Combined radio-immunotherapy leads to complete clinical regression of stage IV Merkel cell carcinoma.
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ABSTRACT:
SUBMITTER: Principe DR
PROVIDER: S-EPMC6720814 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with frequent metastasis and death. MCC has a mortality rate of 30%, making it more lethal than malignant melanoma, and incidence of MCC has increased almost fourfold over the past 20?years in the USA. MCC has long been considered to be an immunogenic cancer because it occurs more frequently in immunosuppressed patients from organ transplant and HIV infection than in those with immunocompetent. Chronic UV light exposure and clonal integration of Merkel cell polyomavirus (MCPyV) are two major causative factors of MCC. Approximately 80% of MCC are associated with MCPyV, and T cells specific for MCPyV oncoproteins are present in the blood and tumors of patients. Several studies have shown that a subset of MCCs express PD-1 on tumor-infiltrating lymphocytes and express PD-L1 on tumor cells, which suggests an endogenous tumor-reactive immune response that might be unleashed by anti-PD-1 or anti-PD-L1 drugs.
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Project description:Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.
| S-EPMC8495203 | biostudies-literature
Project description:Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer.
| S-EPMC5840183 | biostudies-literature
Project description:Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.
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| S-EPMC6226586 | biostudies-literature
Project description:Merkel Cell carcinoma (MCC) is a rare but aggressive cancer, with an estimated disease-associated mortality as high as 46%. MCC has proven to be an immunologically responsive disease and the advent of immune checkpoint inhibitors has changed the treatment landscape for patients with advanced MCC. In this review, we discuss the rationale for the use of immune checkpoint inhibition, review current single agent therapies tested in and approved for MCC, and discuss emerging immunotherapeutic options for these patients.
| S-EPMC5865292 | biostudies-literature
Project description:Merkel cell carcinoma (MCC) is a rare (?2,000 U.S. cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year), suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in approximately 80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/"exhausted," and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials involving three PD-1 pathway blocking agents-avelumab, pembrolizumab, and nivolumab-indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, approximately 50% of patients with MCC do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden antitumor immune responses in these patients. Here, we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade. Clin Cancer Res; 24(9); 2035-43. ©2017 AACR.
| S-EPMC5932211 | biostudies-literature
Project description:BackgroundThe treatment of patients with multiple synchronous tumors is challenging and complex. The use of next generation sequencing (NGS) may help in identification of germline mutations in genes involved in a common etiology for both tumors thus allowing a common effective therapeutic strategy.Patients and methodsWe describe the unexpected positive results obtained in a young woman with relapsed chemo-resistant stage IVB cervical and synchronous stage IV lung cancer, who underwent an interdisciplinary approach including palliative surgery with laparoscopic total pelvic exenteratio followed by a chemo-immunotherapy protocol with the anti-Programmed Death (PD)-1 antibody nivolumab plus metronomic cyclophosphamide. The treatment choice was based on tumor PD-Ligand 1 assessment and NGS analysis for the identification of potential treatment targets. Outcomes included tumor objective response and patient-centered outcomes (pain, performance status and overall quality of life).ResultsLaparoscopic surgery obtained an immediate symptom control and allowed the early start of medical treatment. One month after combined therapy start the patient achieved a significant improvement in performance status, pain, overall Quality of life and after 3 months she resumed working. After 3 and 6 months of treatment we observed an objective dimensional and metabolic response. Currently, after 24 months (and 48 cycles of nivolumab) the patient is continuing to benefit from treatment: she is in complete remission, with good performance status and she is working and leading a self-dependent life.ConclusionOur study strongly affirms the efficacy of an interdisciplinary approach including surgical and innovative medical strategies based on immunotherapy in patients with advanced chemo-resistant synchronous cervical and lung cancer. The present findings support the use of NGS to drive a targeted rational treatment especially in heavily pre-treated patients.
| S-EPMC6459345 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is an intractable cancer with a high mortality rate. Transarterial chemoembolization (TACE), a non-curative method, is the first line therapy for intermediate stage patients. This effectively extends patient survival but requires a complicated intraarterial catheterization procedure and is poorly suited to repeated administration. Here, we investigate gas chemoembolization, a less invasive, more easily administered transient occlusion method that circumvents these limitations. We examined the efficacy of repeated embolization combined with systemically administered doxorubicin, the most common chemotherapeutic in TACE, or tirapazamine, a hypoxia-activated cytotoxic agent, in an ectopic xenograft model of HCC. Emboli were generated in situ using acoustic droplet vaporization, the noninvasive focused ultrasound-mediated conversion of intravenously administered perfluorocarbon microdroplets into microbubbles. Gas embolization alone significantly reduced the Ki67 index and tumor viability (11.6 ± 6.71% non-necrotic vs 100% in control; p < 0.01) after 3 treatments, as assessed by histological analysis. Mice treated for three weeks exhibited significant tumor regression compared to control (23.8 ± 5.37% of initial volume vs 427 ± 49.7% in controls, p < 0.01), irrespective of the chosen chemotherapeutic agent. However, an additional three weeks of monitoring post-treatment elucidated a significant difference in the tumor recurrence rate, with combined gas embolization and doxorubicin resulting in the best treatment outcomes (60% complete regression). While doxorubicin administration resulted in significant cardiotoxicity (p < 0.01), it strongly interacted with the droplet shells, reducing the systemic dose by 11.4%. Overall, gas chemoembolization shows promise as a developmental therapy and merits further study in more complex tumor models.
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Project description:INTRODUCTION:S-1, a new oral fluorouracil chemotherapeutical drug, has been increasingly used in clinical maintenance after first-line chemotherapy for stage III or IV gastric carcinoma (GC) and colorectal carcinoma (CRC) for its own advantages. XiangshaLiujunzi Decoction (XSLJZD), a classic traditional Chinese medicine (TCM) formula with effects of alleviating the adverse reactions of chemotherapy and improving the quality of life of cancer patients has been gradually confirmed, with no more reports about the maintenance therapy mode of combination of chemotherapeutic drugs and TCM. We designed the study of XSLJZD combined with S-1 in the maintenance therapy of Stage III or IV GC and CRC, and hoped that this research program will go further and comprehensively evaluate its efficacy and safety. OBJECTIVES:The aim of this study was to determine the efficacy and safety of XSLJZD combined with S-1 in the maintenance therapy of stage III or IV GC and CRC. METHODS:This study is an open, single-center, randomized study. Patients with stage III or stage IV GC and CRC will be randomized (1:1) into S-1group, S-1 combined with XSLJZD group for 5 years of maintenance therapy. The primary endpoint was progression-free survival, and secondary end point was overall survival and Quality of Life Assessment (QOLA), which include an improvement in symptoms before and after treatment, Karnofsky Performance Status, and adverse events assessment. DISCUSSION:This study will provide meaningful clinical information about the combination of chemotherapeutic drugs S-1 with TCM in the maintenance therapy of stage III or IV GC and CRC. TRIAL REGISTRATION:Chinese Clinical Trial Registry: ChiCTR-INR-16008575.
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