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Melanoma: HELP
Articles by Joseph I. Clark
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, Joseph Clark wrote the following 18 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

2 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.

3 Review Ipilimumab for the treatment of melanoma. 2015

Jain, Shikha / Clark, Joseph I. ·Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153, USA. · Edward Hines Jr VA Hospital, Hines, IL, USA. ·Melanoma Manag · Pubmed #30190829.

ABSTRACT: Melanoma is the sixth most common cancer in the US. Metastatic melanoma has increased in incidence over the past 30 years. In the US approximately 8600 people died from melanoma in 2009. It is an aggressive tumor; the prognosis of stage IV is poor. Before 2011, only dacarbazine and IL-2 were approved for metastatic melanoma. Major advances have been made in understanding the genetic profile, molecular factors that drive malignant transformation and the role of T cells in melanoma patients. Immune regulatory pathways affecting immune responses to cancer are becoming better defined. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) downregulates the pathways of T-cell activation. Ipilimumab is an anti CTLA-4 monoclonal antibody approved in 2011 to treat metastatic or unresectable melanoma.

4 Clinical Trial A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma. 2018

Clark, Joseph I / Singh, Jatinder / Ernstoff, Marc S / Lao, Christopher D / Flaherty, Lawrence E / Logan, Theodore F / Curti, Brendan / Agarwala, Sanjiv S / Taback, Bret / Cranmer, Lee / Lutzky, Jose / Luna, Theresa L / Aung, Sandra / Lawson, David H. ·Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. · Primary Biostatistical Solutions, Victoria, BC, Canada. · Roswell Park Cancer Institute, Buffalo, NY, USA. · University of Michigan, Ann Arbor, MI, USA. · The Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. · St. Luke's Hospital and Health Network, Bethlehem, PA, USA. · Columbia University/Herbert Irving Comprehensive Cancer Center, New York, NY, USA. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. · Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. · Prometheus Laboratories Inc, San Diego, CA, USA. · Nektar Inc, San Diego, CA, USA. · Emory Winship Cancer Institute at Emory University, Atlanta, GA, USA. ·J Immunother Cancer · Pubmed #30053905.

ABSTRACT: BACKGROUND: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. METHODS: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. RESULTS: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. CONCLUSIONS: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. TRIAL REGISTRATION: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

5 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.

6 Clinical Trial Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma. 2013

Gangadhar, Tara C / Clark, Joseph I / Karrison, Theodore / Gajewski, Thomas F. ·Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA. ·Invest New Drugs · Pubmed #23151808.

ABSTRACT: BACKGROUND: Src kinases are activated in melanoma, and inhibition of Src kinase activity has pre-clinical anti-tumor effects. Targeting this pathway could therefore have therapeutic activity in patients with metastatic melanoma. PATIENTS AND METHODS: We conducted a multi-center, open-label study of the Src kinase inhibitor saracatanib (AZD0530) in patients with metastatic melanoma. Twenty-three patients received saracatanib at a dose of 175 mg daily. The primary objectives were to determine whether this agent had clinical activity in patients with advanced melanoma and whether it increased progression free survival. Functional effects on circulating T cells were also assessed. RESULTS: Twenty-three patients received oral saracatanib on a continuous daily dosing regimen. There were no objective clinical responses. Saracatanib was generally well tolerated with few grade 3-4 adverse events. T cell function was inhibited in most patients, based on decreased superantigen-induced IL-2 production in post- versus pre-treatment samples. CONCLUSIONS: Saracatanib has minimal clinical activity as a single agent in an unselected population of patients with advanced melanoma, as evidenced by a lack of objective responses in this study. Reduced T cell cytokine production in most treated patients suggests potential immune suppressive activity by this agent.

7 Clinical Trial Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. 2012

Margolin, Kim / Ernstoff, Marc S / Hamid, Omid / Lawrence, Donald / McDermott, David / Puzanov, Igor / Wolchok, Jedd D / Clark, Joseph I / Sznol, Mario / Logan, Theodore F / Richards, Jon / Michener, Tracy / Balogh, Agnes / Heller, Kevin N / Hodi, F Stephen. ·University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org ·Lancet Oncol · Pubmed #22456429.

ABSTRACT: BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

8 Clinical Trial Improved survival with ipilimumab in patients with metastatic melanoma. 2010

Hodi, F Stephen / O'Day, Steven J / McDermott, David F / Weber, Robert W / Sosman, Jeffrey A / Haanen, John B / Gonzalez, Rene / Robert, Caroline / Schadendorf, Dirk / Hassel, Jessica C / Akerley, Wallace / van den Eertwegh, Alfons J M / Lutzky, Jose / Lorigan, Paul / Vaubel, Julia M / Linette, Gerald P / Hogg, David / Ottensmeier, Christian H / Lebbé, Celeste / Peschel, Christian / Quirt, Ian / Clark, Joseph I / Wolchok, Jedd D / Weber, Jeffrey S / Tian, Jason / Yellin, Michael J / Nichol, Geoffrey M / Hoos, Axel / Urba, Walter J. ·Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu ·N Engl J Med · Pubmed #20525992.

ABSTRACT: BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

9 Clinical Trial Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. 2010

Gunturu, Krishna S / Meehan, Kenneth R / Mackenzie, Todd A / Crocenzi, Todd S / McDermott, David / Usherwood, Edward J / Margolin, Kim A / Crosby, Nancy A / Atkins, Michael B / Turk, Mary Jo / Ahonen, Cory / Fuse, Shinichiro / Clark, Joseph I / Fisher, Jan L / Noelle, Randolph J / Ernstoff, Marc S. ·Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756, USA. ·J Clin Oncol · Pubmed #20124177.

ABSTRACT: PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

10 Article Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. 2019

Buchbinder, Elizabeth I / Dutcher, Janice P / Daniels, Gregory A / Curti, Brendan D / Patel, Sapna P / Holtan, Shernan G / Miletello, Gerald P / Fishman, Mayer N / Gonzalez, Rene / Clark, Joseph I / Richart, John M / Lao, Christopher D / Tykodi, Scott S / Silk, Ann W / McDermott, David F. ·Dana Farber Cancer Institute, Boston, MA, USA. elizabeth_buchbinder@dfci.harvard.edu. · Cancer Research Foundation of NY, Chappaqua,, NY, USA. · Moores UCSD Cancer Center, La Jolla, San Diego, CA, USA. · Providence Health & Services, Portland, OR, USA. · The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · University of Minnesota, Minneapolis, MN, USA. · Hematology/Oncology Clinic, Baton Rouge, LA, USA. · Moffitt Cancer Center, Tampa, FL, USA. · University of Colorado, Aurora, CO, USA. · Loyola University Stritch School of Medicine, Maywood, IL, USA. · Saint Louis University, Saint Louis, MO, 63110, USA. · University of Michigan, Ann Arbor, MI, USA. · University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. ·J Immunother Cancer · Pubmed #30777131.

ABSTRACT: BACKGROUND: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. METHODS: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIM RESULTS: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. CONCLUSION: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.

11 Article Rhabdomyolysis during high dose interleukin-2 treatment of metastatic melanoma after sequential immunotherapies: a case report. 2018

Clark, Joseph I / Bufalino, Shams / Singh, Shruti / Borys, Ewa. ·Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. · Advocate Lutheran General Hospital, Park Ridge, IL, USA. · Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL, 60153, USA. ·J Immunother Cancer · Pubmed #29898784.

ABSTRACT: BACKGROUND: The treatment options for metastatic malignant melanoma have drastically changed recently,including the increased use of immunotherapeutic agents that offer significant responses. Accordingly, it hasbecome common for sequential administration of such agents. Despite this, no guidelines exist on propersequencing or potential unique toxicities associated with such sequencing. CASE PRESENTATION: We describe here the first incidence, to our knowledge, of clinically significant rhabdomyolysis associated with high-dose interleukin-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma. CONCLUSION: Further studies into the biology of sequential immunotherapy in the treatment of cancer are warranted.

12 Article Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. 2018

Moore, Tamson / Wagner, Courtney Regan / Scurti, Gina M / Hutchens, Kelli A / Godellas, Constantine / Clark, Ann Lau / Kolawole, Elizabeth Motunrayo / Hellman, Lance M / Singh, Nishant K / Huyke, Fernando A / Wang, Siao-Yi / Calabrese, Kelly M / Embree, Heather D / Orentas, Rimas / Shirai, Keisuke / Dellacecca, Emilia / Garrett-Mayer, Elizabeth / Li, Mingli / Eby, Jonathan M / Stiff, Patrick J / Evavold, Brian D / Baker, Brian M / Le Poole, I Caroline / Dropulic, Boro / Clark, Joseph I / Nishimura, Michael I. ·Department of Surgery, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. tamoore@luc.edu. · Department of Medicine, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. · Department of Surgery, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. · Department of Pathology, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. · Forefront Dermatology, 801 York St, Manitowoc, WI, 54220, USA. · O. Wayne Rollins Research Center, Emory University, Room 3127, 1510 Clifton Road NE, Atlanta, GA, 30322, USA. · Department of Chemistry & Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46656, USA. · Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA. · Lentigen Technology Inc, A Miltenyi Biotec Company, 910 Clopper Road Suite 200S, Gaithersburg, MD, 20878, USA. · Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St, Charleston, SC, 29425, USA. · Dartmouth-Hitchcock, Norris Cotton Cancer Center, One Medical Center Dr, Lebanon, NH, 03756, USA. · Department of Microbiology, and Immunology, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL, USA. · Bluebird Biology, 60 Binney St., Cambridge, MA, 02142, USA. · Lurie Comprehensive Cancer Center, Department of Dermatology, Northwestern University at Chicago, Room 5-113, 303 East Superior Street, Chicago, IL, 60611, USA. ·Cancer Immunol Immunother · Pubmed #29052782.

ABSTRACT: Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4

13 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

14 Article A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma. 2016

Buchbinder, Elizabeth I / Gunturi, Anasuya / Perritt, Jessica / Dutcher, Janice / Aung, Sandra / Kaufman, Howard L / Ernstoff, Marc S / Miletello, Girald P / Curti, Brendan D / Daniels, Gregory A / Patel, Sapna P / Kirkwood, John M / Hallmeyer, Sigrun / Clark, Joseph I / Gonzalez, Rene / Richart, John M / Lutzky, Joe / Morse, Michael A / Sullivan, Ryan J / McDermott, David F. ·Dana Farber Cancer Institute, Boston, MA USA. · The Cancer Center - Lowell General Hospital, Lowell, MA 01854 USA. · Prometheus Labs, 9410 Carroll Park Drive, San Diego, CA 92121 USA. · Cancer Research Foundation of New York, Chappaqua, NY USA. · Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ USA. · Cleveland Clinic, Cleveland, OH USA. · Hematology/Oncology clinic, Baton Rouge, LA USA. · Providence Health & Services, Portland, OR USA. · Moores UCSD Cancer Center, La Jolla, CA USA. · The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA USA. · Oncology Specialists, SC, Park Ridge, IL USA. · Loyola Medicine, Maywood, IL USA. · University of Colorado, Aurora, CO USA. · Saint Louis University, Saint Louis, MO 63110 USA. · Mount Sinai Medical Center, Miami Beach, FL USA. · Duke, Durham, NC USA. · Massachusetts General Hospital, Boston, MA USA. · Beth Israel Deaconess Medical Center, Boston, MA USA. ·J Immunother Cancer · Pubmed #27660706.

ABSTRACT: BACKGROUND: High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored. METHODS: The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed. RESULTS: A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death. CONCLUSION: In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

15 Article Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma. 2016

Klarquist, Jared / Tobin, Kristen / Farhangi Oskuei, Peyman / Henning, Steven W / Fernandez, Manuel F / Dellacecca, Emilia R / Navarro, Flor C / Eby, Jonathan M / Chatterjee, Shilpak / Mehrotra, Shikhar / Clark, Joseph I / Le Poole, I Caroline. ·Oncology Research Institute, Loyola University Chicago, Maywood, Illinois. · Department of Medicine, Loyola University Chicago, Maywood, Illinois. · Department of Surgery/Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. · Oncology Research Institute, Loyola University Chicago, Maywood, Illinois. ilepool@luc.edu. · Departments of Pathology, Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois. ·Cancer Res · Pubmed #27634754.

ABSTRACT: T regulatory cells (Treg) avert autoimmunity, but their increased levels in melanoma confer a poor prognosis. To explore the basis for Treg accumulation in melanoma, we evaluated chemokine expression in patients. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3

16 Article Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. 2016

Johnson, Douglas B / Sullivan, Ryan J / Ott, Patrick A / Carlino, Matteo S / Khushalani, Nikhil I / Ye, Fei / Guminski, Alexander / Puzanov, Igor / Lawrence, Donald P / Buchbinder, Elizabeth I / Mudigonda, Tejaswi / Spencer, Kristen / Bender, Carolin / Lee, Jenny / Kaufman, Howard L / Menzies, Alexander M / Hassel, Jessica C / Mehnert, Janice M / Sosman, Jeffrey A / Long, Georgina V / Clark, Joseph I. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. · Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia5Department of Medicine, University of Sydney, Sydney, New South Wales, Australia. · Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. · medical student at School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick. · Department of Medicine, Heidelberg University Hospital, Heidelberg, Germany. · Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. · Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick. · Department of Medicine, Loyola University Medical Center, Maywood, Illinois. ·JAMA Oncol · Pubmed #26633184.

ABSTRACT: IMPORTANCE: Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE: Ipilimumab therapy. MAIN OUTCOMES AND MEASURES: Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS: Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

17 Article Evolving treatment strategies in thin cutaneous head and neck melanoma: 1 institution's experience. 2011

Jaber, James J / Clark, Joseph I / Muzaffar, Kamil / Ruggiero, Francis P / Feustel, Paul J / Frett, Michael J / Zender, Chad A. ·Department of Otolaryngology-Head and Neck Surgery, Loyola University Medical Center, Maywood, Illinois, USA. ·Head Neck · Pubmed #20848424.

ABSTRACT: BACKGROUND: Although existing melanoma literature provides recommendations for thinner lesions (≤1 mm) within a heterogeneous population, a focus on the head and neck group is less pervasive. METHODS: The records of 49 node-negative individuals with thin head and neck melanoma that underwent surgical intervention ± sentinel lymph node (SLN) biopsy were reviewed. RESULTS: A significant increased Breslow thickness and mitotic rate, and a trend toward significance in Clark level ≥ IV were shown in patients that underwent an SLN biopsy versus those that did not. The total number of positive biopsies was 2 (5%). In our subset analysis using the modified American Joint Committee on Cancer recommendations by Wong and colleagues, the incidence of positive SLN biopsy would have increased to 11%. CONCLUSION: We advocate performing an SLN biopsy in thin head and neck melanomas for primary tumors > 0.75 mm, regardless of "high-risk" features as described by Wong and colleagues.

18 Unspecified High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma. 2019

Silk, Ann W / Kaufman, Howard L / Curti, Brendan / Mehnert, Janice M / Margolin, Kim / McDermott, David / Clark, Joseph / Newman, Jenna / Bommareddy, Praveen K / Denzin, Lisa / Najmi, Saltanat / Haider, Azra / Shih, Weichung / Kane, Michael P / Zloza, Andrew. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, United States. · Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States. · Replimune, Woburn, MA, United States. · Massachusetts General Hospital, Boston, MA, United States. · Earle a Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States. · City of Hope, Duarte, CA, United States. · Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, United States. · Loyola University Medical Center, Maywood, IL, United States. · Biomedical Health Sciences, Rutgers University, New Brunswick, NJ, United States. · Department of Pediatrics, Child Health Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, United States. · Amgen, Thousand Oaks, CA, United States. · Bristol Myers-Squibb, Princeton, NJ, United States. · Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States. ·Front Oncol · Pubmed #31998643.

ABSTRACT: High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade.