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Melanoma: HELP
Articles by Gregory A. Daniels
Based on 24 articles published since 2010
(Why 24 articles?)
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Between 2010 and 2020, G. Daniels wrote the following 24 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline NCCN Guidelines Insights: Melanoma, Version 3.2016. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Fields, Ryan C / Fleming, Martin D / Gastman, Brian / Gonzalez, Rene / Guild, Valerie / Johnson, Douglas / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ott, Patrick / Gupta, Aparna Priyanath / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. ·From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27496110.

ABSTRACT: The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

2 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

3 Guideline Melanoma, version 4.2014. 2014

Coit, Daniel G / Thompson, John A / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Martini, Mary C / Olszanski, Anthony J / Ross, Merrick I / Salama, April / Swetter, Susan M / Tanabe, Kenneth K / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole R / Ho, Maria / Anonymous5190793. ·From 1Memorial Sloan-Kettering Cancer Center; 2Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 3Huntsman Cancer Institute at the University of Utah; 4University of Michigan Comprehensive Cancer Center; 5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; 6UC San Diego Moores Cancer Center; 7UCSF Helen Diller Family Comprehensive Cancer Center; 8Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; 9St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; 10University of Colorado Cancer Center; 11Aim at Melanoma; 12Dana-Farber/Brigham and Women's Cancer Center; 13Vanderbilt-Ingram Cancer Center; 14Roswell Park Cancer Institute; 15Moffitt Cancer Center; 16The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 18Fox Chase Cancer Center; 19The University of Texas MD Anderson Cancer Center; 20Duke Cancer Institute; 21Stanford Cancer Institute; 22Massachusetts General Hospital Cancer Center; 23City of Hope Comprehensive Cancer Center; 24University of Alabama at Birmingham Comprehensive Cancer Center; and 25National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #24812131.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

4 Review Adjuvant and Neoadjuvant Treatment of Skin Cancer. 2019

Sacco, Assuntina G / Daniels, Gregory A. ·Division of Hematology-Oncology, University of California San Diego, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0658, USA. Electronic address: agsacco@ucsd.edu. · Division of Hematology-Oncology, University of California San Diego, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0658, USA. ·Facial Plast Surg Clin North Am · Pubmed #30420067.

ABSTRACT: Skin cancer represents a broad classification of malignancies, which can be further refined by histology, including basal cell carcinoma, squamous cell carcinoma and melanoma. As these three cancers are distinct entities, we review each one separately, with a focus on their epidemiology, etiology including relevant genomic data, and the current evidence-based recommendations for adjuvant and neoadjuvant therapy. We also discuss future directions and opportunities for continued therapeutic advances.

5 Review Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review. 2018

McDonald, Marin A / Sanghvi, Parag / Bykowski, Julie / Daniels, Gregory A. ·UC San Diego Health Department of Radiology, 200 W. Arbor Drive MC 0834, San Diego, CA, 92103-0834, USA. mamcdonald@ucsd.edu. · UC San Diego Health Department of Radiation Medicine and Applied Sciences, 9500 Gilman Drive, La Jolla, CA, 92093, USA. · UC San Diego Health Department of Radiology, 200 W. Arbor Drive MC 0834, San Diego, CA, 92103-0834, USA. · Department of Medicine, UC San Diego Health Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, San Diego, CA, 92093, USA. ·BMC Cancer · Pubmed #29743050.

ABSTRACT: BACKGROUND: While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response. CASE PRESENTATION: Case #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy. Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease. CONCLUSIONS: These cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow "unmasks" previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.

6 Clinical Trial SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. 2018

Ribas, Antoni / Medina, Theresa / Kummar, Shivaani / Amin, Asim / Kalbasi, Anusha / Drabick, Joseph J / Barve, Minal / Daniels, Gregory A / Wong, Deborah J / Schmidt, Emmett V / Candia, Albert F / Coffman, Robert L / Leung, Abraham C F / Janssen, Robert S. ·Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California. aribas@mednet.ucla.edu. · Medicine/Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, Colorado. · Division of Oncology, Stanford University, Palo Alto, California. · Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina. · Department of Radiation Oncology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California. · Division of Hematology-Oncology, Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, Pennsylvania. · Mary Crowley Cancer Research Center, Dallas, Texas. · Department of Medicine, University of California, San Diego, San Diego, California. · Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California. · Merck & Co., Kenilworth, New Jersey. · Dynavax Technologies Corporation, Berkeley, California. ·Cancer Discov · Pubmed #30154193.

ABSTRACT: PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8

7 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.

8 Clinical Trial Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. 2017

Hallmeyer, Sigrun / Gonzalez, Rene / Lawson, David H / Cranmer, Lee D / Linette, Gerald P / Puzanov, Igor / Taback, Bret / Cowey, C Lance / Ribas, Antoni / Daniels, Gregory A / Moore, Timothy / Gibney, Geoffrey T / Tawbi, Hussein / Whitman, Eric / Lee, Geraldine / Mun, Yong / Liu, Shiyao / Hamid, Omid. ·aDepartment of Internal Medicine, Advocate Medical Group - Oncology North, Park Ridge, Illinois bMelanoma Research Clinic, University of Colorado Cancer Center, Aurora, Colorado cDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia dDepartment of Hematology and Oncology, The University of Arizona Cancer Center, Tucson, Arizona eDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri fDepartment of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee gDepartment of Surgery, Columbia University Medical Center, New York, New York hDepartment of Medical Oncology, Texas Oncology, Dallas, Texas iDepartment of Medicine, Jonsson Comprehensive Cancer Center at University of California jDepartment of Immuno-Oncology, The Angeles Clinic and Research Institute, Los Angeles kDepartment of Oncology, Moores Cancer Center, University of California, San Diego, La Jolla lGenentech Inc., South San Francisco, California mMid Ohio Oncology and Hematology Inc., Columbus, Ohio nDepartment of Melanoma, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC oDepartment of Pathology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania pDepartment of Melanoma, Carol G. Simon Cancer Center, Atlantic Health System, Morristown, New Jersey, USA. ·Melanoma Res · Pubmed #29076950.

ABSTRACT: BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

9 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.

10 Clinical Trial Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. 2014

Chodon, Thinle / Comin-Anduix, Begoña / Chmielowski, Bartosz / Koya, Richard C / Wu, Zhongqi / Auerbach, Martin / Ng, Charles / Avramis, Earl / Seja, Elizabeth / Villanueva, Arturo / McCannel, Tara A / Ishiyama, Akira / Czernin, Johannes / Radu, Caius G / Wang, Xiaoyan / Gjertson, David W / Cochran, Alistair J / Cornetta, Kenneth / Wong, Deborah J L / Kaplan-Lefko, Paula / Hamid, Omid / Samlowski, Wolfram / Cohen, Peter A / Daniels, Gregory A / Mukherji, Bijay / Yang, Lili / Zack, Jerome A / Kohn, Donald B / Heath, James R / Glaspy, John A / Witte, Owen N / Baltimore, David / Economou, James S / Ribas, Antoni. ·Authors' Affiliations: Departments of Medicine, Surgery, Pathology and Laboratory Medicine, Microbiology, Immunology and Molecular Genetics, and Molecular and Medical Pharmacology; Jonsson Comprehensive Cancer Center; Department of Ophthalmology, Jules Stein Eye Institute; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research; Howard Hughes Medical Institute, University of California, Los Angeles (UCLA); The Angeles Clinic Research Institute, Los Angeles; Department of Medicine, University of California San Diego (UCSD) Moores Cancer Center, La Jolla; Divisions of Chemistry and Biology, California Institute of Technology, Pasadena, California; Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility (IU VPF), Indianapolis, Indiana; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada; Mayo Clinic Scottsdale, Scottsdale, Arizona; Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut; and Center for Immunology, Roswell Park Cancer Institute, Buffalo, New York. ·Clin Cancer Res · Pubmed #24634374.

ABSTRACT: PURPOSE: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. EXPERIMENTAL DESIGN: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. RESULTS: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. CONCLUSION: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

11 Clinical Trial Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. 2011

Boasberg, Peter D / Redfern, Charles H / Daniels, Gregory A / Bodkin, David / Garrett, Chris R / Ricart, Alejandro D. ·The Angeles Clinic and Research Institute, Santa Monica, CA 90404-2104, USA. pboasberg@theangelesclinic.org ·Cancer Chemother Pharmacol · Pubmed #21516509.

ABSTRACT: PURPOSE: To assess further the tolerability and preliminary antitumor activity of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. METHODS: This pilot study evaluated PD-0325901 on an intermittent dosing schedule. PD-0325901 was administered orally at 20 mg twice daily (BID) for 21 consecutive days followed by 7 days of no treatment. This dose was not well tolerated and consequently changed to 15 mg BID. RESULTS: Between October and December 2005, 13 patients with metastatic measurable disease were entered into the study (seven melanoma, three breast cancer, and three colon cancer). All patients had received prior systemic therapy and were treated with a total of 61 cycles of PD-0325901 (nine received an initial dose of 20 mg BID, four an initial dose of 15 mg BID). The study was terminated early because of an unexpected high incidence of musculoskeletal and neurological adverse events, including gait disturbance, memory impairment, confusion, mental status changes, mild to moderate visual disturbances, and muscular weakness including neck weakness ("dropped-head syndrome"). Other common toxicities were diarrhea, acneiform rash, fatigue, and nausea. There was no significant hematologic toxicity, and chemistry abnormalities were rare. One patient achieved a confirmed complete response, and five patients had stable disease. CONCLUSIONS: PD-0325901 can cause significant musculoskeletal, neurological, and ocular toxicity at doses ≥ 15 mg BID. Future studies with adaptive designs might evaluate doses ≤ 10 mg BID in tumor types with a high incidence of Ras and Raf mutations. ClinicalTrials.gov identifier NCT00147550.

12 Article Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2019

Larkin, James / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean-Jacques / Rutkowski, Piotr / Lao, Christopher D / Cowey, C Lance / Schadendorf, Dirk / Wagstaff, John / Dummer, Reinhard / Ferrucci, Pier F / Smylie, Michael / Hogg, David / Hill, Andrew / Márquez-Rodas, Ivan / Haanen, John / Guidoboni, Massimo / Maio, Michele / Schöffski, Patrick / Carlino, Matteo S / Lebbé, Céleste / McArthur, Grant / Ascierto, Paolo A / Daniels, Gregory A / Long, Georgina V / Bastholt, Lars / Rizzo, Jasmine I / Balogh, Agnes / Moshyk, Andriy / Hodi, F Stephen / Wolchok, Jedd D. ·From the Royal Marsden NHS Foundation Trust, London (J.L.), and the College of Medicine, Swansea University, Swansea (J.W.) - both in the United Kingdom · the Oncology Institute of Veneto IRCCS, Padua (V.C.-S.), the European Institute of Oncology, IRCCS, Milan (P.F.F.), Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and the Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital, Siena (M.M.) - all in Italy · the University of Colorado Cancer Center, Aurora (R.G.) · Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille Hôpital Timone, Marseille (J.-J.G.), and Université de Paris, INSERM Unité 976, Assistance Publique-Hôpitaux de Paris Dermatology and Centres d'Investigation Clinique, Saint Louis Hospital, Paris (C.L.) - both in France · the Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · the University of Michigan, Ann Arbor (C.D.L.) · Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.) · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Universitäts Spital, Zurich, Switzerland (R.D.) · Cross Cancer Institute, Edmonton, AB (M.S.), and the Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Tasman Oncology Research, Southport, QLD (A.H.), the Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney, Sydney, NSW (M.S.C., G.V.L.), and the Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and the Peter MacCallum Cancer Centre, Melbourne, VIC (G.M.) - all in Australia · General University Hospital Gregorio Marañon and Centro de Investigación Biomédica en Red de Oncología, Madrid (I.M.-R.) · the Netherlands Cancer Institute, Amsterdam (J.H.) · the Leuven Cancer Institute, Department of General Medical Oncology, University Hospital Leuven, Leuven, Belgium (P.S.) · University of California San Diego Health-La Jolla Moores Cancer Center, La Jolla (G.A.D.) · the Department of Oncology, Odense University Hospital, Odense, Denmark (L.B.) · Bristol-Myers Squibb, Princeton, NJ (J.I.R., A.B., A.M.) · Dana-Farber Cancer Institute, Boston (F.S.H.) · and the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W.). ·N Engl J Med · Pubmed #31562797.

ABSTRACT: BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

13 Article Hybrid Capture-Based Genomic Profiling Identifies BRAF V600 and Non-V600 Alterations in Melanoma Samples Negative by Prior Testing. 2019

Boussemart, Lise / Nelson, Annie / Wong, Michael / Ross, Jeffrey S / Sosman, Jeffrey / Mehnert, Janice / Daniels, Gregory / Kendra, Kari / Ali, Siraj Mahamed / Miller, Vincent A / Schrock, Alexa B. ·Department of Dermatology, Pontchaillou Hospital, CHU de Rennes, Rennes, France. · University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France. · Foundation Medicine, Inc., Cambridge, Massachusetts, USA. · MD Anderson Cancer Center, Houston, Texas, USA. · Department of Pathology, SUNY Upstate Medical University, Syracuse, New York, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA. · Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. · Moores Cancer Center, University of California San Diego, La Jolla, California, USA. · The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA. · Foundation Medicine, Inc., Cambridge, Massachusetts, USA aschrock@foundationmedicine.com. ·Oncologist · Pubmed #30683711.

ABSTRACT: BACKGROUND: BRAF and MEK inhibitors are approved for BRAF V600-mutated advanced melanoma, with response rates of up to 70%. Responses to targeted therapies have also been observed for diverse non-V600 BRAF alterations. Thus, sensitive, accurate, and broad detection of BRAF alterations is critical to match patients with available targeted therapies. MATERIALS AND METHODS: Pathology reports were reviewed for 385 consecutive melanoma cases with BRAF mutations or rearrangements identified using a hybrid capture-based next-generation sequencing comprehensive genomic profiling (CGP) assay during the course of clinical care. RESULTS: Records of prior BRAF molecular testing were available for 79 (21%) cases. Of cases with BRAF V600 mutations, 11/57 (19%) with available data were negative by prior BRAF testing. Prior negative BRAF results were also identified in 16/20 (80%) cases with non-V600 mutations, 2 of which harbored multiple BRAF alterations, and in 2/2 (100%) cases with activating BRAF fusions. Clinical outcomes for a subset of patients are presented. CONCLUSION: CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/MEK inhibitors in BRAF-mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative. IMPLICATIONS FOR PRACTICE: Published guidelines for melanoma treatment recommend BRAF mutational analysis, but little guidance is provided as to selection criteria for testing methodologies, or as to clinical implications for non-V600 alterations. This study found that hybrid capture-based next-generation sequencing can detect BRAF alterations in samples from a significant fraction of patients with advanced melanoma with prior negative BRAF results. This study highlights the need for oncologists and pathologists to be critically aware of coverage and sensitivity limitations of various assays, particularly regarding non-V600E alterations, of which many are potentially targetable.

14 Article Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation. 2018

Chang, Victoria A / Simpson, Daniel R / Daniels, Gregory A / Piccioni, David E. ·School of Medicine, University of California San Diego, La Jolla, California, USA. · Department of Radiation Medicine and Applied Sciences, University of California San Diego, Moores Cancer Center, La Jolla, California, USA. · Department of Hematology & Oncology, University of California San Diego, Moores Cancer Center, La Jolla, California, USA. · Division of Neuro-Oncology, Department of Neurosciences, University of California San Diego, La Jolla, California, USA. dpiccioni@ucsd.edu. ·J Immunother Cancer · Pubmed #30577851.

ABSTRACT: BACKGROUND: Neurologic toxicities with immune therapy are rare, but can cause devastating and often permanent injury when they occur. Although there is increasing interest in the potential synergism between immune therapy and radiation, it is possible that such combinations may lead to a greater number or increased severity of immune-related adverse events. We present here a case of extensive and progressive transverse myelitis following combined therapy, which did not improve until treatment with infliximab. This case highlights the unmet need for treatment of adverse events that are refractory to consensus recommendations, and may ultimately require further study and incorporation into future published guidelines. CASE PRESENTATION: We report a case of a 68-year-old with metastatic melanoma, who developed transverse myelitis in the setting of immune checkpoint blockade and spinal irradiation for vertebral metastases. Despite management according to published consensus guidelines: cessation of immune therapy, high-dose steroids, and plasmapheresis, he continued to deteriorate neurologically, and imaging revealed a progressive and ascending transverse myelitis. The patient was then treated with infliximab, and demonstrated dramatic imaging and modest clinical improvement following the first treatment cycle. CONCLUSIONS: This is the first report describing the successful use of infliximab in immune therapy and radiation-related transverse myelitis that was not responding to recommended therapy. Evaluation of additional treatment options such as infliximab for high-grade immune-related neurologic toxicities is warranted, and may be needed earlier in the disease process to prevent significant morbidity. The adverse effects of immune therapy when used in combination with radiation also require further investigation.

15 Article Telomerase reverse transcriptase promoter alterations across cancer types as detected by next-generation sequencing: A clinical and molecular analysis of 423 patients. 2018

Schwaederle, Maria / Krishnamurthy, Nithya / Daniels, Gregory A / Piccioni, David E / Kesari, Santosh / Fanta, Paul T / Schwab, Richard B / Patel, Sandip P / Parker, Barbara A / Kurzrock, Razelle. ·Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Moores Cancer Center at UC San Diego Health, La Jolla, California. · Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, California. ·Cancer · Pubmed #29211306.

ABSTRACT: BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015. RESULTS: Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population. TERT promoter alterations were more frequent in men (P = .031) and were associated with brain cancers (P = .001), skin cancers/melanoma (P = .001), and a higher number of aberrations (P = .0001). A co-alteration analysis found that TERT promoter alterations were significantly correlated with CDKN2A/B (P = .001) and BRAF abnormalities (P = .0003). Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P = .017). However, only a higher number of alterations remained significant in the multivariate analysis. CONCLUSIONS: Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients). These aberrations frequently coexist with a high number of other aberrations, with the latter feature also significantly associated with poorer overall survival. Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development. Cancer 2018;124:1288-96. © 2017 American Cancer Society.

16 Article Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. 2017

Sznol, Mario / Ferrucci, Pier Francesco / Hogg, David / Atkins, Michael B / Wolter, Pascal / Guidoboni, Massimo / Lebbé, Celeste / Kirkwood, John M / Schachter, Jacob / Daniels, Gregory A / Hassel, Jessica / Cebon, Jonathan / Gerritsen, Winald / Atkinson, Victoria / Thomas, Luc / McCaffrey, John / Power, Derek / Walker, Dana / Bhore, Rafia / Jiang, Joel / Hodi, F Stephen / Wolchok, Jedd D. ·Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Pier Francesco Ferrucci, Istituto Europeo di Oncologia, Milan · Massimo Guidoboni, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy · David Hogg, Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Celeste Lebbé, Université Paris Diderot, Paris · Luc Thomas, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France · John M. Kirkwood, Hillman Cancer Center, Pittsburgh, PA · Jacob Schachter, Sheba Medical Center, Ramat Gan, Israel · Gregory A. Daniels, University of California San Diego, Moores Cancer Center, La Jolla, CA · Jessica Hassel, University Hospital, Heidelberg, Germany · Jonathan Cebon, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria · Winald Gerritsen, University of Queensland, St Lucia · Victoria Atkinson, Gallipoli Medical Research Foundation, Greenslopes · Victoria Atkinson, Princess Alexandra Hospital, Brisbane, Queensland, Australia · Winald Gerritsen, Radboud University Medical Center, Nijmegen, the Netherlands · John McCaffrey, Irish Clinical Oncology Research Group, Dublin · Derek Power, Irish Clinical Oncology Research Group, Cork, Ireland · Dana Walker, Rafia Bhore, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · and Jedd D. Wolchok, Parker Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #28915085.

ABSTRACT: Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

17 Article Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. 2017

Goodman, Aaron M / Kato, Shumei / Bazhenova, Lyudmila / Patel, Sandip P / Frampton, Garrett M / Miller, Vincent / Stephens, Philip J / Daniels, Gregory A / Kurzrock, Razelle. ·Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California. a1goodman@ucsd.edu. · Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, La Jolla, California. · Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California. · Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California. · Foundation Medicine, Cambridge, Massachusetts. ·Mol Cancer Ther · Pubmed #28835386.

ABSTRACT: Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (

18 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

19 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.

20 Article Implementation of an Interleukin-2 National Registry: an opportunity to improve cancer outcomes. 2014

Wong, Michael K / Kaufman, Howard L / Daniels, Gregory A / McDermott, David F / Aung, Sandra / Lowder, James N / Morse, Michael A. ·Department of Medicine, Suite 3455, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. · Department of Surgery, Room 2007, Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. · Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA. · Beth Israel Hospital Deaconess Medical Center, Masco Building, 375 Longwood Avenue, Boston, MA 02215, USA. · Prometheus Laboratories Inc., 9410 Carroll Park Drive, San Diego, CA 92121, USA. · Duke University Medical Center, Mudd Building, Rm 437, 10 Bryan Searle Drive, Durham, NC 27710, USA. ·J Immunother Cancer · Pubmed #25031835.

ABSTRACT: Cancer registries have proven valuable with respect to validating therapeutic safety and drug efficacy, uncovering real-world implementation practices, and their evolution over time. Modern cancer therapeutics are approved as single agents oftentimes compared to the least active approved standard agent in randomized trials. However, the burgeoning diversity and number of drugs introduces a complexity that quickly outstrips the knowledge provided by these pivotal trials. This gap in information is particularly relevant when survival is the primary therapeutic endpoint. In addition, the inherent complexity of the immune response will make registries a particularly important tool in expeditiously understanding solid tumor immunotherapy and patient outcomes.

21 Article The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics. 2014

Ribas, Antoni / Zhang, Weijiang / Chang, Ilsung / Shirai, Keisuke / Ernstoff, Marc S / Daud, Adil / Cowey, C Lance / Daniels, Gregory / Seja, Elizabeth / O'Laco, Elizabeth / Glaspy, John A / Chmielowski, Bartosz / Hill, Todd / Joe, Andrew K / Grippo, Joseph F. ·Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. ·J Clin Pharmacol · Pubmed #24374975.

ABSTRACT: Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.

22 Article Activity of the HMGB1-derived immunostimulatory peptide Hp91 resides in the helical C-terminal portion and is enhanced by dimerization. 2014

Saenz, R / Messmer, B / Futalan, D / Tor, Y / Larsson, M / Daniels, G / Esener, S / Messmer, D. ·Rebecca and John Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA 92093, USA. ·Mol Immunol · Pubmed #24172222.

ABSTRACT: We have previously shown that an 18 amino acid long peptide, named Hp91, whose sequence corresponds to a region within the endogenous protein HMGB1, activates dendritic cells (DCs) and acts as adjuvant in vivo by potentiating Th1-type antigen-specific immune responses. We analyzed the structure-function relationship of the Hp91 peptide to investigate the amino acids and structure responsible for immune responses. We found that the cysteine at position 16 of Hp91 enabled formation of reversible peptide dimmers, monomer and dimmer were compared for DC binding and activation. Stable monomers and dimers were generated using a maleimide conjugation reaction. The dimer showed enhanced ability to bind to and activate DCs. Furthermore, the C-terminal 9 amino acids of Hp91, named UC1018 were sufficient for DC binding and Circular dichroism showed that UC1018 assumes an alpha-helical structure. The ninemer peptide UC1018 induced more potent antigen-specific CTL responses in vivo as compared to Hp91 and it protected mice from tumor development when used in a prophylactic vaccine setting. We have identified a short alpha helical peptide that acts as potent adjuvant inducing protective immune responses in vivo.

23 Article Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. 2012

Ramsköld, Daniel / Luo, Shujun / Wang, Yu-Chieh / Li, Robin / Deng, Qiaolin / Faridani, Omid R / Daniels, Gregory A / Khrebtukova, Irina / Loring, Jeanne F / Laurent, Louise C / Schroth, Gary P / Sandberg, Rickard. ·Ludwig Institute for Cancer Research, Stockholm, Sweden. ·Nat Biotechnol · Pubmed #22820318.

ABSTRACT: Genome-wide transcriptome analyses are routinely used to monitor tissue-, disease- and cell type–specific gene expression, but it has been technically challenging to generate expression profiles from single cells. Here we describe a robust mRNA-Seq protocol (Smart-Seq) that is applicable down to single cell levels. Compared with existing methods, Smart-Seq has improved read coverage across transcripts, which enhances detailed analyses of alternative transcript isoforms and identification of single-nucleotide polymorphisms. We determined the sensitivity and quantitative accuracy of Smart-Seq for single-cell transcriptomics by evaluating it on total RNA dilution series. We found that although gene expression estimates from single cells have increased noise, hundreds of differentially expressed genes could be identified using few cells per cell type. Applying Smart-Seq to circulating tumor cells from melanomas, we identified distinct gene expression patterns, including candidate biomarkers for melanoma circulating tumor cells. Our protocol will be useful for addressing fundamental biological problems requiring genome-wide transcriptome profiling in rare cells.

24 Article Additive melanoma suppression with intralesional phospholipid-conjugated TLR7 agonists and systemic IL-2. 2011

Hayashi, Tomoko / Chan, Michael / Norton, John T / Wu, Christina C N / Yao, Shiyin / Cottam, Howard B / Tawatao, Rommel I / Corr, Maripat / Carson, Dennis A / Daniels, Gregory A. ·aRebecca and John Moores UCSD Cancer Center bDepartment of Medicine, University of California, San Diego, La Jolla, California, USA. ·Melanoma Res · Pubmed #21030882.

ABSTRACT: There remains a compelling need for the development of treatments for unresectable melanoma. Agents that stimulate the innate immune response could provide advantages for cell-based therapies. However, there are conflicting reports concerning whether toll-like receptor (TLR) signaling controls tumor growth. The objective of this study was to evaluate the effect of intralesional administration of a TLR7 agonist in melanoma therapy. B16cOVA melanoma was implanted to TLR7 mice to evaluate the roles of stromal TLR7 on melanoma growth. To capitalize on the potential deleterious effects of TLR7 stimulation on the tumor growth, we injected melanoma tumor nodules with a newly developed and potent TLR7 agonist. B16 melanoma nodules expanded more rapidly in TLR7-deficient and MyD88 mice compared with TLR9 and wild type mice. Repeated injections with low doses of unconjugated TLR7 agonist were more effective at attenuating nodule size than a single high dose injection. To improve the efficacy we conjugated the agonist to phospholipid or phospholipids-polyethylene glycol, which retained TLR7 specificity. The phospholipid conjugate was indeed more effective in reducing lesion size. Furthermore, intralesional administration of the phospholipid TLR7 agonist conjugate enhanced the antimelanoma effects of systemic treatment with interleukin (IL)-2 and prolonged the survival of mice compared with IL-2 alone. Our study showed that: (1) TLR7/MyD88 signaling in the stroma is involved in melanoma growth; and (2) intralesional administration of a TLR7 agonist reduces the growth of melanoma nodules and enhances the antimelanoma effects of IL-2.