scholarly journals Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

2021 ◽  
Vol 11 (3) ◽  
pp. 206
Author(s):  
Teresa Troiani ◽  
Stefania Napolitano ◽  
Gabriella Brancaccio ◽  
Valentina Belli ◽  
Annarita Nappi ◽  
...  
Keyword(s):  
Melanoma Cell Line ◽  
Immune Checkpoint Inhibitors ◽  
Clinical Case ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Durable Response ◽  
Melanoma Patients ◽  
New Treatment ◽  
First Time

Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target.

Immunotherapy for advanced melanoma: current situation in Japan

2020 ◽  
Vol 51 (1) ◽  
pp. 3-9
Author(s):  
Junji Kato ◽  
Hisashi Uhara
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Advanced Melanoma ◽  
Current Evidence ◽  
Clinical Effects ◽  
Durable Response ◽  
Term Survival

Abstract Treatment with immune checkpoint inhibitors provides long-term survival for patients with advanced melanoma. Improvements in the overall survival of advanced melanoma patients have been achieved with anti-PD-1 monotherapy and anti-PD-1+ CTLA4 combination therapy, but there are still many issues to resolve. Acral, mucosal and uveal melanoma have been less responsive to immune checkpoint inhibitors than cutaneous melanoma. For patients who have achieved a good response, it is still not known how long the anti-PD-1 therapy should be administered. Moreover, there is limited treatment for patients who relapse during or after adjuvant anti-PD-1 therapy. Here, we review the current evidence regarding the clinical effects of immunotherapy for advanced melanoma. Moreover, we review previous studies of acral, mucosal and uveal melanoma, and we discuss the recent findings regarding durable response after the cessation of anti-PD-1 therapy, and treatment options for recurrence after adjuvant therapy.

scholarly journals Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors

2020 ◽  
Vol 21 (23) ◽  
pp. 9056
Author(s):  
Valentina Tateo ◽  
Lisa Manuzzi ◽  
Andrea De Giglio ◽  
Claudia Parisi ◽  
Giuseppe Lamberti ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cancer Biology ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors ◽  
New Treatment ◽  
Light Side ◽  
Thoracic Malignancies

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.

scholarly journals Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6366
Author(s):  
Joosje C. Baltussen ◽  
Marij J. P. Welters ◽  
Elizabeth M. E. Verdegaal ◽  
Ellen Kapiteijn ◽  
Anne M. R. Schrader ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Suppressor Cells ◽  
Cochrane Library ◽  
Durable Response ◽  
Melanoma Patients

Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers.

Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 138-138
Author(s):  
Jesus Vera Aguilera ◽  
Jonas Paludo ◽  
Jarrett Failing ◽  
Robert R. McWilliams ◽  
Lisa A. Kottschade ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Efficacy And Safety ◽  
Wild Type ◽  
Lung Cancer Patients ◽  
Melanoma Patients

138 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]

scholarly journals Psychological Distress of Metastatic Melanoma Patients during Treatment with Immune Checkpoint Inhibitors: Results of a Prospective Study

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2642
Author(s):  
Lisa Wiens ◽  
Norbert Schäffeler ◽  
Thomas Eigentler ◽  
Claus Garbe ◽  
Andrea Forschner
Keyword(s):  
Side Effects ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Female Gender ◽  
Self Assessment ◽  
Prospective Longitudinal Study ◽  
Melanoma Patients ◽  
Prospective Longitudinal

Background: Immune checkpoint inhibitors (ICI) provide effective treatment options for advanced melanoma patients. However, they are associated with high rates of immune-related side effects. There are no data on the distress of melanoma patients during their ICI treatment. We, therefore, conducted a prospective longitudinal study to assess distress and the need for psycho-oncological support in these patients. Methods: Questionnaires were completed before initiation of ICI (T0), after 6–8 weeks (T1), and after 12–14 weeks (T2). We furthermore included the Hornheide Screening Instrument (HSI), distress thermometer (DT), and patients’ self-assessment. Binary logistic regression was performed to identify factors indicating a need for psychooncological support. Results: 36.3%/55.8% (HSI / DT) of the patients were above the threshold, indicating a need for psychooncological support at T0, and 7.8% of the patients reported practical problems. In contrast, at T2, the distress values had decreased to 29.0%/40.2% (HSI/DT), respectively. Female gender and occurrence of side effects significantly correlated to values above the threshold. The strongest factor was the patient’s self-assessment. Conclusion: With the beginning of ICI, psychooncological support should be offered. Furthermore, practical problems should be considered, e.g., transport to therapy. Female patients and patients with side effects should be given special attention, as well as the patient self-assessment.

Durable response after immunotherapy discontinuation for delayed and severe immune-related adverse event: a case report

Immunotherapy ◽  
2021 ◽  
Author(s):  
Guido Pesola ◽  
Veronica Murianni ◽  
Sara Elena Rebuzzi ◽  
Giuseppe Luigi Banna ◽  
Luigi Cerbone ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Renal Cell Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Clinical Case ◽  
Renal Toxicity ◽  
Checkpoint Inhibitors ◽  
Durable Response ◽  
Disease Outcomes ◽  
Clinical Benefits ◽  
Metastatic Rcc

Recent studies have shown that immune-related adverse events (irAEs), occurring even after the discontinuation of immune checkpoint inhibitors (ICIs), may be associated with favorable disease outcomes, particularly in patients with melanoma and lung cancer. However, a few clinical cases have been described on the correlation between irAEs and ICIs efficacy in renal cell carcinoma (RCC) patients. This study reports the clinical case of a metastatic RCC patient who has experienced severe immune-related renal toxicity after 19 months of nivolumab use. Despite immunotherapy discontinuation, the patient has maintained clinical benefit and disease progression-free for 3 years. We examined the correlation between the occurrence and the severity of irAEs, treatment discontinuation and clinical benefits. The evidence on ICI retreatment following ICI discontinuation due to irAEs was also reviewed.

Evolution of Molecular Targets in Melanoma Treatment

2020 ◽  
Vol 26 (4) ◽  
pp. 396-414 ◽  
Author(s):  
Khanh B. Tran ◽  
Christina M. Buchanan ◽  
Peter R. Shepherd
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Durable Response ◽  
History Of ◽  
Melanoma Treatment ◽  
Melanoma Patients

Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.

Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

2020 ◽  
Author(s):  
Guanghui Xu ◽  
Yuhao Wang ◽  
Hushan Zhang ◽  
Xueke She ◽  
Jianjun Yang
Keyword(s):  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
The Body ◽  
Low Grade ◽  
Ablative Therapies ◽  
Cancer Types ◽  
New Treatment ◽  
Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

scholarly journals Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3708
Author(s):  
Bhaba K. Das ◽  
Aarthi Kannan ◽  
Quy Nguyen ◽  
Jyoti Gogoi ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Aurora Kinase ◽  
Selective Inhibition ◽  
Potential Candidate ◽  
Cycle Arrest

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

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