Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Jan. 21, 2022

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, dostarlimab) three α-PD-L1 antibodies (atezolizumab, durvalumab, avelumab) have been approved for various types of cancers. Nevertheless, low rate α-PD-1/PD-L1 therapy remains to be resolved. For most patients, PD-1/PD-L1 pathway is not sole speed-limiting factor antitumor immunity, it insufficient motivate effective by blocking axis. It has validated that some combination therapies, including plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other checkpoint agonists co-stimulatory molecule, stimulator interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, metabolic superior efficacies higher rates. Moreover, bifunctional bispecific containing moiety also elicited more potent activity. These strategies simultaneously boost multiple processes cancer-immunity cycle, remove immunosuppressive brakes, orchestrate an immunosupportive tumor microenvironment. In this review, we summarized synergistic mechanisms with therapies. focused advances α-PD-1/PD-L1-based immunomodulatory studies. Given heterogeneity across patients types, individualized selection could improve effects relieve treatment resistance.

Language: Английский

---

Roles of IFN-γ in tumor progression and regression: a review

Biomarker Research, Journal Year: 2020, Volume and Issue: 8(1)

Published: Sept. 29, 2020

Abstract Background Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation antitumor immune-response. Based on its cytostatic, pro-apoptotic antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy different types cancer. Moreover, it may inhibit angiogenesis tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity M1 proinflammatory macrophages to overcome progression. However, current understanding roles microenvironment (TME) be misleading terms clinical application. Main body Some researchers believe has anti-tumorigenic properties, while others suggest that contributes growth In our recent work, we have shown concentration TME determines function. Further, was reported tumors treated with low-dose acquired metastatic properties those infused high dose led regression. Pro-tumorigenic described through signaling insensitivity, downregulation major histocompatibility complexes, upregulation indoleamine 2,3-dioxygenase, checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required decipher IFN-γ-dependent pro- effects. This review discusses knowledge concerning part complex immune response cancer highlights importance identifying responsive patients improve their sensitivity immuno-therapies.

Language: Английский

---

Combination strategies to maximize the benefits of cancer immunotherapy

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Sept. 27, 2021

Abstract Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary secondary resistance to single agent immunotherapy often results treatment failure, only a minority of experience long-term benefits. This review article will discuss the relationship between response mechanisms immunotherapy. It also provide comprehensive on latest clinical status combination therapies (e.g., with chemotherapy, radiation targeted therapy), approved by US Food Drug Administration. an overview targeting cytokines other soluble immunoregulatory factors, ACT, virotherapy, innate modifiers vaccines, well that exploit alternative targets therapeutic modalities. Finally, this include stimulating insights from 2020 China Immuno-Oncology Workshop co-organized Chinese American Hematologist Oncologist Network (CAHON), National Medical Product Administration (NMPA) Tsinghua University School Medicine.

Language: Английский

---

CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: March 31, 2022

Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) immunotherapy has made tremendous progress five CAR T therapies approved by the US Food and Drug Administration for hematological malignancies. However, in solid tumors lags significantly behind. Some of major hurdles include manufacturing, lack tumor-specific antigens, inefficient trafficking infiltration into tumor sites, immunosuppressive microenvironment (TME), therapy-associated toxicity, escape. Natural Killer (NK) cells have several advantages over as NK can be manufactured from pre-existing lines or allogeneic unmatched histocompatibility complex (MHC); kill cancer through both CAR-dependent CAR-independent pathways; less especially cytokine-release syndrome neurotoxicity. At least one clinical trial showed efficacy tolerability therapy. Macrophages efficiently infiltrate tumors, are immune regulators abundantly present TME. The M2 macrophages at efficient proinflammatory M1 phagocytosis target cells; induced to differentiate phenotype. Consequently, there is significant interest developing overcome some associated T/NK therapy, tumors. Nevertheless, their own limitations. This comprehensive review article will discuss current status followed structure cutting-edge research cancer-specific phagocytes, presenters, immunostimulators, TME modifiers.

Language: Английский

---

Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: March 24, 2022

Abstract Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor stromal cells to promote proliferation, migration, invasion, angiogenesis immune evasion. Both ECM itself stiffening-induced mechanical stimuli may activate cell membrane receptors mechanosensors such as integrin, Piezo1 TRPV4, thereby modulating the malignant phenotype of cells. A better understanding how stiffness regulates progression will contribute development new therapeutics. rapidly expanding evidence in this research area suggests that regulators effectors represent potential therapeutic targets cancer. This review summarizes recent work on regulation cancer, effects progression, immunity drug resistance. We also discuss be druggable intervene Based these advances, future efforts can made develop more effective safe drugs interrupt stiffness-induced oncogenic signaling,

Language: Английский

---

Neoantigen: A New Breakthrough in Tumor Immunotherapy

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: April 16, 2021

Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over past few decades, has shown remarkable efficacy in treatment of cancer, particularly success checkpoint blockade targeting CTLA-4, PD-1 PDL1, which led a breakthrough tumor immunotherapy. Tumor neoantigens, new approach immunotherapy, include antigens produced viruses integrated into genome mutant proteins, are abundantly expressed only cells have strong immunogenicity heterogeneity. A growing number studies highlighted relationship between neoantigens T cells’ recognition Vaccines developed against now being used clinical trials various solid tumors. In this review, we summarized latest advances classification process classification, identification synthesis tumor-specific as well their role current Finally, application prospects existing problems were discussed.

Language: Английский

---

Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1312 - 1324.e6

Published: Aug. 24, 2022

Language: Английский

---

Artificial Intelligence–Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as Complementary Biomarker for Immune Checkpoint Inhibition in Non–Small-Cell Lung Cancer

Journal of Clinical Oncology, Journal Year: 2022, Volume and Issue: 40(17), P. 1916 - 1928

Published: March 10, 2022

Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting effectiveness immune checkpoint inhibitors (ICI). However, clinical application remains challenging because methodologic limitations and laborious process involved spatial analysis TIL distribution whole-slide images (WSI).We have developed an artificial intelligence (AI)-powered WSI analyzer tumor microenvironment that can define three phenotypes (IPs): inflamed, immune-excluded, immune-desert. These IPs were correlated with response to ICI survival two independent cohorts patients advanced non-small-cell lung cancer (NSCLC).Inflamed IP enrichment local cytolytic activity, higher rate, prolonged progression-free compared immune-excluded or immune-desert phenotypes. At level, there was significant positive correlation between proportion score (TPS) as determined by AI model control TPS analyzed pathologists (P < .001). Overall, 44.0% tumors 37.1% 18.9% Incidence inflamed programmed death ligand-1 at 1%, 1%-49%, ≥ 50% 31.7%, 42.5%, 56.8%, respectively. Median overall were, respectively, 4.1 months 24.8 IP, 2.2 14.0 2.4 10.6 IP.The AI-powered NSCLC. This is a supplementary biomarker pathologist.

Language: Английский

---

The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Feb. 16, 2021

Abstract Background Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset patients benefits from anti-PD-1/PD-L1 therapies. As negative regulator immunity, TGF-β impairs the efficacy induces drug resistance. Developing novel treatment strategy to simultaneously block PD-1/PD-L1 would be valuable enhance effect relieve Methods Based on Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell western blotting, CCK-8, flow cytometry. anti-PD-L1 measured T activation assays. EMT-6, CT26, 3LL tumor models were used investigate activity YM101 vivo. RNA-seq, immunohistochemical staining, cytometry utilized analyze microenvironment. Results could bind PD-L1 specifically. In vitro experiments showed that effectively counteracted biological effects pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, immunosuppression. Besides, vivo indicated superior monotherapies. Mechanistically, promoted formation ‘hot tumor’: increasing numbers infiltrating lymphocytes dendritic cells, elevating ratio M1/M2, enhancing cytokine production cells. This normalized immune microenvironment enhanced response might contribute robust Conclusion Our results demonstrated pathways had compared

Language: Английский

---

Gut Microbiota Modulation of Efficacy and Toxicity of Cancer Chemotherapy and Immunotherapy

Gastroenterology, Journal Year: 2022, Volume and Issue: 164(2), P. 198 - 213

Published: Oct. 27, 2022

Accumulating evidence supports not only the functional role of gut microbiome in cancer development and progression but also its defining efficacy toxicity chemotherapeutic agents (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) immunotherapeutic compounds (anti–programmed death-ligand 1/anti–programmed cell death protein 1 anti–cytotoxic T-lymphocyte-associated antigen 4). This is supported numerous vitro, animal, clinical studies that highlight importance microbial mechanisms therapeutic responses. The therefore shapes oncologic outcomes now being leveraged for novel personalized approaches treatment. However, if to be successfully translated into next-generation treatments, a new multimodal model oncomicrobiome must conceptualized incorporates cometabolism pharmacologic care. objective this review outline current knowledge pharmacomicrobiomics describe how multiparametric functions influence treatment response across types. secondary propose innovative modulating environments improve therapy diminish toxic effects derived from antineoplastic patient benefit.

Language: Английский

---