scholarly journals A REVIEW OF MODERN IMMUNOTHERAPY IN GASTROINTESTINAL MALIGNANT TUMORS

2020 ◽  
Vol 6 (5(74)) ◽  
pp. 9-21
Author(s):  
A.A. Yusupbekov ◽  
S.V. Kamishov ◽  
A.A. Adilkhodjaev ◽  
Kh. J. Islamov ◽  
D.M. Egamberdiev
Keyword(s):  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Malignant Tumors ◽  
Unmet Need ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Drugs ◽  
Special Focus ◽  
Fda Approval

Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of several solid tumors including melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. This review will summarize the current clinical progress of modern immunotherapy in the field of GI tumors, with a special focus on immune checkpoint blockade

scholarly journals Cis interactions make immune checkpoint blockade more trans-parent

2020 ◽  
Vol 5 (43) ◽  
pp. eaba7107
Author(s):  
Natasha Khatwani ◽  
Asha B. Pillai
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Effector T Cell

PD-L1:CD80 cis-heterodimer formation preferentially blocks CTLA-4 trans-signaling while allowing CD28-mediated effector T cell activation.

scholarly journals Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2484-2494 ◽  
Author(s):  
Monika Herrmann ◽  
Christina Krupka ◽  
Katrin Deiser ◽  
Bettina Brauchle ◽  
Anetta Marcinek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Adaptive Immune ◽  
Acute Myeloid

Abstract The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell–engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1ex), which naturally holds a low affinity to PD-L1, to an αCD3.αCD33 BiTE-like scaffold. By a synergistic effect of checkpoint blockade and avidity-dependent binding, the PD-1ex attachment increases T-cell activation (3.3-fold elevation of interferon-γ) and leads to efficient and highly selective cytotoxicity against CD33+PD-L1+ cell lines (50% effective concentration = 2.3-26.9 pM) as well as patient-derived AML cells (n = 8). In a murine xenograft model, the CiTE induces complete AML eradication without initial signs of irAEs as measured by body weight loss. We conclude that our molecule preferentially targets AML cells, whereas high-affinity blockers, such as clinically approved anticancer agents, also address PD-L1+ non-AML cells. By combining the high efficacy of T-cell engagers with immune checkpoint blockade in a single molecule, we expect to minimize irAEs associated with the systemic application of immune checkpoint inhibitors and suggest high therapeutic potential, particularly for patients with relapsed/ refractory AML.

Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade

2020 ◽  
Vol 12 (560) ◽  
pp. eaax2282 ◽  
Author(s):  
Liangliang Wang ◽  
Yan Gao ◽  
Gao Zhang ◽  
Dan Li ◽  
Zhenda Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tensin Homolog ◽  
Cancer Models

Immune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogonal mechanisms: (i) increasing KDM5A abundance, which suppressed expression of the gene PTEN (encoding phosphatase and tensin homolog) and increased programmed cell death ligand 1 abundance through a pathway involving PI3K-AKT-S6K1, and (ii) activating Toll-like receptors 7 and 8 (TLR7/8) signaling pathways. Combination treatment increased T cell activation and expansion, CD103+ tumor-infiltrating dendritic cells, and tumor-associated M1 macrophages, ultimately enhancing the overall recruitment of activated CD8+ T cells to tumors. In patients with melanoma, a high KDM5A gene signature correlated with KDM5A expression and could potentially serve as a marker of response to anti–PD-1 immunotherapy. Furthermore, our results indicated that bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents.

scholarly journals B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Johannes Griss ◽  
Wolfgang Bauer ◽  
Christine Wagner ◽  
Martin Simon ◽  
Minyi Chen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Immune Checkpoint Blockade ◽  
Human Melanoma ◽  
Checkpoint Blockade ◽  
Inflammatory Factors

Abstract Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy.

scholarly journals The Current Landscape of Immune Checkpoint Blockade in Metastatic Lung Squamous Cell Carcinoma

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1392
Author(s):  
Hong Yuan ◽  
Jing Liu ◽  
Jun Zhang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Unmet Need ◽  
Lung Squamous Cell Carcinoma ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Programmed Death

In addition to surgery, chemotherapy, radiotherapy, and targeted therapy, immunotherapy has emerged as a standard pillar of cancer treatment. Immune checkpoint inhibitors (ICIs) such as targeting programmed death-1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have been integrated into standard-of-care regimens for patients with advanced lung squamous cell carcinoma (LUSC), who were previously limited by the lack of treatment options. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Recent successes and failures of immune checkpoint blockade-based combination therapies have provided significant insights into implementing combination strategies in LUSC. Therefore, there is an urgent need to correctly select patients who are more likely to respond to immunotherapy and understand the mechanisms of primary or acquired resistance. In this review, we aim at summarizing the emerging clinical data on the promise and challenge of ICIs, discussing the unmet need of potential biomarkers for predicting response or resistance to immunotherapy, and providing an overview of the current immune landscape and future directions in advanced LUSC.

scholarly journals High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege

2021 ◽  
Vol 9 (8) ◽  
pp. e003246
Author(s):  
Casey R Ager ◽  
Akash Boda ◽  
Kimal Rajapakshe ◽  
Spencer Thomas Lea ◽  
Maria Emilia Di Francesco ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Pancreatic Adenocarcinoma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Intratumoral Injection ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Potency

BackgroundIntratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking.MethodsHere, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy.ResultsHighly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach.ConclusionsThis study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.

scholarly journals Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

2021 ◽  
Vol 9 ◽  
Author(s):  
Juan Yang ◽  
Xianzhi Yang ◽  
Wenfeng Pan ◽  
Mingshuo Wang ◽  
Yuxiong Lu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Synergistic Effects ◽  
Immune Checkpoint Blockade ◽  
Stat Pathway

Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo. Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8+ T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8+ T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.

scholarly journals Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Selina K. Wong ◽  
Caroline A. Nebhan ◽  
Douglas B. Johnson
Keyword(s):  
Clinical Efficacy ◽  
T Cell Activation ◽  
Anticancer Agents ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Significant Heterogeneity ◽  
Older Individuals ◽  
Age Related

The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs. While generally better tolerated than traditional cytotoxic chemotherapy, ICIs are associated with unique toxicities, termed immune-related adverse events (irAEs), which can be severe or even lethal. As a disease of aging, older individuals make up a large proportion of patients diagnosed with cancer, yet this population is often underrepresented in clinical trials. Because ICIs indirectly target malignant cells through T cell activation, it has been hypothesized that age-related changes to the immune system may impact the efficacy and toxicity of these drugs. In this review, we discuss differences in the clinical efficacy and toxicity of ICIs in patients at the extremes of age.

scholarly journals Expression and Significance of Immune Checkpoints in Clear Cell Carcinoma of the Uterine Cervix

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Liju Zong ◽  
Qianqian Zhang ◽  
Yuncan Zhou ◽  
Yujia Kong ◽  
Shuangni Yu ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Checkpoint Proteins ◽  
Immune Checkpoint Proteins

The purpose of this study was to investigate the expression levels of the immune checkpoint proteins, programmed cell death-ligand 1 (PD-L1), B7-H3, B7-H4, and V-domain Ig suppressor of T cell activation (VISTA), as well as the significance thereof, in clear cell carcinoma (CCC) of the cervix (a rare histological subtype of cervical cancer). We also compared the expression statuses of these biomarkers in cervical CCCs with those in cervical squamous cell carcinomas (SCCs). We evaluated the expression of PD-L1, B7-H3, B7-H4, and VISTA in 50 cervical CCCs and 100 SCCs using immunohistochemical staining and investigated the associations between these markers, clinicopathologic features, and survival in patients with CCCs. Of the cervical CCC samples examined, 22%, 16%, 32%, and 34% were positive for PD-L1, B7-H3, B7-H4, and VISTA, respectively. Nineteen samples (38%) were negative for all 4 of these markers, whereas 31 (62%) expressed at least 1 marker. None of these markers was associated with the investigated clinicopathologic variables or patient survival. PD-L1, B7-H3, and VISTA were observed significantly more frequently in SCCs than in CCCs of the cervix. Our study confirmed the expression of immune checkpoint proteins in cervical CCCs and indicated their nonredundant and complementary roles. As such, our data suggest that monotherapeutic immune checkpoint blockade may not be sufficiently effective in patients with cervical CCC.

scholarly journals The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy

ESMO Open ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. e000544 ◽  
Author(s):  
Cinzia Solinas ◽  
Chunyan Gu-Trantien ◽  
Karen Willard-Gallo
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Activated T Cells

Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.

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