACT: PURPOSE: The aim of this study was to characterize the primary gp100(209-2M)-specific T-cell response in vaccine-draining, metastases-free lymph nodes and peripheral blood of peptide-vaccinated stage I to III melanoma patients. EXPERIMENTAL DESIGN: After two or three gp100(209-2M) vaccinations, sentinel lymph nodes that drained both the primary tumor and adjacent vaccine sites were excised concomitant with wide excision of the tumor. Comparative 7-color flow cytometry phenotype analysis was done on gp100 tetramer-positive CD8(+) T cells from sentinel lymph nodes, closely proximate time-related peripheral blood mononuclear cells (PBMC) collected 2 to 4 weeks after sentinel lymph node excision, and on PBMC collected 6 months later after 7 or 11 more immunizations. Lymph node and peripheral blood T cells were tested for proliferative response, functional avidity, and tumor cell-induced CD107 mobilization. RESULTS: The frequencies of gp100-specific CD8(+) T cells from time-related PBMC and sentinel lymph nodes were comparable and were similar to those reported for virus-specific memory T cells. Their respective in vitro proliferation responses were also equivalent but statistically higher than proliferation responses of peripheral blood T cells collected after completion of the entire vaccine regimen. By contrast, functional avidity and CD107 responses were significantly higher in circulating T cells. Sentinel lymph node-derived, gp100-specific CD8(+) T cells predominantly expressed central and effector memory phenotype signatures, whereas there were higher frequencies of effector T cells in the peripheral blood. CONCLUSION: Priming immunization with gp100(209-2M) without coadministration of CD4(+) helper T cell-restricted antigens induced the effective expansion of peptide-specific central and effector memory CD8(+) T cells with high proliferation potential in vaccine-draining lymph nodes of stage I to III melanoma patients. Lymph node memory T cells gave rise to circulating gp100-specific effector T cells exhibiting increased functional maturation.

17 Unspecified Future perspectives in melanoma research. Meeting report from the "Melanoma research: a bridge from Naples to the World. Napoli, December 5th-6th 2011". 2012

Ascierto, Paolo A / Grimaldi, Antonio M / Curti, Brendan / Faries, Mark B / Ferrone, Soldano / Flaherty, Keith / Fox, Bernard A / Gajewski, Thomas F / Gershenwald, Jeffrey E / Gogas, Helen / Grossmann, Kenneth / Hauschild, Axel / Hodi, F Stephen / Kefford, Richard / Kirkwood, John M / Leachmann, Sancy / Maio, Michele / Marais, Richard / Palmieri, Giuseppe / Morton, Donald L / Ribas, Antoni / Stroncek, David F / Stewart, Rodney / Wang, Ena / Mozzillo, Nicola / Marincola, Franco M. ·Department of Melanoma, Sarcoma, and Head and Neck Disease, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #22551296.

ABSTRACT: After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization.After the first congress in December 2010, the second edition of "Melanoma Research: a bridge from Naples to the World" meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5-6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies. This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma.