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 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immune checkpoint inhibitors (ICI) have emerged as a remarkable treatment option for diverse cancer types. Currently, ICIs are approved for an expanding array of cancer indications. However, the majority of patients still do not demonstrate a durable long-term response following ICI therapy. In addition, many patients receiving ICI therapy develop immune-related adverse events (irAEs) affecting a wide variety of organs. To increase the percentage of patients who benefit from ICI therapy and to reduce the occurrence of irAEs, there is an ongoing effort to combine current ICIs with novel checkpoints inhibitors or other therapeutic approaches to achieve a synergistic effect which is larger than the sum of its parts. In this review we highlight the essential factors for more effective ICI combinations. We describe how the design of these strategies should be driven by the tumor's immunological context. We analyze current combination strategies and describe how they can be improved to unleash the immune system's full anti-cancer potential as well as convert immunologically "cold" tumors into "hot" ones. We examine the efforts to combine current ICIs (PD-1 and CTLA-4) with novel checkpoints (TIM-3, LAG-3, VISTA, TIGIT and others), immunotherapies (CAR-T cells and Cancer Vaccines) and delivery strategies (bispecific antibodies and other delivery platforms). Importantly, we outline how can one optimally combine ICIs with traditional pillars of cancer therapy such as radiation therapy (RT) and chemotherapy. We discuss the considerations regarding successful combination with RT and chemotherapy; these include fractionation schemes and selection of chemotherapeutics which can both directly eradicate cancer cells as well as increase the infiltration of immune cells into tumors. Finally, we critically assess these approaches and attempt to establish their strengths and weaknesses based on pre-clinical and clinical data.
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PMID:Immune checkpoint inhibitor combinations: Current efforts and important aspects for success. 3138 44

Introduction: Lung cancer is a devastating disease with poor overall survival. Despite significant advances in the treatment of lung cancers using radiochemotherapy, targeted therapies and/or immune therapies prognosis remains poor. The capacity of natural killer (NK) cells to provide a first line of defense that can bridge and orchestrate innate and 'downstream' adaptive immune responses renders them to be an ideal platform on which to base new cancer therapeutics.Areas covered: We provide an overview of the mechanisms controlling the effector functions of NK cells, tumor-directed immune escape, the impact and influence of NK cells on the development of effective, protective anti-tumor immunity and the therapeutic potential of combined cytokine-, complement-dependent- and antibody-dependent cellular cytotoxicity (CDC/ADCC), NK-92-, KIR mismatch- and CAR-NK cell-based therapies.Expert opinion: Despite promising results of immuno-oncological approaches, a relevant proportion of patients do not profit from these therapies, partly due to an ineffective NK cell activation, a lack of tumor-specific NK cells, an upregulated expression of checkpoint pathways, and a low mutational burden, which hinders the development of long-term adaptive immunity. Strategies that re-activate NK cells in combination with other therapies are therefore likely to be beneficial for the clinical outcome of patients with lung cancer.Abbreviations: ADCC: antibody-dependent cell-mediated cytotoxicity; ALK: anaplastic lymphoma kinase; CAR: chimeric antigen receptor; CDC: complement-dependent cytotoxicity; CEACAM-1: carcinoembryonic antigen-related cell adhesion molecule 1; DC: dendritic cell; DNAM: activating, maturation receptor; EGFR, epidermal growth factor receptor; EMT: epithelial-to-mesenchymal transition; EpCAM: epithelial cell adhesion molecule; GM-CSF: granulocyte monocyte colony stimulating factor; HIF: hypoxia inducible factor; IDO, indoleamine 2,3-dioxygenase; IFN: interferon; IL: interleukin; ITIM/ITAM: immune tyrosine-based inhibitory/activatory motif; KIR: killer cell immunoglobulin-like receptor; LAG-3: lymphocyte activation gene 3; MDSC: myeloid derived suppressor cells; MICA/B: MHC class I-related proteins A/B; MHC: major histocompatibility complex; mTOR: mechanistic target of rapamycin; NCAM: neuronal adhesion molecule; NCR: natural cytotoxicity receptor; NK: natural killer; NSCLC: non-small cell lung cancer; PD-1: programmed cell death 1; PS: phosphatidylserine; SCLC: small cell lung cancer; STAT: signal transducer and activator of transcription; TAM: tumor-associated M2 macrophages; TCR: T cell receptor; TIGIT: T cell immunoglobulin and ITIM domain; Tim-3: T cell immunoglobulin- and mucin domain-containing 3; TNF: tumor necrosis factor; ULBP: UL16-binding protein.
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PMID:NK cell-based therapeutics for lung cancer. 3171 56