Browsing by Subject "PD-1 BLOCKADE"

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  • Cervera-Carrascon, Victor; Quixabeira, Dafne C. A.; Santos, Joao M.; Havunen, Riikka; Milenova, Ioanna; Verhoeff, Jan; Heinio, Camilla; Zafar, Sadia; Garcia-Vallejo, Juan J.; van Beusechem, Victor W.; de Gruijl, Tanja D.; Kalervo, Aino; Sorsa, Suvi; Kanerva, Anna; Hemminki, Akseli (2021)
    Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
  • Escudier, Bernard; Sharma, Padmanee; McDermott, David F.; George, Saby; Hammers, Hans J.; Srinivas, Sandhya; Tykodi, Scott S.; Sosman, Jeffrey A.; Procopio, Giuseppe; Plimack, Elizabeth R.; Castellano, Daniel; Gurney, Howard; Donskov, Frede; Peltola, Katriina; Wagstaff, John; Gauler, Thomas C.; Ueda, Takeshi; Zhao, Huanyu; Waxman, Ian M.; Motzer, Robert J.; CheckMate 025 Investigators (2017)
    Background: The randomized, phase 3 CheckMate 025 study of nivolumab (n = 410) versus everolimus (n = 411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective: To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Design, setting, and participants: Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention: Nivolumab 3 mg/kg every 2 wk or everolimus 10 mg once daily. Results and limitations: The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and >= 65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. Conclusion: The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
  • Dufva, Olli; Pölönen, Petri; Brück, Oscar; Keränen, Mikko A. I.; Klievink, Jay; Mehtonen, Juha; Huuhtanen, Jani; Kumar, Ashwini; Malani, Disha; Siitonen, Sanna; Kankainen, Matti; Ghimire, Bishwa; Lahtela, Jenni; Mattila, Pirkko; Vähä-Koskela, Markus; Wennerberg, Krister; Granberg, Kirsi; Leivonen, Suvi-Katri; Meriranta, Leo; Heckman, Caroline; Leppä, Sirpa; Nykter, Matti; Lohi, Olli; Heinäniemi, Merja; Mustjoki, Satu (2020)
    Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.
  • Mohty, Mohamad; Malard, Florent; Abecasis, Manuel; Aerts, Erik; Alaskar, Ahmed S.; Aljurf, Mahmoud; Arat, Mutlu; Bader, Peter; Baron, Frederic; Basak, Grzegorz; Bazarbachi, Ali; Blaise, Didier; Ciceri, Fabio; Corbacioglu, Selim; Dalle, Jean-Hugues; Dignan, Fiona; Fukuda, Takahiro; Huynh, Anne; Kuball, Jurgen; Lachance, Silvy; Lazarus, Hillard; Masszi, Tamas; Michallet, Mauricette; Nagler, Arnon; NiChonghaile, Mairead; Okamoto, Shinichiro; Pagliuca, Antonio; Peters, Christina; Petersen, Finn B.; Richardson, Paul G.; Ruutu, Tapani; Saber, Wael; Savani, Bipin N.; Soiffer, Robert; Styczynski, Jan; Wallhult, Elisabeth; Yakoub-Agha, Ibrahim; Duarte, Rafael F.; Carreras, Enric (2020)
    Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group.
  • Ålgars, Annika; Kemppinen, Lotta; Fair-Mäkelä, Ruth; Mustonen, Harri; Haglund, Caj; Jalkanen, Sirpa (2021)
    Simple Summary Tumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1(+) macrophages, CD68(+) macrophages, and CLEVER-1(+) lymphatic vessels in stage I-IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray). Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68(+) and CLEVER-1(+) (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1(+) lymphatic vessels in 498 stage I-IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median,
  • Pollari, Marjukka; Leivonen, Suvi-Katri; Leppä, Sirpa (2021)
    Simple Summary Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive lymphoma entity that mainly affects elderly men. It has a high relapse rate with especially the relapses of the central nervous system associating with dismal outcome. T-DLBCL has a unique biology with distinct genetic characteristics and clinical presentation, and the increasing knowledge on the tumor microenvironment of T-DLBCL highlights the significance of the host immunity and immune escape in this rare lymphoma, presenting in an immune-privileged site of the testis. This review provides an update on the latest progress made in T-DLBCL research and summarizes the clinical perspectives in T-DLBCL. Primary testicular lymphoma is a rare lymphoma entity, yet it is the most common testicular malignancy among elderly men. The majority of the cases represent non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) with aggressive clinical behavior and a relatively high relapse rate. Due to the rareness of the disease, no randomized clinical trials have been conducted and the currently recognized standard of care is based on retrospective analyses and few phase II trials. During recent years, the tumor microenvironment (TME) and tumor-related immunity have been the focus of many tumor biology studies, and the emergence of targeted therapies and checkpoint inhibitors has significantly modulated the field of cancer therapies. Testicular DLBCL (T-DLBCL) is presented in an immune-privileged site of the testis, and the roles of NF-kappa B pathway signaling, 9p24.1 aberrations, and tumor-infiltrating immune cells, especially immune checkpoint expressing lymphocytes and macrophages, seem to be unique compared to other lymphoma entities. Preliminary data on the use of immune checkpoint inhibitors in the treatment of T-DLBCL are promising and more studies are ongoing.