EXTH-81. STING ACTIVATION PROMOTES ROBUST IMMUNE RESPONSE AND TUMOR REGRESSION IN GLIOBLASTOMA MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi182-vi182
Author(s):  
Gilles Berger ◽  
Erik Knelson ◽  
Michal Nowicki ◽  
David Mooney ◽  
E Antonio Chiocca ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
Immune Memory ◽  
Term Survival ◽  
Major Barrier ◽  
Robust Immune Response ◽  
Immunosuppressive Tumor Microenvironment ◽  
Human Gbm ◽  
Sting Pathway

Abstract The immunosuppressive tumor microenvironment in glioblastoma presents a major barrier to effective application of immunotherapeutic approaches in this disease. Although immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease glioblastoma remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties, but has not been well investigated in glioblastoma to date. Here we investigated the presence of STING pathway components in glioblastoma patient specimens and cell lines by Western blotting and immunostaining. The functionality of the pathway was determined by ELISA, and immune infiltrates, and animal survival were investigated in mouse glioblastoma models after treatment with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature, and appears to be activated as evidenced by elevated phosphoTBK1 staining. We show that human GBM cells do not respond agonists, but that GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.

scholarly journals Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1026
Author(s):  
Jana Wood ◽  
Sayeda Yasmin-Karim ◽  
Romy Mueller ◽  
Akila N. Viswanathan ◽  
Wilfred Ngwa
Keyword(s):  
Cervical Cancer ◽  
Tumor Regression ◽  
Treatment Options ◽  
Metastatic Tumor ◽  
Current Treatment ◽  
Immune Memory ◽  
Advanced Cervical Cancer ◽  
Term Survival ◽  
Fraction Dose ◽  
Radiotherapy Dose

Current treatment options for advanced cervical cancer are limited, especially for patients in poor-resource settings, with a 17% 5-year overall survival rate. Here, we report results in animal models of advanced cervical cancer, showing that anti-CD40 therapy can effectively boost the abscopal effect, whereby radiotherapy of a tumor at one site can engender therapeutically significant responses in tumors at distant untreated sites. In this study, two subcutaneous cervical cancer tumors representing one primary and one metastatic tumor were generated in each animal. Only the primary tumor was treated and the responses of both tumors were monitored. The study was repeated as a function of different treatment parameters, including radiotherapy dose and dosing schedule of immunoadjuvant anti-CD40. The results consistently suggest that one fraction dose of radiotherapy with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses, with a significant increase in animal survival (p = 0.0004). Overall, 60% of the mice treated with this combination showed long term survival with complete tumor regression, where tumors of mice in other cohorts continued to grow. Moreover, re-challenged responders to the treatment developed vitiligo, suggesting developed immune memory for this cancer. The findings offer a potential new therapy approach, which could be further investigated and developed for the treatment of advanced cervical cancer, with major potential impact, especially in resource-poor settings.

scholarly journals Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3375
Author(s):  
Annabelle Vogt ◽  
Farsaneh Sadeghlar ◽  
Tiyasha H. Ayub ◽  
Carlo Schneider ◽  
Christian Möhring ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Regression ◽  
Combined Therapy ◽  
Term Survival ◽  
Effector Cells ◽  
Tumor Environment ◽  
The Impact

Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

Immunotherapy in Pancreatic Cancer

2020 ◽  
Vol 04 (04) ◽  
pp. 351-357
Author(s):  
Bassel F. El-Rayes ◽  
Mehmet Akce
Keyword(s):  
Pancreatic Cancer ◽  
Single Agent ◽  
Standard Of Care ◽  
Ongoing Research ◽  
Modest Improvement ◽  
Major Barrier ◽  
Dismal Prognosis ◽  
Rigorous Research ◽  
Tumor Mutational Burden ◽  
Immunosuppressive Tumor Microenvironment

AbstractPancreatic cancer has a dismal prognosis and is projected to be the second most common cause of cancer-related mortality by 2030. Although modest improvement in survival with current conventional cytotoxic chemotherapy-based regimens, 5-year overall survival is still 9%. Despite becoming standard of care in several malignancies, single agent or dual check point inhibitor therapy is not effective in pancreatic cancer except in subgroup of patients with high microsatellite instability or high tumor mutational burden. Profoundly immunosuppressive tumor microenvironment of pancreatic cancer is a major barrier for success of immunotherapy. Rigorous research efforts are underway to explore immune-based combination therapy with chemotherapy, radiation therapy, stroma-modifying agents, vaccines, and targeted therapies. This article aims to provide a review of the ongoing research in pancreatic cancer immunotherapy.

17 Activity sensors for noninvasive monitoring of immune response and tumor resistance during immune checkpoint blockade therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A17-A17
Author(s):  
Quoc Mac ◽  
James Bowen ◽  
Hathaichanok Phuengkham ◽  
Anirudh Sivakumar ◽  
Congmin Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Growth Curves ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Tumor Resistance ◽  
Activity Sensors ◽  
Therapeutic Responses

BackgroundDespite the curative potential of immune checkpoint blockade (ICB) therapy, only small subsets of patients achieve tumor regression while many responders relapse and acquire resistance. Monitoring treatment response and detecting the onset of resistance are critical for improving patient prognoses. Here we engineered ICB antibody-sensor conjugates known as ICB-Dx by coupling peptides sensing the activity of granzyme B (GzmB), a T cell cytotoxic protease, directly on αPD1 antibody to monitor therapeutic responses by producing a fluorescent reporter into urine. To develop biomarkers that indicate mechanisms of resistance to ICB, we generated B2m-/- and Jak1-/- tumor models and performed transcriptomic analyses to identify unique protease signatures of these resistance mechanisms. We then built a multiplexed library of αPD1-Dx capable of detecting early therapeutic response and illuminating resistance mechanisms during ICB therapy.MethodsFITC-labeled GzmB substrates were synthesized (CEM) and conjugated to αPD1 antibody. B2m-/- and Jak1-/- tumors were generated from WT MC38 cells using CRISPR/Cas9. For tumor studies, 106 cells were inoculated s.c. in B6 mice. Tumor mice were treated with αPD1 or IgG1 isotype conjugates (0.1 mg), and urine was collected at 3 hours. Tumor RNA was isolated with RNEasy kit (Qiagen) and prepared for sequencing with TruSeq mRNA kit (Illumina).ResultsTo synthesize αPD1-Dx, we coupled FITC-labeled GzmB substrates to αPD1 antibody (figure 1a). In MC38 tumors, systemic administration of αPD1-Dx lowered tumor burden relative to control treatment while producing significantly elevated urine signals that preceded tumor regression (figure 1b, c). To investigate the ability to monitor tumor resistance to ICB, we developed knockout tumors to model B2m and Jak1 mutations, which are observed in human patients. in vivo, B2m-/- and Jak1-/- MC38 tumors were resistant to αPD1 monotherapy (figure 1d). Tumor RNA sequencing revealed that gene expression was altered during αPD1 treatment only in WT tumors. Importantly, B2m-/- tumors showed very different expression profiles than Jak1-/- tumors during αPD1 treatment, indicative of unique regulation of resistance (figure 1e). We used differential expression analyses to discover unique protease signatures associated with these two resistance mechanisms. Finally, a multiplexed library of αPD1-Dx engineered to monitor both tumor and immune proteases detected early on-treatment responses and stratified B2m-/- from Jak1-/- resistance with high diagnostic validity (figure 1f).Abstract 17 Figure 1Monitoring response and resistance with ICB-Dx(a) αPD1-Dx can reinvigorate T cell response and monitor protease activities in the tumor microenvironment. (b) Growth curves of WT MC38 tumors treated with αPD1- or IgG1-Dx (ANOVA). (c) Urine signals detect treatment response to αPD1 monotherapy (ANOVA). (d) Growth curves of B2m-/- and Jak1-/- tumors treated with αPD1- or IgG1-Dx (ANOVA). (e) TSNE plot showing RNA profiles of WT, B2m-/-, Jak1-/- tumors treated with αPD1 or isotype control. (f) ROC curves of random forest classifiers built from urine signals that differentiate on-treatment response from on-treatment resistance and B2m-/- from Jak1-/- resistance.ConclusionsWe have engineered activity sensors that accurately detect therapeutic responses and stratify resistance mechanisms noninvasively from urine, thereby potentially expanding the precision of ICB therapy to benefit cancer patients.Ethics ApprovalAll animal studies were approved by Georgia Tech IACUC (A100193)

scholarly journals Impact of SARS-COV-2 Pandemic on Kidney Cancer Management

Kidney Cancer ◽  
2021 ◽  
pp. 1-14
Author(s):  
Melissa Bersanelli ◽  
Camillo Porta
Keyword(s):  
Survival Rates ◽  
Delayed Diagnosis ◽  
Case Series ◽  
Cost Benefit ◽  
Original Data ◽  
Immune Checkpoint Blockade ◽  
Retrospective Case ◽  
Renal Masses ◽  
Term Survival ◽  
Cancer Management

Background: The SARS-CoV-2 pandemic still has a huge impact on the management of many chronic diseases such as cancer. Few data are presently available reagarding how the management of renal cell carcinoma (RCC) has changed due to this unprecedented situation. Objective: To discuss the challenges and issues of the diagnosis and treatment of RCC in the COVID-19 era, and to provide recommendations based on the collected literature and our personal experience. Methods: Systematic review of the available Literature regarding the management of RCC during the SARS-CoV-2 pandemic. Results: Our review showed a prevalence of narrative publications, raising the issue of the real relevance of the evidence retrieved. Indeed, the only original data about RCC and COVID-19 found were a small retrospective case series and two surveys, providing either patients’ or physicians’ viewpoints. Conclusions: The expected delayed diagnosis of RCC could lead to an increase of advanced/metastatic cases; thus, proper therapeutic choices for patients with small renal masses should be carefully evaluated case by case, in order to avoid negative effects on long-term survival rates. The controversial interaction between immune checkpoint blockade and COVID-19 pathogenesis is more hypothetical than evidence-based, and thus immunotherapy should not be denied, whenever appropriate. To avoid treatments which won’t have an impact on patients’ survival, a honest and accurate evaluation of the cost/benefit ratio of each treatment option should be always performed. Finally, SARS-CoV-2 swab positivity should not prevent the continuation of ongoing active treatments in asymptomatic cases, or or after symptoms’ resolution.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

scholarly journals Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5912
Author(s):  
Angèle Luby ◽  
Marie-Clotilde Alves-Guerra
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Stress ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Therapeutic Approaches ◽  
Immunosuppressive Tumor Microenvironment

Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

scholarly journals Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huapan Fang ◽  
Zhaopei Guo ◽  
Jie Chen ◽  
Lin Lin ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Epigenetic Regulation ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Memory ◽  
Escape Mechanism ◽  
Immune Escape Mechanism

AbstractImmunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

scholarly journals Role of Sex Hormones at Different Physiobiological Conditions and Therapeutic Potential in MBD2 Mediated Severe Asthma

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Binaya Wasti ◽  
Zhifeng Chen ◽  
Yi Ke ◽  
Wen Tao Duan ◽  
Shao-Kun Liu ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Sex Hormones ◽  
Human Body ◽  
Therapeutic Potential ◽  
Corticosteroid Treatment ◽  
Sex Hormone ◽  
Asthma Prevalence ◽  
Term Survival

Sex hormone has become a “hot topic” to evaluate the hormonal therapeutic potential in severe asthma. Th17 cell is one of the main influencing factors involved in the pathogenesis of severe asthma, hence also called as kernel of severe asthma, and Th17 subtype of non-T2 asthma is less responsive (resistance) to inhaled corticosteroid (ICS), so severe in nature. Methyl-CpG binding domain protein 2 (MBD2) is overexpressed and regulates the Th17 differentiation, showing the possibility of therapeutic target in treating Th17 mediated severe asthma. Sex hormone fluctuates at the different physiobiological conditions of the human body and affects the asthma pathobiology showing its role in asthma prevalence, severity, remission, and therapy. This review briefly overviews the sex hormones, their influence in asthma at the different physiobiological conditions of human body, and MBD2 severe asthma connection with the possible therapeutic potential of sex steroids in MBD2 mediated Th17 predominant severe asthma. Male sex hormone tends to show a beneficial effect and possibly downregulates the expression of Th17 cells via regulating MBD2 through a mechanism distinct from corticosteroid treatment and guides us towards discovery of new therapeutic agent, reduces the asthma-related complications, and promotes long-term survival by lowering the risk of therapy-resistant issues of old age severe asthma.

scholarly journals Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

2020 ◽  
Author(s):  
Padma Kadiyala ◽  
Stephen V. Carney ◽  
Jessica C. Gauss ◽  
Maria B. Garcia-Fabiani ◽  
Felipe J. Núñez ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Immunological Memory ◽  
Immune Checkpoint Blockade ◽  
Metabolic Reprogramming ◽  
Lower Grade ◽  
Combination Strategy ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh1 R132h ◽  
Mutant Idh1 ◽  
Promoter Mutations

AbstractMutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas’ subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.Brief SummaryInhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.

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