Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: A report of 2 cases

Blackmon, Jonathan T.; Dhawan, Ratika; Viator, Toni M.; Terry, Nina; Conry, Robert M.

doi:10.1016/j.jdcr.2017.02.003

Cited by 30 publications

(22 citation statements)

References 25 publications

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“…It is likely that vaccination or adoptive cell therapy that bolsters T-Ag-specific T cells will need to be combined with measures that modify immune evasion in MCC tumors to obtain significant antitumor effects in the majority of persons. Licensed drugs that inhibit the PD-1 pathway, as well as local therapy with cytokines, oncolytic viruses, and innate immune agonists, each have activity in MCC (5)(6)(7)(8)10), providing candidate approaches to combination therapy. MCPyV-specific CD8 þ T cells with defined fine specificity recognize HLAdefined, antigen-loaded moDCs.…”

Section: Discussionmentioning

confidence: 99%

“…Immune checkpoint inhibitors that block ligand interactions with programmed death-1 (PD-1) have led to deep, durable responses for MCPyV þ MCC, and this therapy is now standard for advanced disease (5,6). Local immunotherapy with toll-like receptor agonists, cytokines, oncolytic virus, and systemic infusion of MCPyV-specific CD8 þ T cells can also mediate responses (7)(8)(9)(10). However, many patients show no durable improvement.…”

Section: Introductionmentioning

confidence: 99%

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Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Jing

Ott

Church

et al. 2020

Cancer Immunology Research

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Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to TAg specific T cells. Strategies to increase CD8 þ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigenpresenting cell (aAPC) system and confirmed TAg recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8 þ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8 þ TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV þ MCC had HLA alleles with the genetic potential that restrict CD8 þ T-cell responses to MCPyV TAg. The LT AA 70-110 region was epitope rich, whereas the oncogenic domains of TAg were not commonly recognized. Specific recognition of TAg expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8 þ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of TAg can be modified without impacting immunogenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Jing

Ott

Church

et al. 2020

Cancer Immunology Research

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“…Finally, there have been isolated case reports of responses to other immunotherapies, such as talimogene laherparepvec (T‐VEC) in patients with locally advanced disease , cytokines or adoptive T‐cell therapy . Consequently, various immunotherapy combinations are currently being investigated in clinical trials.…”

Section: Treatment Of Metastatic MCC (M1)mentioning

confidence: 99%

Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma

et al. 2019

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Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun‐exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%–46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group. Implications for Practice Merkel cell carcinoma (MCC) is an uncommon aggressive skin cancer associated with advanced age, UV light exposure, and immunosuppression. Up to 80% are associated with Merkel cell polyomavirus. MCC is a chemosensitive disease, but tumor responses in the advanced setting are short‐lived with no long‐term survivors. Recent clinical trials with immune checkpoint inhibitors (i.e., pembrolizumab, avelumab, nivolumab) have shown promising results, with avelumab becoming the first drug to receive regulatory approval for this orphan indication. Further follow‐up is needed, however, to define more adequately the long‐term benefits of these drugs, and continued research is warranted to optimize immunotherapeutic strategies in this setting.

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“…Deterioration of tumor cells elicits an enhanced liberation of tumor antigens and a priming and increase of tumor-specific T cells. T-VEC is designed to express human granulocytemacrophage colony-stimulating factor (GM-CSF) and US11 [2,4]. This cytokine stimulus synergistically enhances the ongoing immune activation, hence promoting a local and systemic anti-tumor immune response, even at non-injected lesions and distant sites [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with the primary analysis, a subgroup analysis showed no significant beneficial effects of T-VEC on overall survival in patients with stage IVM1b/c disease. Recently, clinical studies have investigated therapy with T-VEC in diverse other tumor types and in combination with other systemic treatments, specifically immunotherapy [4,9,10]. More widely, there have been substantial advances in the development of oncolytic virotherapy based on diverse DNA and RNA viruses [2].…”

Section: Introductionmentioning

confidence: 99%

Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB–IV M1c melanoma patients

Fröhlich

Niebel

Fietz

et al. 2020

Cancer Immunol Immunother

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Background Resistance to immune checkpoint blockade and targeted therapy in melanoma patients is currently one of the major clinical challenges. With the approval of talimogene laherparepvec (T-VEC), oncolytic viruses are now in clinical practice for locally advanced or non-resectable melanoma. Here, we describe the usage of T-VEC in stage IVM1b-M1c melanoma patients, who achieved complete remission or stable disease upon systemic treatment but suffered from a locoregional recurrence. To our knowledge, there are no case reports so far describing T-VEC as a means to overcome acquired resistance to immune checkpoint blockade or targeted therapy. Methods All melanoma patients in our department treated with T-VEC in the period of 2016-2018 were evaluated retrospectively. Data on clinicopathological characteristics, treatment response, and toxicity were analyzed. Results Fourteen melanoma patients were treated with T-VEC in our center. Six patients (43%) received T-VEC first-line. In eight patients (57%), T-VEC followed a prior systemic therapy. Three patients with M1b stage and one patient with M1c stage melanoma were treated with T-VEC. These patients suffered from loco-regional progress, whilst distant metastases had regressed during prior systemic treatment. 64% of patients showed a benefit from therapy with T-VEC. The durable response rate was 36%. Conclusion T-VEC represents an effective and tolerable treatment option. This is true not only for loco-regionally advanced melanoma patients, but also for patients with stable or regressive systemic metastases who develop loco-regionally acquired resistance upon treatment with immune checkpoint blockade or targeted therapy. A sensible selection of suitable patients seems to be crucial.

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Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: A report of 2 cases

Cited by 30 publications

References 25 publications

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma

Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB–IV M1c melanoma patients

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