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Melanoma: HELP
Articles by Jedd D. Wolchok
Based on 181 articles published since 2010
(Why 181 articles?)
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Between 2010 and 2020, J. Wolchok wrote the following 181 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
1 Review Checkpoint inhibition and melanoma: Considerations in treating the older adult. 2017

Friedman, Claire F / Wolchok, Jedd D. ·Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center 1275 York Ave., New York, NY 10065, USA. Electronic address: Friedmac@mskcc.org. · Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center 1275 York Ave., New York, NY 10065, USA. ·J Geriatr Oncol · Pubmed #28506536.

ABSTRACT: The incidence of melanoma and associated mortality rate from advanced disease in older adults is increasing over time. Checkpoint inhibitors have demonstrated a survival benefit for the treatment of stage IV or unresectable stage III disease and have become one of the standards of care. Data suggests that adults aged 65 and older benefit from treatment with checkpoint inhibitors without an increased incidence in adverse events. However, clinicians should be aware of the potential side effects of this class of medications and how to manage them in older adults.

2 Review Immunotherapy of Melanoma. 2015

Snyder, Alexandra / Zamarin, Dmitriy / Wolchok, Jedd D. · ·Prog Tumor Res · Pubmed #26376963.

ABSTRACT: The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma.

3 Review CTLA-4 antibodies: new directions, new combinations. 2014

Funt, Samuel A / Page, David B / Wolchok, Jedd D / Postow, Michael A. · ·Oncology (Williston Park) · Pubmed #25387681.

ABSTRACT: Checkpoint blockade is a transformative therapeutic approach to a broad spectrum of malignancies because it increases the power of antitumor immunity to obtain durable responses. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is the prototypical inhibitory checkpoint receptor. Since US Food and Drug Administration approval of the anti-CTLA-4 antibody ipilimumab for use in patients with melanoma, there has been ever-increasing excitement among oncologists about new ways to use this method of releasing the "brakes" on patients' endogenous immune systems. This review will summarize the preclinical and clinical development of CTLA-4-blocking antibodies, discuss recent insights into the biology of CTLA-4 blockade, review the use of these antibodies in combination with established and novel therapeutic modalities, and comment on ongoing questions regarding their administration.

4 Review Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. 2014

McDermott, David / Lebbé, Celeste / Hodi, F Stephen / Maio, Michele / Weber, Jeffrey S / Wolchok, Jedd D / Thompson, John A / Balch, Charles M. ·Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, 375 Longwood Ave, Mailstop: MASCO 428, Boston, MA 02215, USA. Electronic address: dmcdermo@bidmc.harvard.edu. · APHP Department of Dermatology, CIC, U976 Hôpital Saint-Louis University Paris Diderot, 1 Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Center for Immuno-Oncology, Melanoma Center, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Electronic address: Stephen_Hodi@dfci.harvard.edu. · Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena 53100, Italy. Electronic address: mmaiocro@gmail.com. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address: jeffrey.weber@moffitt.org. · Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Electronic address: wolchokj@mskcc.org. · Seattle Cancer Care Alliance, 825 Eastlake Ave E, G4-830, Seattle, WA 98109, USA. Electronic address: jat@uw.edu. · Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: charles.balch@utsouthwestern.edu. ·Cancer Treat Rev · Pubmed #25060490.

ABSTRACT: Historically, the median overall survival for patients with stage IV melanoma was less than 1 year and the 5-year survival rate was ∼10%. Recent advances in therapy have raised 5-year survival expectations to ∼20%. Notably, a subset of melanoma patients who receive immunotherapy with high-dose interleukin-2, and now ipilimumab, can achieve long-term survival of at least 5 years. A major goal in melanoma research is to increase the number of patients who experience this overall survival benefit. In this review, we discuss the attributes of immunotherapy and newer targeted agents, and consider how combination strategies might improve the chances of achieving durable benefit and long-term survival. We also discuss three areas that we believe will be critical to making further advances in melanoma treatment. To better understand the clinical profile of patients who achieve long-term survival with immunotherapy, we first present data from ipilimumab clinical trials in which a subset of patients experienced durable responses. Second, we discuss the limitations of traditional metrics used to evaluate the benefits of immunotherapies. Third, we consider emerging issues that clinicians are currently facing when making treatment decisions regarding immunotherapy. A better understanding of these novel treatments may improve survival outcomes in melanoma, increase the number of patients who experience this overall survival benefit, and inform the future use of these agents in the treatment of other cancer types.

5 Review Immune checkpoint blockade. 2014

Naidoo, Jarushka / Page, David B / Wolchok, Jedd D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: naidooj@mskcc.org. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. · Melanoma and Immunotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. ·Hematol Oncol Clin North Am · Pubmed #24880949.

ABSTRACT: Since the development and approval of Ipilimumab, the first immune checkpoint inhibitor licensed for the treatment of metastatic melanoma, clinicians have gained a better understanding of the mode of action, management of toxicities, and assessment of response to this class of drugs. Several antibodies are now in development, aimed at blocking novel immune checkpoint molecules, such as PD-1 and it's corresponding ligand PD-L1. This article summarizes the mechanism of action, preclinical development, and subsequent clinical studies of immune checkpoint antibodies in melanoma.

6 Review Ipilimumab in patients with cancer and the management of dermatologic adverse events. 2014

Lacouture, Mario E / Wolchok, Jedd D / Yosipovitch, Gil / Kähler, Katharina C / Busam, Klaus J / Hauschild, Axel. ·Memorial Sloan Kettering Cancer Center, New York, New York; Weill-Cornell Medical College, New York, New York. Electronic address: lacoutum@mskcc.org. · Memorial Sloan Kettering Cancer Center, New York, New York; Weill-Cornell Medical College, New York, New York; Ludwig Institute for Cancer Research, New York, New York. · Departments of Dermatology, Neurobiology and Anatomy, and Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina. · Department of Dermatology, University of Kiel, Kiel, Germany. · Memorial Sloan Kettering Cancer Center, New York, New York. ·J Am Acad Dermatol · Pubmed #24767731.

ABSTRACT: Ipilimumab is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor T-cell responses. Phase III studies have demonstrated survival benefit in both previously treated and treatment-naïve patients with metastatic melanoma. In clinical trials, adverse events (AEs) related to treatment with ipilimumab were mostly grade 1/2 (as per Common Terminology Criteria for AEs, Version 4.02), and mostly reversible with appropriate management. Distinct immune-related AEs that may reflect the mechanism of action of ipilimumab have been identified, and occur commonly in the skin, typically presenting as a maculopapular rash, which can be accompanied by pruritus, pruritus with no skin lesions, alopecia, and vitiligo. Histologic analyses have revealed epidermal spongiosis, and perivascular CD4(+) T-cell infiltrates with some eosinophils in areas of rash. Timely implementation of toxicity-specific treatment guidelines that emphasize vigilance and early intervention allows mitigation of dermatologic AEs. Adherence to guidelines is necessary to maintain quality of life, ensure consistent dosing, and obtain the best possible clinical outcome.

7 Review Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. 2014

Ryder, Mabel / Callahan, Margaret / Postow, Michael A / Wolchok, Jedd / Fagin, James A. ·Human Oncology and Pathogenesis Program, Department of Medicine Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA. ·Endocr Relat Cancer · Pubmed #24610577.

ABSTRACT: Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

8 Review Immune modulation in cancer with antibodies. 2014

Page, David B / Postow, Michael A / Callahan, Margaret K / Allison, James P / Wolchok, Jedd D. ·Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York 10065; email: paged@mskcc.org , postowm@mskcc.org , callaham@mskcc.org , wolchokj@mskcc.org. ·Annu Rev Med · Pubmed #24188664.

ABSTRACT: Ipilimumab is the prototypical immunomodulatory antibody, approved by the FDA in 2011 for advanced melanoma on the basis of survival benefit. Since that time, we have made significant strides in optimizing this therapy: we have characterized the spectrum of immune-related adverse events and learned how to mitigate them with treatment algorithms, discovered potential biomarkers of activity, and identified the potential synergy between checkpoint modulation and other therapeutic modalities. Recent phase I trials have established the efficacy and safety of next-generation checkpoint agents, including PD-1 and PD-L1 inhibitors, across multiple tumor types. Much work lies ahead in developing these next-generation checkpoint agents, testing them in combination, and determining how to integrate them into the treatment paradigms of various tumor types.

9 Review The delicate balance of melanoma immunotherapy. 2013

Gyorki, David E / Callahan, Margaret / Wolchok, Jedd D / Ariyan, Charlotte E. ·Memorial Sloan-Kettering Cancer Center , New York, NY, USA. · Memorial Sloan-Kettering Cancer Center , New York, NY, USA ; Ludwig Center, Memorial Sloan-Kettering Cancer Center , New York, NY, USA. · Memorial Sloan-Kettering Cancer Center , New York, NY, USA ; Ludwig Center, Memorial Sloan-Kettering Cancer Center , New York, NY, USA ; Weill Cornell Medical College , New York, NY, USA. · Memorial Sloan-Kettering Cancer Center , New York, NY, USA ; Weill Cornell Medical College , New York, NY, USA. ·Clin Transl Immunology · Pubmed #25505953.

ABSTRACT: The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted.

10 Review Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. 2013

Barker, Christopher A / Postow, Michael A / Khan, Shaheer A / Beal, Kathryn / Parhar, Preeti K / Yamada, Yoshiya / Lee, Nancy Y / Wolchok, Jedd D. ·Authors' Affiliations: Weill Cornell Medical College, New York, New York. ·Cancer Immunol Res · Pubmed #24777500.

ABSTRACT: Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted.

11 Review Checkpoint modulation in melanoma: an update on ipilimumab and future directions. 2013

Page, David B / Postow, Michael A / Callahan, Margaret K / Wolchok, Jedd D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA, paged@mskcc.org. ·Curr Oncol Rep · Pubmed #23933888.

ABSTRACT: Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma. Since ipilimumab's approval by the FDA in 2011, a wealth of data has amassed, helping clinicians to optimize its use. We have learned how to mitigate the adverse effects of ipilimumab, identified its effects in melanoma subpopulations such as those with brain metastases, uveal melanoma, and mucosal melanoma, discovered potential biomarkers of activity, and investigated its use in combination with other therapeutic modalities. These discoveries have paved the way for rapid development of second-generation immunomodulatory antibodies such as inhibitors of the programmed cell death 1 receptor axis. These new agents hold promise as monotherapy, but perhaps the greatest allure lies in the possibility of combining these agents in synergistic multidrug regimens.

12 Review Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. 2013

Wolchok, Jedd D / Hodi, F Stephen / Weber, Jeffrey S / Allison, James P / Urba, Walter J / Robert, Caroline / O'Day, Steven J / Hoos, Axel / Humphrey, Rachel / Berman, David M / Lonberg, Nils / Korman, Alan J. ·Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. wolchokj@mskcc.org ·Ann N Y Acad Sci · Pubmed #23772560.

ABSTRACT: The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune-related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long-term follow-up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

13 Review Immunomodulatory therapy for melanoma: ipilimumab and beyond. 2013

Callahan, Margaret K / Postow, Michael A / Wolchok, Jedd D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. ·Clin Dermatol · Pubmed #23438382.

ABSTRACT: In 2011, the U.S. Food and Drug Administration approved the first new therapy for melanoma in more than a decade, ipilimumab (Yervoy). Ipilimumab is a novel antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a regulatory molecule expressed on activated T cells. Blockade of this important immune checkpoint can lead to durable tumor regression, and phase III studies show an overall survival benefit for patients with advanced melanoma. During the clinical development of ipilimumab, several unique features of this immunotherapy were identified, including the remarkable durability of responses and a distinct side-effects profile. We review the preclinical and clinical development of CTLA-4-blocking antibodies and describe current practices using ipilimumab for the treatment of advanced melanoma. Unique clinical issues related to ipilimumab will be summarized. Lastly, we will briefly preview combination therapies that incorporate ipilimumab and new checkpoint-targeting antibodies currently in clinical development.

14 Review How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. 2012

Wolchok, J. ·Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. wolchokj@mskcc.org ·Ann Oncol · Pubmed #22918923.

ABSTRACT: In 2011, two therapies were approved for the treatment of metastatic melanoma: ipilimumab, an immunotherapeutic agent, and vemurafenib, a BRAF kinase inhibitor. These approvals were based on data from phase III trials, which showed that treatment with these agents produced substantial improvements in overall survival (OS). Ipilimumab has been investigated in two phase III trials: one as monotherapy in patients with pretreated metastatic melanoma at a dose of 3 mg/kg and the second in combination with dacarbazine (DTIC) chemotherapy in patients with previously untreated metastatic melanoma at a dose of 10 mg/kg. Among the pretreated patients, ipilimumab monotherapy significantly improved median OS (Hazard ratio (HR): 0.66, P = 0.003) from 6.4 months in gp100 vaccine controls to 10.1 months. The rates of OS in the ipilimumab-alone group and the gp100 group, respectively, were 45.6% and 25.3% at 12 months and 23.5% and 13.7% at 24 months. In the second trial, OS was significantly longer in previously untreated patients receiving ipilimumab plus DTIC than those receiving DTIC plus placebo (11.2 months versus 9.1 months; HR: 0.72, P < 0.001), with higher survival rates in the ipilimumab plus DTIC group at 1 year (47.3% versus 36.3%), 2 years (28.5% versus 17.9%) and 3 years (20.8% versus 12.2%). When using ipilimumab in the clinic, special consideration should be given to immune-related adverse events (irAEs) and assessment of response. Established guidelines can be used to manage the majority of irAEs effectively. Proposed modifications made to the existing response criteria mean that the clinician can accurately detect immune-related responses that would have been considered representative of progressive disease using conventional criteria. Further research is warranted to establish how immunotherapeutic agents can be combined with conventional agents, with each other or with molecularly targeted agents such as vemurafenib, to further optimise clinical outcomes.

15 Review Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. 2012

Postow, Michael A / Harding, James / Wolchok, Jedd D. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. ·Cancer J · Pubmed #22453017.

ABSTRACT: Insight into the mechanisms of anti-tumor immunity has generated great enthusiasm for the treatment of patients with advanced melanoma. Particularly, negative regulators of the immune system, called immunologic checkpoints, have been found to play important roles in restraining otherwise effective anti-tumor immunologic responses. Therapies that target these negative regulator checkpoints, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1), have demonstrated promising clinical results. Treatment is generally well tolerated, but a novel spectrum of side effects, termed immune-related adverse events, has been experienced. Unfortunately, not all patients respond to these therapies, and evaluation of biomarkers predictive of response is ongoing. Based on their unique mechanisms of action, radiographic assessment of response differs from methods traditionally applied to cytotoxic chemotherapy. We expect ongoing and future efforts combining agents that target immunologic checkpoints with other immunotherapeutic approaches, targeted therapy, chemotherapy, and radiotherapy may additionally be beneficial.

16 Review Patient responses to ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses? 2012

Pennock, Gregory K / Waterfield, William / Wolchok, Jedd D. ·M.D. Anderson Cancer Center, Orlando, FL, USA. ·Am J Clin Oncol · Pubmed #21336089.

ABSTRACT: Advanced melanoma has defied treatment advances for several decades. Immunotherapy with high-dose interleukin-2 or interferon-α has been beneficial in some cases, but significant toxicities limit its use. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling switches off T-cell activation and induces immune tolerance. Inhibiting CTLA-4 prolongs the antitumor T-cell response, reversing tolerance. Ipilimumab is a first-in-class anti-CTLA-4 monoclonal antibody, currently under review by the Food and Drug Administration for pretreated melanoma. Ipilimumab has shown durable responses and manageable toxicities in a large phase 3 clinical trial in patients with advanced melanoma. Variable response patterns have been observed, including: (1) response in baseline lesions; (2) a slow, steady decline in tumor burden; (3) response after an increase in tumor burden; and (4) response in index and new lesions accompanied by the appearance of other new lesions. Although responses (1) and (2) may be captured using standard methods, atypical responses (3) and (4) would be classified as progressive disease using conventional assessments. Patients on ipilimumab may have delayed responses or durable stable disease even after apparent disease progression, therefore using new immune-related response criteria is recommended to avoid premature treatment withdrawal. This review compares and contrasts responses to ipilimumab with those after chemotherapy, and discusses treatment implications.

17 Review Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. 2011

Sharma, Padmanee / Wagner, Klaus / Wolchok, Jedd D / Allison, James P. ·Department of Genitourinary Medical Oncology, University of Texas M D Anderson Cancer Center, Box 0018-7, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ·Nat Rev Cancer · Pubmed #22020206.

ABSTRACT: The US Food and Drug Administration (FDA) recently approved two novel immunotherapy agents, sipuleucel-T and ipilimumab, which showed a survival benefit for patients with metastatic prostate cancer and melanoma, respectively. The mechanisms by which these agents provideclinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order to understand what distinguishes responders from non-responders. The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit.

18 Review CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. 2011

Yuan, Jianda / Ginsberg, Brian / Page, David / Li, Yanyun / Rasalan, Teresa / Gallardo, Humilidad F / Xu, Yinyan / Adams, Sylvia / Bhardwaj, Nina / Busam, Klaus / Old, Lloyd J / Allison, James P / Jungbluth, Achim / Wolchok, Jedd D. ·Immunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute, New York, NY 10065, USA. ·Cancer Immunol Immunother · Pubmed #21465316.

ABSTRACT: BACKGROUND: Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential for immunogenicity and may produce an effector-memory T-cell response. METHODS: To determine the effect of CTLA-4 blockade on antigen-specific responses following vaccination, in-depth immune monitoring was performed on three ipilimumab-treated patients prevaccinated with gp100 DNA (IMF-24), gp100(209-217) and tyrosinase peptides plus GM-CSF DNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11); peripheral blood mononuclear cells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culture with HLA-A*0201-restricted gp100(209-217) (ITDQVPFSV), tyrosinase(369-377) (YMDGTMSQV), or 20-mer NY-ESO-1 overlapping peptides, respectively. Tumors from IMF-32 were analyzed by immunohistochemistry to help elucidate mechanism(s) underlying tumor escape. RESULTS: Following vaccination, patients generated weak to no CD4(+) or CD8(+) T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7(lo)CD45RA(lo)) tetramer(+)CD8(+) T cells. After ipilimumab induction, patients experienced a robust, although sometimes transient, antigen-specific response for gp100 (IMF-32 and IMF-24) or NY-ESO-1 (IMF-11) and produced polyfunctional intracellular cytokines. Primary and metastatic tumors expressed tyrosinase but not gp100 or class I/II MHC molecules. CONCLUSION: Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially "boosting" the vaccine-primed response. Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited number of patients support the need for further research into combining vaccination with ipilimumab and provide insight into mechanisms underlying tumor escape.

19 Review Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. 2010

Callahan, Margaret K / Wolchok, Jedd D / Allison, James P. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. ·Semin Oncol · Pubmed #21074063.

ABSTRACT: Cytotoxic T-lymphocyte-associated antigen (CTLA-4), also known as CD152, is a co-inhibitory molecule that functions to regulate T-cell activation. Antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including antitumor immunity. Two CTLA-4-blocking antibodies are presently under clinical investigation: ipilimumab and tremelimumab. CTLA-4 blockade has shown promise in treatment of patients with metastatic melanoma, with a recently completed randomized, double-blind phase III trial demonstrating a benefit in overall survival (OS) in the treated population. However, this approach appears to benefit only a subset of patients. Understanding the mechanism(s) of action of CTLA-4 blockade and identifying prognostic immunologic correlates of clinical endpoints to monitor are presently areas of intense investigation. Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed.

20 Review Targeting cytotoxic T-lymphocyte antigen 4 in immunotherapies for melanoma and other cancers. 2010

Page, David B / Yuan, Jianda / Wolchok, Jedd D. ·Melanoma/Sarcoma Service, Memorial Sloan-Kettering Cancer Center, NY, USA. ·Immunotherapy · Pubmed #20635901.

ABSTRACT: The immune system can simultaneously protect against tumor growth and sculpt resistant tumor strains. By a variety of mechanisms, anti-cytotoxic T-lymphocyte antigen (CTLA)-4 therapy may shift such opposing forces towards tumor elimination. In recent clinical trials, anti-CTLA-4 therapy induces durable responses that correlate with markers of immune activity, such as antigen-specific CD4(+) or CD8(+) cytokine release, antitumor antibody formation or cellular phenotype differentiation. However, some patients exhibit atypical responses to anti-CTLA-4 therapy, demonstrating transient/delayed responses or heterogeneity by lesion site. Such atypical responses may offer insight into the mechanism of anti-CTLA-4 therapy. The immunogram - a newly described graphical synthesis of treatment data and immune correlates in individual patients - may help us to confirm, reject or formulate new hypotheses regarding the mechanism of anti-CTLA-4 activity.

21 Clinical Trial Rational design of anti-GITR-based combination immunotherapy. 2019

Zappasodi, Roberta / Sirard, Cynthia / Li, Yanyun / Budhu, Sadna / Abu-Akeel, Mohsen / Liu, Cailian / Yang, Xia / Zhong, Hong / Newman, Walter / Qi, Jingjing / Wong, Phillip / Schaer, David / Koon, Henry / Velcheti, Vamsidhar / Hellmann, Matthew D / Postow, Michael A / Callahan, Margaret K / Wolchok, Jedd D / Merghoub, Taha. ·Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Leap Therapeutics, Cambridge, MA, USA. · Immune Monitoring Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Case Western Reserve University, Cleveland, OH, USA. · Department of Hematology and Oncology, New York University School of Medicine, New York, NY, USA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Weill Cornell Medical College, New York, NY, USA. · Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org. · Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org. · Weill Cornell Medical College, New York, NY, USA. wolchokj@mskcc.org. · Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. · Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. ·Nat Med · Pubmed #31036879.

ABSTRACT: Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses

22 Clinical Trial Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. 2019

Hamid, O / Robert, C / Daud, A / Hodi, F S / Hwu, W J / Kefford, R / Wolchok, J D / Hersey, P / Joseph, R / Weber, J S / Dronca, R / Mitchell, T C / Patnaik, A / Zarour, H M / Joshua, A M / Zhao, Q / Jensen, E / Ahsan, S / Ibrahim, N / Ribas, A. ·Medical Oncology, The Angeles Clinic and Research Institute, Los Angeles, USA. Electronic address: ohamid@theangelesclinic.org. · Department of Dermatology, Gustave Roussy, Villejuif; Department of Medicine, University of Paris-Sud, Paris, France. · Department of Medicine, University of California, San Francisco, San Francisco. · Medical Oncology, Dana-Farber Cancer Institute, Boston. · Department of Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA. · Medical Oncology, Westmead Hospital, Westmead; Medical Oncology, Melanoma Institute Australia, Sydney; Medical Oncology, Macquarie University, Macquarie Park; Medical Oncology, University of Sydney, Sydney, Australia. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. · Medical Oncology, University of Sydney, Sydney, Australia; Department of Medicine, Centenary Institute, Sydney, Australia. · Medical Oncology, Mayo Clinic Cancer Center-Florida, Jacksonville. · Department of Medicine, Perlmutter Cancer Center, NYU Langone Health, New York. · Division of Hematology Oncology, Abramson Cancer Center, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia. · Medical Oncology, South Texas Accelerated Research Therapeutics, San Antonio. · Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, USA. · Medical Oncology, Melanoma Institute Australia, Sydney; Medical Oncology, University of Sydney, Sydney, Australia; Kinghorn Cancer Centre, St. Vincent's Hospital, Medical Oncology, Garvan Institute of Medical Research, Sydney; Medical Oncology, University of New South Wales, Sydney, Australia. · Merck & Co., Inc., Kenilworth. · Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA. ·Ann Oncol · Pubmed #30715153.

ABSTRACT: BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

23 Clinical Trial Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. 2018

Hodi, Frank Stephen / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean-Jacques / Rutkowski, Piotr / Cowey, Charles Lance / Lao, Christopher D / Schadendorf, Dirk / Wagstaff, John / Dummer, Reinhard / Ferrucci, Pier Francesco / Smylie, Michael / Hill, Andrew / Hogg, David / Marquez-Rodas, Ivan / Jiang, Joel / Rizzo, Jasmine / Larkin, James / Wolchok, Jedd D. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. · University of Colorado Cancer Center, Denver, CO, USA. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Maria Skłodowska-Curie Institute - Oncology Centre, Warsaw, Poland. · Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, USA. · Department of Oncology, University of Michigan, Ann Arbor, MI, USA. · Department of Dermatology, University of Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · The College of Medicine, Swansea University, Swansea, UK. · Department of Dermatology, Universitäts Spital, Zürich, Switzerland. · European Institute of Oncology, Milan, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · Tasman Oncology Research, Southport, QLD, Australia. · Princess Margaret Cancer Centre, Toronto, ON, Canada. · General University Hospital Gregorio Marañón, Madrid, Spain. · Bristol-Myers Squibb, Princeton, NJ, USA. · The Royal Marsden NHS Foundation Trust, London, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #30361170.

ABSTRACT: BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis. INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. FUNDING: Bristol-Myers Squibb.

24 Clinical Trial MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. 2018

Rodig, Scott J / Gusenleitner, Daniel / Jackson, Donald G / Gjini, Evisa / Giobbie-Hurder, Anita / Jin, Chelsea / Chang, Han / Lovitch, Scott B / Horak, Christine / Weber, Jeffrey S / Weirather, Jason L / Wolchok, Jedd D / Postow, Michael A / Pavlick, Anna C / Chesney, Jason / Hodi, F Stephen. ·Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. · Department of Pathology, Brigham and Women's Hospital, Boston, MA 20115, USA. · Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Bristol-Myers Squibb, Princeton, NJ 08540, USA. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. · Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. · James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. · Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. ·Sci Transl Med · Pubmed #30021886.

ABSTRACT: Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8

25 Clinical Trial Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. 2018

Ariyan, Charlotte E / Brady, Mary Sue / Siegelbaum, Robert H / Hu, Jian / Bello, Danielle M / Rand, Jamie / Fisher, Charles / Lefkowitz, Robert A / Panageas, Kathleen S / Pulitzer, Melissa / Vignali, Marissa / Emerson, Ryan / Tipton, Christopher / Robins, Harlan / Merghoub, Taha / Yuan, Jianda / Jungbluth, Achim / Blando, Jorge / Sharma, Padmanee / Rudensky, Alexander Y / Wolchok, Jedd D / Allison, James P. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. ariyanc@mskcc.org. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Anesthesia, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Statistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Adaptive Biotechnology, Seattle, Washington. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Immunology, MD Anderson Cancer Center, Houston, Texas. · Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York. ·Cancer Immunol Res · Pubmed #29339377.

ABSTRACT: Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8

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