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Melanoma: HELP
Articles by Howard L. Kaufman
Based on 52 articles published since 2010
(Why 52 articles?)

Between 2010 and 2020, H. Kaufman wrote the following 52 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
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 Management of Metastatic Melanoma in 2018. 2018

Kaufman, Howard L / Margolin, Kim / Sullivan, Ryan. ·Department of Surgery, Massachusetts General Hospital, Boston. · City of Hope, Duarte, California. · Department of Medicine, Massachusetts General Hospital, Boston. ·JAMA Oncol · Pubmed #29621376.

ABSTRACT: -- No abstract --

4 Review Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development. 2018

Cohen-Solal, Karine A / Kaufman, Howard L / Lasfar, Ahmed. ·Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. · Section of Surgical Oncology Research, Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. · Department of Surgery, Rutgers University, New Brunswick, NJ, USA. · Department of Medicine, Rutgers University, New Brunswick, NJ, USA. · Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. ·Pigment Cell Melanoma Res · Pubmed #29090514.

ABSTRACT: Resistance to targeted therapy in cancer is often coupled with the acquisition of a pro-invasive phenotype by tumors cells and a highly permissive tumor microenvironment promoting drug resistance. Transcription factors are frequently shown as major points of convergence of multiple dysregulated receptors and signaling pathways in cancer. Several transcription factors are now incriminated as drivers of both drug resistance and invasiveness. We focused this review on critical transcription factors playing a causal role in both the resistance to BRAF V600E-targeted therapy and the pro-invasive behavior of melanoma cells. Simultaneous rewiring of pro-oncogenic signaling pathways, phenotype switching or phenotypic plasticity supporting pro-invasive/pro-metastatic behavior, actin remodeling, and bidirectional interactions between tumor microenvironment and melanoma cells represent major challenges for overcoming resistance to BRAF V600E inhibitors (BRAFi) and will be discussed. Although it represents an underdeveloped area of translational investigation, inhibition of transcription factors may open new avenues to combat resistance to BRAFi.

5 Review High-dose interleukin-2 (IL-2) for the treatment of melanoma: safety considerations and future directions. 2017

Marabondo, Stephen / Kaufman, Howard L. ·a Departments of Surgery and Medicine, Rutgers Robert Wood Johnson Medical School , Rutgers University , New Brunswick , NJ , USA. ·Expert Opin Drug Saf · Pubmed #28929820.

ABSTRACT: INTRODUCTION: In 1998, high-dose interleukin-2 (IL-2) was the first immunotherapy approved for the treatment of metastatic melanoma based on durable objective responses documented in a subset of patients but widespread utilization was limited by significant toxicity. Advances in targeted therapy and the emergence of T cell checkpoint inhibitors, which can generally be given in the ambulatory setting, have further limited consideration of IL-2 for melanoma patients and the role of IL-2 in the current landscape of melanoma treatment is uncertain. Areas covered: In this review, we will describe advances in clinical diagnostic and management strategies that have improved the therapeutic window for IL-2 therapy in patients with melanoma. Further, we will describe the potential for using IL-2 in patients whose disease has progressed after other interventions or as part of combination immunotherapy approaches that are now in clinical development. We will also review the common toxicities of IL-2 therapy and their current management will be discussed. Expert opinion: High-dose IL-2 remains an important option for patients with melanoma and has an improved therapeutic window in the contemporary era. The reasons why IL-2 is not utilized more frequently and measures for enhancing its use will be detailed.

6 Review Intratumoral Approaches for the Treatment of Melanoma. 2017

Bommareddy, Praveen K / Silk, Ann W / Kaufman, Howard L. ·From the Departments of *Surgery and †Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. ·Cancer J · Pubmed #28114253.

ABSTRACT: There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.

7 Review Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma. 2017

Bommareddy, Praveen K / Patel, Anand / Hossain, Saamia / Kaufman, Howard L. ·Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, NJ, 08901, USA. · Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. · Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, NJ, 08901, USA. howard.kaufman@rutgers.edu. ·Am J Clin Dermatol · Pubmed #27988837.

ABSTRACT: Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; Imlygic™), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. T-VEC demonstrated significant improvement in durable response rate, objective response rate, and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non-melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses.

8 Review Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy. 2016

Kohlhapp, Frederick J / Kaufman, Howard L. ·Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. · Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. hk553@cinj.rutgers.edu. ·Clin Cancer Res · Pubmed #26719429.

ABSTRACT: Oncolytic viruses are native or engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more efficient viral replication, and with selected deletion of specific viral genes, replication in normal cells with activated PKR may not be possible. Direct tumor cell lysis, release of soluble tumor antigens, and danger-associated molecular factors are all thought to help prime and promote tumor-specific immunity. Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type I and is the first oncolytic virus to demonstrate a clinical benefit in patients with melanoma. T-VEC has also been evaluated for the treatment of head and neck cancer, pancreatic cancer, and likely other types of cancer will be targeted in the near future. T-VEC has been modified for improved safety, tumor-selective replication, and induction of host immunity by deletion of several viral genes and expression of human granulocyte-macrophage colony stimulating factor. Although the mechanism of action for T-VEC is incompletely understood, the safety profile of T-VEC and ability to promote immune responses suggest future combination studies with other immunotherapy approaches including checkpoint blockade through PD-1, PD-L1, and CTLA-4 to be a high priority for clinical development. Oncolytic viruses also represent unique regulatory and biosafety challenges but offer a potential new class of agents for the treatment of cancer.

9 Review Surgical Management of Melanoma. 2016

Koshenkov, Vadim P / Broucek, Joe / Kaufman, Howard L. ·Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St., Suite 3001, New Brunswick, NJ, 08901, USA. vpk10@cinj.rutgers.edu. · Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St., Suite 3001, New Brunswick, NJ, 08901, USA. ·Cancer Treat Res · Pubmed #26601862.

ABSTRACT: The surgical management of melanoma has undergone considerable changes over the past several decades, as new strategies and treatments have become available. Surgeons play a pivotal role in all aspects of melanoma care: diagnostic, curative, and palliative. There is a high potential for cure in patients with early-stage melanoma and the selection of an appropriate operation is very important for this reason. Staging the nodal basin has become widespread since the adoption of sentinel lymph node biopsy (SLNB) for the management of melanoma. This operation provides the best prognostic information that is currently available for patients with melanoma. The surgeon plays a central role in the palliation of symptoms resulting from nodal disease and metastases, as melanoma has a propensity to spread to almost any site in the body.

10 Review Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy. 2015

Harrington, Kevin J / Puzanov, Igor / Hecht, J Randolph / Hodi, F Stephen / Szabo, Zsolt / Murugappan, Swami / Kaufman, Howard L. ·a Division of Hematology-Oncology, Vanderbilt University Medical Center , Nashville , TN , USA. · b David Geffen School of Medicine , UCLA , Los Angeles , CA , USA. · c Melanoma Center and the Center for Immuno-Oncology , Dana-Farber Cancer Institute , Boston , MA , USA. · d Department of Oncology , Amgen (Europe) GmbH , Zug , Switzerland. · e Department of Oncology , Amgen Inc ., Thousand Oaks , CA , USA. · f Division of Surgical Oncology , Rutgers Cancer Institute of New Jersey , New Brunswick , NJ , USA. ·Expert Rev Anticancer Ther · Pubmed #26558498.

ABSTRACT: Tumor immunotherapy is emerging as a promising new treatment option for patients with cancer. T-VEC is an intralesional oncolytic virus therapy based on a modified herpes simplex virus type-1. T-VEC selectively targets tumor cells, causing regression in injected lesions and inducing immunologic responses that mediate regression at uninjected/distant sites. In a randomized phase III trial, T-VEC met its primary endpoint of improving the durable response rate vs granulocyte-macrophage colony-stimulating factor in patients with unresectable melanoma. Responses were observed in injected and uninjected regional and visceral lesions. Exploratory analyses suggested survival differences in favor of T-VEC in patients with untreated or stage IIIB/IIIC/IVM1a disease. T-VEC was generally well tolerated, the most common adverse events being flu-like symptoms. Here, we overview recent advances in cancer immunotherapy, focusing on the clinical development of T-VEC, from first-in-human studies and studies in other cancer types, to ongoing combination trials with checkpoint inhibitors.

11 Review Talimogene laherparepvec (T-VEC) as cancer immunotherapy. 2015

Kohlhapp, F J / Zloza, A / Kaufman, H L. ·Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. · Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. howard.kaufman@rutgers.edu. ·Drugs Today (Barc) · Pubmed #26488034.

ABSTRACT: Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice.

12 Review Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review. 2015

Goyal, Sharad / Silk, Ann W / Tian, Sibo / Mehnert, Janice / Danish, Shabbar / Ranjan, Sinthu / Kaufman, Howard L. ·Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick. · Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick. · Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick. ·JAMA Oncol · Pubmed #26181286.

ABSTRACT: IMPORTANCE: The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. OBJECTIVE: To review the current evidence regarding the treatment of MBM from melanoma. EVIDENCE REVIEW: The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included. FINDINGS: Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. CONCLUSIONS AND RELEVANCE: At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

13 Review Oncolytic virus immunotherapy for melanoma. 2015

Dharmadhikari, Neal / Mehnert, Janice M / Kaufman, Howard L. ·Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, NJ, 08901, USA. ·Curr Treat Options Oncol · Pubmed #25777572.

ABSTRACT: Melanoma is a type of skin cancer arising from melanocytes and is increasing in incidence. Although complete surgical excision of early stage lesions may be curative, metastatic melanoma continues to be a major therapeutic challenge. Advances in understanding the molecular pathways that promote tumorigenesis and the interactions between melanoma cells and the immune system have resulted in the approval of several newly targeted agents and immunotherapy strategies for the treatment of advanced disease. Oncolytic virus immunotherapy is a new approach that uses native or attenuated live viruses to selectively kill melanoma cells and induce systemic tumor-specific immune responses. A variety of viruses are now in clinical development with the attenuated oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor, known as talimogene laherparepvec, recently demonstrating an improvement in durable response rate in patients with advanced melanoma compared with granulocyte-macrophage colony stimulating factor alone. A major advantage of talimogene laherparepvec and related agents is the limited toxicity and ability to use each individual tumor as a source of antigen to generate a highly specific antitumor immune response. These agents are easily administered in the out-patient setting and may be a reasonable option for patients with limited metastatic tumor burden, those with a good performance status and without extensive prior treatment, and in those who cannot tolerate more difficult therapeutic regimens. Further investigation into the impact on overall survival as monotherapy and combination of oncolytic virus immunotherapy with other forms of immunotherapy merit high priority for further clinical application of these novel agents for the treatment of melanoma and perhaps other cancers as well.

14 Review High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. 2014

Dutcher, Janice P / Schwartzentruber, Douglas J / Kaufman, Howard L / Agarwala, Sanjiv S / Tarhini, Ahmad A / Lowder, James N / Atkins, Michael B. ·Associate Director, Cancer Research Foundation, Chappaqua, NY, USA. jpd4401@aol.com. · Associate Director of Clinical Operations, Professor of Surgery, IU Simon Cancer Center, 550 N University Blvd, Indianapolis, 46202, IN, USA. · Chief Surgical Officer and Associate Director for Clinical Science, Professor of Surgery, Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, Room 2007, New Brunswick, 08901, NJ, USA. · Chief of Medical Oncology and Professor of Medicine, St. Luke's Cancer Center, Bethlehem, 18015, PA, USA. · Associate Professor of Medicine and Translational Science, University of Pittsburgh Cancer Institute, Suite 555, 5150 Centre Ave, Pittsburgh, 15232, PA, USA. · Senior Medical Director, Prometheus Laboratories Inc, 9410 Carroll Park Drive, San Diego, 92121, CA, USA. · Deputy Director, Professor of Medicine, Georgetown-Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd NW, NRB-E501, Washington, 20057, DC, USA. ·J Immunother Cancer · Pubmed #31546315.

ABSTRACT: Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.

15 Review Critical analysis of an oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor for the treatment of malignant melanoma. 2014

Hughes, Tasha / Coffin, Robert S / Lilley, Caroline E / Ponce, Rafael / Kaufman, Howard L. ·Departments of General Surgery and Immunology and Microbiology, Rush University Medical Center, Chicago IL, USA. · BioVex, Inc, a subsidiary of Amgen, Inc, Sherman Oaks, CA, USA. ·Oncolytic Virother · Pubmed #27512660.

ABSTRACT: Oncolytic viruses that selectively lyse tumor cells with minimal damage to normal cells are a new area of therapeutic development in oncology. An attenuated herpesvirus encoding the granulocyte-macrophage colony stimulating factor (GM-CSF), known as talimogene laherparepvec (T-VEC), has been identified as an attractive oncolytic virus for cancer therapy based on preclinical tumor studies and results from early-phase clinical trials and a large randomized Phase III study in melanoma. In this review, we discuss the basic biology of T-VEC, describe the role of GM-CSF as an immune adjuvant, summarize the preclinical data, and report the outcomes of published clinical trials using T-VEC. The emerging data suggest that T-VEC is a safe and potentially effective antitumor therapy in malignant melanoma and represents the first oncolytic virus to demonstrate therapeutic activity against human cancer in a randomized, controlled Phase III study.

16 Review Current status of granulocyte-macrophage colony-stimulating factor in the immunotherapy of melanoma. 2014

Kaufman, Howard L / Ruby, Carl E / Hughes, Tasha / Slingluff, Craig L. ·Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. · Rush University Medical Center, 600 S Paulina St Suite 527, Chicago, IL 60612, USA. · University of Virginia, P.O. Box 800709, Charlottesville, VA 22908, USA. ·J Immunother Cancer · Pubmed #24971166.

ABSTRACT: In 2012, it was estimated that 9180 people in the United States would die from melanoma and that more than 76,000 new cases would be diagnosed. Surgical resection is effective for early-stage melanoma, but outcomes are poor for patients with advanced disease. Expression of tumor-associated antigens by melanoma cells makes the disease a promising candidate for immunotherapy. The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has a variety of effects on the immune system including activation of T cells and maturation of dendritic cells, as well as an ability to promote humoral and cell-mediated responses. Given its immunobiology, there has been interest in strategies incorporating GM-CSF in the treatment of melanoma. Preclinical studies with GM-CSF have suggested that it has antitumor activity against melanoma and can enhance the activity of anti-melanoma vaccines. Numerous clinical studies have evaluated recombinant GM-CSF as a monotherapy, as adjuvant with or without cancer vaccines, or in combination with chemotherapy. Although there have been suggestions of clinical benefit in some studies, results have been inconsistent. More recently, novel approaches incorporating GM-CSF in the treatment of melanoma have been evaluated. These have included oncolytic immunotherapy with the GM-CSF-expressing engineered herpes simplex virus talimogene laherparepvec and administration of GM-CSF in combination with ipilimumab, both of which have improved patient outcomes in phase 3 studies. This review describes the diverse body of preclinical and clinical evidence regarding use of GM-CSF in the treatment of melanoma.

17 Review Optimal management of metastatic melanoma: current strategies and future directions. 2013

Batus, Marta / Waheed, Salman / Ruby, Carl / Petersen, Lindsay / Bines, Steven D / Kaufman, Howard L. ·Rush University Melanoma Program and Departments of Medicine, General Surgery and Immunology and Microbiology, Rush University Medical Center, 1725 W. Harrison Street, Room 845, Chicago, IL 60612, USA. ·Am J Clin Dermatol · Pubmed #23677693.

ABSTRACT: Melanoma is increasing in incidence and remains a major public health threat. Although the disease may be curable when identified early, advanced melanoma is characterized by widespread metastatic disease and a median survival of less than 10 months. In recent years, however, major advances in our understanding of the molecular nature of melanoma and the interaction of melanoma cells with the immune system have resulted in several new therapeutic strategies that are showing significant clinical benefit. Current therapeutic approaches include surgical resection of metastatic disease, chemotherapy, immunotherapy, and targeted therapy. Dacarbazine, interleukin-2, ipilimumab, and vemurafenib are now approved for the treatment of advanced melanoma. In addition, new combination chemotherapy regimens, monoclonal antibodies blocking the programmed death-1 (PD-1)/PD-ligand 1 pathway, and targeted therapy against CKIT, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and other putative signaling pathways in melanoma are beginning to show promise in early-phase clinical trials. Further research on these modalities alone and in combination will likely be the focus of future clinical investigation and may impact the outcomes for patients with advanced melanoma.

18 Review Vaccines for melanoma and renal cell carcinoma. 2012

Kaufman, Howard L. ·Rush University Cancer Center, Chicago, IL 60612, USA. Howard_Kaufman@rush.edu ·Semin Oncol · Pubmed #22595049.

ABSTRACT: The inherent immunogenicity of melanoma and renal cell carcinoma (RCC) has made these tumors a focus of considerable research in vaccine development. Recent data from murine studies of immunosurveillance have highlighted the importance of both innate and adaptive immune responses in shaping a tumor's inherent susceptibility to immune surveillance and immunotherapy. Melanoma has been a useful model for the identification of tumor-associated antigens and a number of putative renal cell antigens have been described more recently. These antigens have been targeted using a variety of vaccine strategies, including protein- and peptide-based vaccines, recombinant antigen-expressing vectors, and whole cell vaccine approaches. While evidence for clinical benefit has been disappointing to date, several current phase III clinical trials are in progress based on promising results from phase II studies. Accumulating data suggest that the tumor microenvironment and mechanisms of immunological escape by established tumors are significant barriers that must be overcome before vaccine therapy can be fully realized. This review will discuss the basis for vaccine development, describe some of the more promising vaccine strategies in development, and mention some of the tumor escape mechanisms that block effective anti-tumor immunity for melanoma and RCC.

19 Review An association between corticosteroid use and melanoma recurrence: a case report and review of the literature. 2012

Lazarus, Mark / Kaufman, Howard. ·Rush Medical College, Rush University, Chicago, IL, USA. lazarus.m.a@gmail.com ·Med Oncol · Pubmed #21922297.

ABSTRACT: -- No abstract --

20 Review Herpes simplex virus oncolytic vaccine therapy in melanoma. 2010

Sivendran, Shanthi / Pan, Michael / Kaufman, Howard L / Saenger, Yvonne. ·The Mount Sinai School of Medicine, The Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, New York, NY 10029, USA. ·Expert Opin Biol Ther · Pubmed #20515292.

ABSTRACT: IMPORTANCE OF THE FIELD: Advanced melanoma is a devastating disease with a five year survival for Stage IV disease of 10 - 20% and a median survival of 6 - 18 months depending on sub-stage. Current FDA approved therapies demonstrate limited response rates, few complete remissions and no proven survival benefit. New therapies are clearly needed. JSI/34.5-/47-/GM-CSF is a herpes simplex virus-1 (OncoVEX(GM-CSF)) oncolytic vaccine therapy designed to induce local and systemic anti-tumor immune responses. AREAS COVERED IN THIS REVIEW: Evolution of current herpes simplex virus oncolytic vaccines from preclinical to clinical studies from 1994 to 2010. WHAT THE READER WILL GAIN: Preclinical studies have shown that herpes simplex virus-1 oncolytic vaccines generate local tumor destruction through the lytic action of the virus and local and systemic immune responses. Phase I studies demonstrated limited toxicities with no neurotoxicty. Phase II studies demonstrated durable regressions in patients with metastatic melanoma. A Phase III trial in melanoma is ongoing to determine clinical effectiveness, and a Phase III trial in head and neck cancer will initiate during 2010. TAKE HOME MESSAGE: JSI/34.5-/47-/GM-CSF is a new generation herpes simplex virus-1 oncolytic vaccine that demonstrates direct tumor lysis and systemic immune responses. Early clinical studies have yielded preliminary evidence of activity.

21 Clinical Trial Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. 2018

Chesney, Jason / Puzanov, Igor / Collichio, Frances / Singh, Parminder / Milhem, Mohammed M / Glaspy, John / Hamid, Omid / Ross, Merrick / Friedlander, Philip / Garbe, Claus / Logan, Theodore F / Hauschild, Axel / Lebbé, Celeste / Chen, Lisa / Kim, Jenny J / Gansert, Jennifer / Andtbacka, Robert H I / Kaufman, Howard L. ·Jason Chesney, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY · Igor Puzanov, Roswell Park Cancer Institute, Buffalo · Philip Friedlander, Mt Sinai School of Medicine, New York, NY · Frances Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · Parminder Singh, Mayo Clinic, Phoenix, AZ · Mohammed M. Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · John Glaspy, University of California Los Angeles School of Medicine · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Lisa Chen, Jenny J. Kim, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Merrick Ross, MD Anderson Cancer Center, Houston, TX · Claus Garbe, University Hospital Tuebingen, Tuebingen · Axel Hauschild, University of Kiel, Kiel, Germany · Theodore F. Logan, Indiana University Simon Cancer Center, Indianapolis, IN · Celeste Lebbé, Assistance Publique-Hôpital De Paris Dermatology and CIC Hôpital Saint Louis University Paris Diderot Sorbonne, Institut National de la Santé et de la Recherche Médicale U976, Paris, France · Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT · and Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. ·J Clin Oncol · Pubmed #28981385.

ABSTRACT: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10

22 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.

23 Clinical Trial Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. 2017

Kaufman, Howard L / Andtbacka, Robert H I / Collichio, Frances A / Wolf, Michael / Zhao, Zhongyun / Shilkrut, Mark / Puzanov, Igor / Ross, Merrick. ·Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. howard.kaufman@rutgers.edu. · Huntsman Cancer Institute, University of Utah, 1950 Circle of Hope Drive, Salt Lake City, UT, 84112, USA. · The University of North Carolina Chapel Hill, 170 Manning Drive, Box 7305, Chapel Hill, NC, 27599, USA. · Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. · Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. · MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. ·J Immunother Cancer · Pubmed #28923101.

ABSTRACT: BACKGROUND: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. METHODS: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). RESULTS: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025). CONCLUSIONS: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.

24 Clinical Trial Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma. 2016

Andtbacka, Robert H I / Agarwala, Sanjiv S / Ollila, David W / Hallmeyer, Sigrun / Milhem, Mohammed / Amatruda, Thomas / Nemunaitis, John J / Harrington, Kevin J / Chen, Lisa / Shilkrut, Mark / Ross, Merrick / Kaufman, Howard L. ·University of Utah Huntsman Cancer Institute, Salt Lake City, Utah. · St. Luke's University Hospital and Temple University, Philadelphia, Pennsylvania. · University of North Carolina, Chapel Hill, North Carolina. · Advocate Lutheran General Hospital, Park Ridge, Illinois. · University of Iowa Hospitals and Clinics, Iowa City, Iowa. · Minnesota Oncology, Fridley, Minnesota. · Mary Crowley Cancer Research Center, Dallas, Texas. · The Institute of Cancer Research/The Royal Marsden Hospital, London, UK. · Amgen, Inc, Thousand Oaks, California. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Rutgers Cancer Institute of New Jersey, Rutgers, New Jersey. ·Head Neck · Pubmed #27407058.

ABSTRACT: BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016.

25 Clinical Trial Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. 2016

Andtbacka, Robert H I / Ross, Merrick / Puzanov, Igor / Milhem, Mohammed / Collichio, Frances / Delman, Keith A / Amatruda, Thomas / Zager, Jonathan S / Cranmer, Lee / Hsueh, Eddy / Chen, Lisa / Shilkrut, Mark / Kaufman, Howard L. ·Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Robert.Andtbacka@hci.utah.edu. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Vanderbilt University Medical Center, Nashville, TN, USA. · University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · University of North Carolina, Chapel Hill, NC, USA. · Emory University, Atlanta, GA, USA. · Minnesota Oncology, Fridley, MN, USA. · Moffitt Cancer Center, Tampa, FL, USA. · University of Washington School of Medicine, Seattle, WA, USA. · Saint Louis University Cancer Center, St Louis, MO, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Rutgers Cancer Institute of New Jersey, Rutgers, NJ, USA. ·Ann Surg Oncol · Pubmed #27342831.

ABSTRACT: PURPOSE: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma. METHODS: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. RESULTS: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. CONCLUSIONS: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.