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BACKGROUND: Serum antibodies to the Merkel oncoprotein (AMERK) are detectable in approximately 50% of patients with Merkel cell carcinoma (MCC) and can be used to monitor for recurrence. The objective of this study was to characterize AMERK levels in patients receiving curative-intent radiation therapy (RT) for MCC and identify associations between AMERK and recurrence. METHODS: This was a retrospective study of patients with MCC who had baseline AMERK measurements before they received curative-intent RT from 2010 to 2020. Event-free survival (EFS) was calculated using the Kaplan-Meier method and Cox regression. The cumulative incidence of MCC-related recurrence (CIMR) was analyzed with death as a competing risk and the Gray test. RESULTS: The authors identified 88 patients who had baseline AMERK measurements, including 52 (59%) with detectable levels. AMERK positivity was associated with younger median age (67.8 vs. 72.0 years; p = .02) and tumor site (p = 0.02), with lower rates for those who had disease in the head/neck region (17.3% vs. 44.4%). EFS (71.3% vs. 60.4%; p = .30) and CIMR (24.4% vs. 39.6%; p = .23) were more favorable in AMERK-positive patients. Two patients had recurrences in the RT field, and both were AMERK-negative at baseline. The median time to AMERK nadir after RT was 11.2 months; and, in a 6-month post-RT landmark analysis, the proportion of patients who were AMERK-positive who became negative or who had levels that decreased by ≥50% were not associated with EFS (87.1% vs. 85.0%; p = .90) or CIMR (12.9% vs. 15.0%; p = .62). CONCLUSIONS: Positive AMERK baseline levels were correlated with younger age at MCC diagnosis and nonhead and neck tumor location, possibly related to the distribution of viral etiology. A specific post-RT AMERK decline correlating with EFS could not be identified.
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BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
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Anticorpos Antivirais , Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/sangue , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/imunologia , Poliomavírus das Células de Merkel/imunologia , Poliomavírus das Células de Merkel/isolamento & purificação , Feminino , Masculino , Estudos Retrospectivos , Idoso , Prognóstico , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Anticorpos Antivirais/sangue , Idoso de 80 Anos ou mais , Infecções Tumorais por Vírus/virologia , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/imunologiaRESUMO
BACKGROUND: Metastatic basal cell carcinoma (mBCC) is rare and there are limited data regarding patient and tumor risk factors, optimal treatments, and disease prognosis. OBJECTIVE: To assess patient and tumor characteristics, therapeutics, and outcomes of mBCC stratified by location of metastasis. METHODS: Retrospective cohort study of 53 patients with mBCC treated at 4 large academic centers in Boston, Massachusetts; Philadelphia, Pennsylvania; and Cleveland, Ohio between January 1, 2005 and December 31, 2021. RESULTS: A total of 53 patients with mBCC were identified across 4 centers, 22 (42%) of whom had mBCC with spread limited to lymph nodes and 31 (58%) patients with distant organ spread (with or without lymph node involvement). Overall, half (n = 11) of patients with nodal metastasis achieved complete remission of disease, compared with just 1 (3%) patient with distant metastasis. The 5-year survival for nodal and distant metastatic patients was 89.3% and 61.0%, respectively. LIMITATIONS: Small sample size due to disease rarity. CONCLUSIONS AND RELEVANCE: Patients with nodal disease are more likely to have disease remission whereas patients with distant metastasis are more likely to have persistent disease and die from their disease. However, 5-year survival rates exceed 50%, even for stage IV disease.
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Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Estudos Retrospectivos , Carcinoma Basocelular/patologia , Prognóstico , Linfonodos/patologia , Fatores de Risco , PhiladelphiaRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. OBJECTIVES: This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). METHODS: Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. RESULTS: Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. CONCLUSION: Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.
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Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/secundário , Carcinoma de Célula de Merkel/terapia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/mortalidade , Masculino , Feminino , Idoso , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Metástase Linfática , Metástase Neoplásica , Neoplasias Hepáticas/secundário , Estadiamento de NeoplasiasRESUMO
Anti-PD-1 and oncolytic viruses (OVs) have non-overlapping anti-tumor mechanisms, since each agent works at different steps of the cancer-immunity cycle. Evidence suggests that OVs improve therapeutic responses to anti-PD-1 therapy by reversing immunosuppressive factors, increasing the number and diversity of infiltrating lymphocytes, and promoting PD-L1 expression in both injected and non-injected tumors. Many studies in preclinical models suggest that the timing of anti-PD-1 administration influences the therapeutic success of the combination therapy (anti-PD-1 + OV). Therefore, determining the appropriate sequencing of agents is of critical importance to designing a rationale OV-based combinational clinical trial. Currently, the combination of anti-PD-1 and OVs are being delivered using various schedules, and we have classified the timing of administration of anti-PD-1 and OVs into five categories: (i) anti-PD-1 lead-in â OV; (ii) concurrent administration; (iii) OV lead-in â anti-PD-1; (iv) concurrent therapy lead-in â anti-PD-1; and (v) OV lead-in â concurrent therapy. Based on the reported preclinical and clinical literature, the most promising treatment strategy to date is hypothesized to be OV lead-in â concurrent therapy. In the OV lead-in â concurrent therapy approach, initial OV treatment results in T cell priming and infiltration into tumors and an immunologically hot tumor microenvironment (TME), which can be counterbalanced by engagement of PD-L1 to PD-1 receptor on immune cells, leading to T cell exhaustion. Therefore, after initial OV therapy, concurrent use of both OV and anti-PD-1 is critical through which OV maintains T cell priming and an immunologically hot TME, whereas PD-1 blockade helps to overcome PD-L1/PD-1-mediated T cell exhaustion. It is important to note that the hypothetical conclusion drawn in this review is based on thorough literature review on current understanding of OV + anti-PD-1 combination therapies and rhythm of treatment-induced cancer-immunity cycle. A variety of confounding factors such as tumor types, OV types, presence or absence of cytokine transgenes carried by an OV, timing of treatment initiation, varying dosages and treatment frequencies/duration of OV and anti-PD-1, etc. may affect the validity of our conclusion that will need to be further examined by future research (such as side-by-side comparative studies using all five treatment schedules in a given tumor model).
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Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Terapia Viral Oncolítica/métodos , Antígeno B7-H1/genética , Vírus Oncolíticos/genética , Microambiente Tumoral , Neoplasias/terapiaRESUMO
BACKGROUND: CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB-IV melanoma. METHODS: Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. RESULTS: Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3â5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8- T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). CONCLUSIONS: These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment. TRIAL REGISTRATION NUMBER: NCT02565992.
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Melanoma , Vírus Oncolíticos , Humanos , Animais , Cabras , Anticorpos Monoclonais Humanizados/efeitos adversos , Melanoma/tratamento farmacológico , Microambiente TumoralRESUMO
Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
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Imunoterapia/métodos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Injeções Intralesionais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Linfócitos B , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Celular , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana , Interleucina-10 , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Estações do Ano , Pele , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Esqualeno/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , VacinaçãoAssuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Acetamidas , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Pirazóis/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Immunotherapy has revolutionised the treatment of advanced cutaneous squamous cell carcinoma (cSCC). It is important to understand both safety and efficacy in a real-world and trial-ineligible cSCC population. We aimed to evaluate safety, efficacy and molecular insights among a broader cSCC population, including immunosuppressed patients, treated with immune checkpoint inhibitors (CPI). METHODS: We present a cohort of advanced cSCC patients (n = 61) treated from 2015 to 2020 evaluating the best overall response (BOR) (RECISTv1.1) to CPI therapy, immune-related adverse events (irAEs) and tumour mutational burden (TMB) to correlate with outcomes. A validated geriatric scoring index (CIRS-G) was utilised to assess comorbidities among patients ≥75. These data were compared with published clinical trial results among the broader cSCC population. RESULTS: BOR to CPI was lower among the entire cohort when compared with trial data (31.5 vs. 48%, P < 0.01), with higher rates of progression (59 vs. 16.5%, P < 0.01), regardless of immunosuppression history or age. Grade 3+ irAEs were more common among responders (P = 0.02), while pre-treatment lymphocyte count and TMB predicted response (P = 0.02). CONCLUSIONS: We demonstrate comparatively lower response rates to CPI among real-world cSCC patients not explained by older age or immunosuppression history alone. Immune-related toxicity, absolute lymphocyte count and TMB predicted CPI response.
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Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Comorbidade , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Avaliação Geriátrica/estatística & dados numéricos , Humanos , Terapia de Imunossupressão/efeitos adversos , Terapia de Imunossupressão/estatística & dados numéricos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Resultado do TratamentoAssuntos
Carcinoma de Células Escamosas , DNA Tumoral Circulante , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , DNA Tumoral Circulante/genética , Biomarcadores TumoraisAssuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Basocelular/patologia , Carcinoma Basocelular/secundário , Estudos de Coortes , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundárioAssuntos
Carcinoma de Célula de Merkel , Linfoma de Célula do Manto , Neoplasias Cutâneas , Humanos , Adulto , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfonodos/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Pele/patologiaAssuntos
Carcinoma de Célula de Merkel/terapia , Procedimentos Cirúrgicos Dermatológicos , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/mortalidade , Humanos , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Resultado do TratamentoAssuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Aloenxertos , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Humanos , Imunoterapia/métodos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Receptor de Morte Celular Programada 1/imunologiaAssuntos
Custos de Cuidados de Saúde , Imunoterapia/economia , Imunoterapia/estatística & dados numéricos , Melanoma/terapia , Terapia de Alvo Molecular/economia , Terapia de Alvo Molecular/estatística & dados numéricos , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Estudos Transversais , Humanos , Medicare , Fatores de Tempo , Estados UnidosRESUMO
A recent report sheds light on the tumor-associated macrophages (TAM) in Merkel cell carcinoma (MCC), and the association of S100A8-expressing TAMs with resistance to anti-PD-(L)1 inhibitors. These data improve our understanding about why some tumors with brisk tumor-infiltrating lymphocytes do not respond to immunotherapy and provide a compelling rationale to target myeloid checkpoints in MCC. See related article by Tabachnick-Cherny et al., p. xxxx.
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A recent report sheds light on the tumor-associated macrophages (TAMs) in MCC, and the association of S100A8-expressing TAMs with resistance to anti-PD-(L)1 inhibitors. These data improve our understanding about why some tumors with brisk TIL do not respond to immunotherapy and provide a compelling rationale to target myeloid checkpoints in MCC.
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Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.7 mg/kg to 25 mg/kg), which resulted in improved responses in female mice but not male mice. The greatest reduction in tumor progression was observed in male mice treated with single-agent troriluzole and anti-PD-1. Furthermore, a randomly selected group of mice was removed from treatment after 18 weeks and maintained for up to an additional 48 weeks demonstrating the utility of the TGS mouse model to perform a ≥1-year preclinical therapeutic study in a physiologically relevant tumor-host environment. Digital spatial imaging analyses were performed in tumors and tumor microenvironments across treatment modalities using antibody panels for immune cell types and immune cell activation. The results suggest that immune cell populations and cytotoxic activities of T cells play critical roles in treatment responses in these mice. Examination of a group of molecular protein markers based on the proposed mechanisms of action of inhibitors of glutamatergic signaling and immune checkpoint showed that alterations in expression levels of xCT, γ-H2AX, EAAT2, PD-L1, and PD-1 are likely associated with the loss of treatment responses. These results suggest the importance of tracking changes in molecular markers associated with the mechanism of action of therapeutics over the course of a longitudinal preclinical therapeutic study in spatial and temporal manners.