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International audience; Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease.

Purpose/objective: The association of 3D Conformal External Beam Radiotherapy (3D-CEBRT) with adjuvant Androgen Deprivation Therapy (ADT) proved to treat patients with intermediate- and high-risk localized prostate cancer (IR and HR). However, older patients were underrepresented in literature. We aimed to report the oncological results and morbidity 3D-CEBRT +ADT in &ge, 80 years patients. Material and Methods: From June 1998 to July 2017, 101 patients &ge, 80 years were included in a tertiary center. The median age was 82 years. ADT was initiated 3 months prior 3D-CEBRT in all patients, with a total duration of 6 months for IR prostate cancer (group A, n = 41) and 15 months for HR prostate cancer (group B, n = 60). Endpoints included overall survival (OS), metastasis-free survival (DMFS), biochemical recurrence-free survival (BRFS) and toxicity. Results: Five years-OS was 95% and 86.7% in groups A and B, respectively. Cardiovascular events occurred in 22.8% of &ge, 80 years patients with no impact on OS. In the multivariate analysis, age &lt, 82 years, Karnofsky index and normalization of testosterone levels were significantly associated with better OS. Conclusion: Age &ge, 80 years should not be a limitation for the treatment of IR and HR prostate cancer patients with 3D-CEBRT and ADT, but cardiovascular monitoring and prevention are mandatory.

Simple Summary The approval of the two antibody combinations trastuzumab/pertuzumab and ipilimumab/nivolumab in oncology has paved the way for novel antibody combinations or oligoclonal antibody mixtures to improve their efficacy in cancer. The underlying biological mechanisms and challenges of these strategies will be discussed using data from clinical trials listed in databases. These therapeutic combinations also lead to questions on how to optimize their formulation and delivery to induce a therapeutic polyclonal response in patients with cancer. Abstract Monoclonal antibodies have revolutionized the treatment of many diseases, but their clinical efficacy remains limited in some other cases. Pre-clinical and clinical trials have shown that combinations of antibodies that bind to the same target (homo-combinations) or to different targets (hetero-combinations) to mimic the polyclonal humoral immune response improve their therapeutic effects in cancer. The approval of the trastuzumab/pertuzumab combination for breast cancer and then of the ipilimumab/nivolumab combination for melanoma opened the way to novel antibody combinations or oligoclonal antibody mixtures as more effective biologics for cancer management. We found more than 300 phase II/III clinical trials on antibody combinations, with/without chemotherapy, radiotherapy, small molecules or vaccines, in the ClinicalTrials.gov database. Such combinations enhance the biological responses and bypass the resistance mechanisms observed with antibody monotherapy. Usually, such antibody combinations are administered sequentially as separate formulations. Combined formulations have also been developed in which separately produced antibodies are mixed before administration or are produced simultaneously in a single cell line or a single batch of different cell lines as a polyclonal master cell bank. The regulation, toxicity and injection sequence of these oligoclonal antibody mixtures still need to be addressed in order to optimize their delivery and their therapeutic effects.

The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti‑PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from a previously described derivation cohort. BRAF or NRAS mutations were quantified on plasma DNA by digital PCR at baseline and after two or four weeks of treatment. ctDNA kinetics were interpreted according to pre-established biological response criteria. A biological progression (bP, i.e., a significant increase in ctDNA levels) at week two or week four was associated with a lack of benefit from anti-PD1 (4-month PFS = 0%, 1‑year OS = 13%, n = 12/102). Patients without initial bP had significantly better PFS and OS (4-month PFS = 78%, 1‑year OS = 73%, n = 26/102), as did patients whose ctDNA kinetics were not evaluable, due to low/undetectable baseline ctDNA (4-month PFS = 80%, 1‑year OS = 81%, n = 64/102). ctDNA detection at first-line anti-PD1 initiation was an independent prognostic factor for OS and PFS in multivariate analysis. Overall, early ctDNA quantitative monitoring may allow the detection of primary resistances of metastatic melanoma to anti-PD1 immunotherapies.

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III&ndash, IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-&alpha, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3&ndash, 4 IrAEs in advanced NSCLC treated with ICIs.

Simple Summary We present a review of the most relevant epidemiological, diagnostic and therapeutic aspects of primary central nervous system lymphoma (PCNSL) in elderly patients. Abstract The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.

International audience; Macrophages are tissue-resident cells that act as immune sentinels to maintain tissue integrity, preserve self-tolerance and protect against invading pathogens. Lung macrophages within the distal airways face around 8000⁻9000 L of air every day and for that reason are continuously exposed to a variety of inhaled particles, allergens or airborne microbes. Chronic exposure to irritant particles can prime macrophages to mediate a smoldering inflammatory response creating a mutagenic environment and favoring cancer initiation. Tumor-associated macrophages (TAMs) represent the majority of the tumor stroma and maintain intricate interactions with malignant cells within the tumor microenvironment (TME) largely influencing the outcome of cancer growth and metastasis. A number of macrophage-centered approaches have been investigated as potential cancer therapy and include strategies to limit their infiltration or exploit their antitumor effector functions. Recently, strategies aimed at targeting IL-1 signaling pathway using a blocking antibody have unexpectedly shown great promise on incident lung cancer. Here, we review the current understanding of the bridge between TAM metabolism, IL-1 signaling, and effector functions in lung adenocarcinoma and address the challenges to successfully incorporating these pathways into current anticancer regimens.