Development of Immunotherapy Combination Strategies in Cancer

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(6), P. 1368 - 1397

Published: April 2, 2021

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized landscape cancer. Rational combination strategies aim enhance antitumor effects immunotherapies, but require a deep understanding mechanistic underpinnings robust preclinical clinical drug development strategies. We review current approved immunotherapy combinations, before discussing promising combinatorial approaches in trials detailing innovative model systems being used develop rational combinations. also discuss promise high-order as well novel biomarker trial SIGNIFICANCE: Although immune-checkpoint are dual checkpoint strategies, with cytotoxic chemotherapy angiogenesis for multiple cancers, patient benefit remains limited. Innovative required guide ranging from improvements tumor biomarker-driven

Language: Английский

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Trial watch: STING agonists in cancer therapy

OncoImmunology, Journal Year: 2020, Volume and Issue: 9(1)

Published: Jan. 1, 2020

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves a signaling hub, receiving input from several pattern recognition receptors, most which sense ectopic DNA species in the cytosol. In particular, STING ensures production type I (IFN) to invading viruses, bacterial pathogens, well leaking mitochondria or nucleus (e.g., cells exposed chemotherapy radiotherapy). As IFN critical for initiation anticancer immune responses, pharmaceutical industry has generated molecules directly activate use oncological indications. Such agonists are being tested clinical trials with rationale activating tumor tumor-infiltrating (including dendritic cells) elicit immunostimulatory effects, alone combination range established chemotherapeutic and immunotherapeutic regimens. this Trial Watch, we discuss preclinical evidence accumulating experience shaping design Phase II evaluate safety preliminary efficacy cancer patients.

Language: Английский

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Trial watch: TLR3 agonists in cancer therapy

OncoImmunology, Journal Year: 2020, Volume and Issue: 9(1)

Published: Jan. 1, 2020

Toll-like receptor 3 (TLR3) is a pattern recognition that senses exogenous (viral) as well endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates signal transduction pathway culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter essential not only for innate immune responses to infection but also initiation antigen-specific immunity against viruses and malignant cells. These aspects biology have supported development various agonists use stand-alone agents or combined other therapeutic modalities cancer patients. Here, we review recent preclinical clinical advances oncological disorders.Abbreviations cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dsRNA, RNA; FLT3LG, fms-related tyrosine kinase ligand; HNSCC, head neck squamous cell IFN, interferon; IL, interleukin; ISV, situ vaccine; MUC1, mucin 1, surface associated; PD-1, programmed death 1; PD-L1, death-ligand polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic TLR,

Language: Английский

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Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

Genome Medicine, Journal Year: 2019, Volume and Issue: 11(1)

Published: June 20, 2019

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection immune checkpoint blockade (ICB) therapy. Growing evidence suggests mutation-associated neoantigens drive ICB responses in tumors with high mutational burden. In most patients, only a few the mutations cancer exome predicted to be immunogenic cells. One factor limits this recognition level mutated gene product Substantial preclinical data show radiation can convert irradiated into site priming tumor-specific cells, is, an situ vaccine, and induce otherwise ICB-resistant tumors. Critical radiation-elicited T-cell activation induction viral mimicry, which mediated accumulation cytosolic DNA consequent cyclic GMP-AMP synthase (cGAS)/stimulator interferon (IFN) genes (STING) pathway downstream production type I IFN other pro-inflammatory cytokines. Recent suggest also enhance cell antigenicity upregulating large number involved response damage cellular stress, thus potentially exposing system. Here, we discuss how principles antigen presentation favor peptides derived from newly synthesized proteins These concepts support model incorporates presence upregulated predict patients might benefit treatment combinations radiotherapy ICB.

Language: Английский

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Contemporary radiotherapy: present and future

The Lancet, Journal Year: 2021, Volume and Issue: 398(10295), P. 171 - 184

Published: June 21, 2021

Language: Английский

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