Immunohistochemical characterisation of the immune landscape in primary uveal melanoma and liver metastases.

BACKGROUND: The immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied. METHODS: Immune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value. RESULTS: ICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis. CONCLUSIONS: TILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.

Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy.

BACKGROUND: Prescribing anti-programmed death-1 (PD-1) immunotherapy for advanced melanoma is currently not restricted by any biomarker assessment. Determination of programmed death-ligand-1 (PD-L1)-expression status is technically challenging and is not mandatory, because negative tumours also achieve therapeutic responses. However, reproducible biomarkers predictive of a response to anti-PD-1 therapy could contribute to improving therapeutic decision-making. METHODS: This retrospective study on 70 metastatic melanoma patients was undertaken to evaluate the relationships between clinical, histological, immunohistochemical and/or molecular criteria, and the 6-month objective response rate. RESULTS: Better objective response rates were associated with metachronous metastases (P = 0.04), PD-L1 tumour- and/or immune-cell status (P = 0.01), CD163+ histiocytes at advancing edges (P = 0.009) of primary melanomas and NRAS mutation (P = 0.019). Moreover, CD163+ histiocytes at advancing edges (P = 0.04) were associated with longer progression-free survival (PFS), and metachronous metastases with longer overall survival (P = 0.02) and PFS (P = 0.049). CONCLUSIONS: Combining these reproducible biomarkers could help improve therapeutic decision-making for patients with progressive disease.

Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.

BACKGROUND: Recent meta-analysis showed that immune checkpoint inhibitors (ICIs) have comparable activity between younger and older patients. However, little is known about efficacy and safety of ICI in elderly patients with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare the efficacy of ICI for patients aged ≥70 y to that for younger patients, while taking into account potential confounding factors. METHODS: A retrospective study was conducted at four hospitals in France. Patients treated with ICI for R/M SCCHN between September 2014 and December 2018 were eligible. Patients' charts were reviewed for clinical and radiological data as well as oncologic outcomes. RESULTS: We included 226 patients, of whom 67 were aged ≥70 years. Objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were 23%, 9.7 months and 2.7 months, respectively, for elderly patients, compared to 13%, 8.7 months and 1.9 months for younger patients (respective p-values: 0.071, 0.87 and 0.21). After adjustment for performance status, site of progression, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (hazard ratio [HR], 0.66; p = 0.021) but not OS (HR, 0.91; p = 0.59). Grade 3-5 adverse events (AEs) occurred in 15% of patients aged ≥70 years and in 8% of younger patients (p = 0.13). CONCLUSION: Patients aged ≥70 years with R/M SCCHN may respond to ICI similarly as younger patients in terms of ORR, OS and PFS, while maintaining comparable rate of AEs.

Dissociated Responses in Patients with Metastatic Solid Tumors Treated with Immunotherapy.

BACKGROUND: Immune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR. PATIENTS AND METHODS: Patients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL. RESULTS: A total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02). CONCLUSIONS: A DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy.

Advances in theranostic biomarkers for tumor immunotherapy.

Cancer treatment has known a revolution with the emergence of immune checkpoint inhibitors. However, accurate theranostic biomarkers are lacking. In this review, we discuss different types of biomarkers currently under investigation. First, we focus on tissue biomarkers including PD-L1 expression by immunohistochemistry-the first Food and Drug Administration-approved biomarker-despite conflicting results. In addition, we report on novel biomarkers, including protein-based, molecular (tumor mutational load, immune signature…), circulating (neutrophil-to-lymphocyte ratio, serum cytokines…), and imaging-based biomarkers (radiomic signatures and positron-emission tomography using radiolabeled antibodies). We highlight the limitations of each candidate biomarker and finally discuss combinatorial approaches for their use and the opportunity to switch from a predictive strategy of biomarker research to an adaptive one in the field of cancer immunotherapy.

Clinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma.

A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of efficacy has been used for patients' selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients' selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.

Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells.

Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Polychemotherapy involving doxorubicin is the standard first-line treatment but for the 25 to 35% of patients who relapse and develop resistance the prognosis remains poor. We studied the potential role of the microRNA miR-125b in the development of resistance to doxorubicin in NPM-ALK(+) ALCL. Our results show that miR-125b expression is repressed in NPM-ALK(+) cell lines and patient samples through hypermethylation of its promoter. NPM-ALK activity, in cooperation with DNA topoisomerase II (Topo II) and DNA methyltransferase 1 (DNMT1), is responsible for miR-125b repression through DNA hypermethylation. MiR-125b repression was reversed by the inhibition of DNMTs with decitabine or the inhibition of DNA topoisomerase II with either doxorubicin or etoposide. In NPM-ALK(+) cell lines, doxorubicin treatment led to an increase in miR-125b levels by inhibiting the binding of DNMT1 to the MIR125B1 promoter and downregulating the pro-apoptotic miR-125b target BAK1. Reversal of miR-125b silencing, increased miR-125b levels and reduced BAK1 expression also led to a lower efficacy of doxorubicin, suggestive of a pharmacoresistance mechanism. In line with this, miR-125b repression and increased BAK1 expression correlated with early relapse in human NPM-ALK(+) ALCL primary biopsies. Collectively our findings suggest that miR-125b could be used to predict therapeutic outcome in NPM-ALK(+) ALCL.

Metastasis of ciliary body melanoma to the contralateral eye: a case report and review of uveal melanoma literature.

Many types of cancers metastasize to the eye. However, uveal melanoma metastasizing to the contralateral choroid is very rare. We report the case of a 68-year-old man with history of treated uveal melanoma of the right eye that developed metastasis to the liver and the choroid of the left eye. Ten years earlier, he was diagnosed to have uveal melanoma of the right eye and was initially treated with plaque radiotherapy. Two years later, upon progression of the disease in the right eye he had enucleation of the eye. We describe the patient's clinical history, the diagnosis of recurrent disease in the contralateral eye, therapy of the left eye, and systemic metastasis. In addition, we reviewed the published medical literature and described the recent advances in the management of uveal melanoma.