Beyond PD-1/PD-L1 Axis Blockade: New Combination Strategies in Metastatic Melanoma Treatment

Metastatic melanoma treatment has dramatically changed in the last few years, having a breakthrough with the introduction of targeted agents and immunotherapy. PD-1/PD-L1 pathway is one of the physiologic mechanisms of peripheral immune tolerance, but it also represents a mechanism of tumor immune escape. PD-1/PD-L1 inhibitors represent new immune-checkpoint drugs currently used in metastatic melanoma treatment. Resistance to PD-1/PD-L1 axis blockade, which is the main cause of therapeutic failure during therapeutic use of these drugs, could be linked to several mechanism of immune escape. In fact, other inhibitory receptor such as CTLA-4, LAG-3, TIM-3 and TIGIT might be co-expressed on T cells, deleting the effect of anti-PD-1/PD-L1; overexpression of the enzyme IDO could cause immunosuppression through the depletion of tryptophan in the tumor microenvironment; defective c ostimulation (through reduced activity of 4-1BB and OX40 receptors) could result in T-cell energy. Combination of anti-PD-1/PD-L1 with drugs targeting inhibitory or costimulatory receptors, intracellular pathways, enzymes or neoangiogenesis could be a possible strategy to overcome resistance to single PD-1/PD-L1 blockade. Clinical trials evaluating combination therapies have already showed interesting results, although most of them are still on going.
Source: Current Cancer Therapy Reviews - Category: Cancer & Oncology Source Type: research

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ConclusionThese results demonstrated the potential usage of a piTRL with laser irradiation for immuno-photothermal therapy against various types of cancer and their metastases.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
The cell wall skeleton of Bacillus Calmette–Guérin (BCG-CWS) is a bioactive component that is a strong immune adjuvant for cancer immunotherapy. BCG-CWS activates the innate immune system through various pattern recognition receptors and is expected to elicit antigen-specific cellular immune responses when co-administered with tumor antigens. To determine the recommended dose (RD) of BCG-CWS based on its safety profile, we conducted a phase I dose-escalation study of BCG-CWS in combination with WT1 peptide for patients with advanced cancer. The primary endpoint was the proportion of treatment-related adverse ...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
Publication date: Available online 23 July 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Huan Deng, Songwei Tan, Xueqin Gao, Chenming Zou, Chenfeng Xu, Kun Tu, Qingle Song, Fengjuan Fan, Wei Huang, Zhiping ZhangAbstractBlocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic co...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research
Publication date: Available online 11 July 2019Source: American Journal of Kidney DiseasesAuthor(s): Roman Shingarev, Ilya G. GlezermanImmunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more ar...
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
Patients Selection for Immunotherapy in Solid Tumors: Overcome the Naïve Vision of a Single Biomarker. Biomed Res Int. 2019;2019:9056417 Authors: Signorelli D, Giannatempo P, Grazia G, Aiello MM, Bertolini F, Mirabile A, Buti S, Vasile E, Scotti V, Pisapia P, Cona MS, Rolfo C, Malapelle U, Group IY Abstract Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a larg...
Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research
Emily Roarty Jing Wang Fei Yang Michelle Barton Jeffrey Rosen Sendurai Mani Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Marjolein Schluck1,2, Roel Hammink1,2, Carl G. Figdor1,2,3, Martijn Verdoes1,3*† and Jorieke Weiden1,2,3*† 1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands 2Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, Netherlands 3Institute for Chemical Immunology, Nijmegen, Netherlands Traditional tumor vaccination approaches mostly focus on activating dendritic cells (DCs) by providing them with a source of tumor antigens and/or adjuvants, which in turn activate tumor-reactive T c...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Discussion MDSCs violently emerge in pathological conditions in an attempt to limit potentially harmful immune and inflammatory responses. Mechanisms supporting their expansion and survival are deeply investigated in cancer, in the perspective to reactivate specific antitumor responses and prevent their contribution to disease evolution. These findings will likely contribute to improve the targeting of MDSCs in anticancer immunotherapies, either alone or in combination with immune checkpoint inhibitors. New evidence indicates that the expansion of myeloid cell differentiation in pathology is subject to fine-tuning, as its...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Michal Yalon1†, Amos Toren1,2†, Dina Jabarin2, Edna Fadida3, Shlomi Constantini3 and Ruty Mehrian-Shai1* 1Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel 2The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 3Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv-Sourasky Medical Center, Tel Aviv, Israel Pediatric brain tumors are the most common solid tumor type and the leading cause of cancer-related death in children. The immune system plays an important r...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions Several model systems are now available to characterize the MSC-tumour interplay in the TME. These offer early promise in establishing robust preclinical platforms for the identification of crucial molecular pathways and for the assessment of clinical efficacy of novel drugs to inhibit cancer development and progression. However, selection of the right model for a given study should be shaped on the purpose, and should also consider fixed biological, biochemical, and biophysical parameters according to the specific tumour type. Finally, in order to get reliable and useful results to be translated to the clinic...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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