scholarly journals The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship

2020 ◽  
Author(s):  
Irem Sahin ◽  
Sevda Turen ◽  
Pranav Santapuram ◽  
Ibrahim Halil Sahin
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Inhibitor Resistance

Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
Sunil Chada ◽  
Dora B Wiederhold ◽  
Kerstin Menander ◽  
Hyomin Ahn ◽  
Eonju Oh ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tumor Suppressor ◽  
Immune Checkpoint ◽  
Tumor Suppressors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Adenoviral Vectors ◽  
Immune Gene ◽  
Primary Tumors ◽  
Inhibitor Resistance

64 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients either do not respond or become resistant to this therapy. Methods: We evaluated the ability of tumor suppressors p53 and IL-24, delivered via adenoviral vectors, to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before intra-tumoral delivery of adenoviral vectors encoding tumor suppressors p53 (Ad-p53) or IL-24 (Ad-IL24). Results: Anti-PD-1 had minimal or no therapeutic efficacy when compared to PBS controls. However, there was a reversal of anti-PD-1 resistance in animals treated with Ad-p53, or Ad-IL24, in combination with anti-PD-1. Evaluation of primary tumor growth using ANOVA confirmed synergistic effects of the combination treatments over either agent used as monotherapy (p = 0.0001 for p53, p = 0.002 for IL-24). We also observed statistically significant decreases in contralateral abscopal tumor growth in animals whose primary tumors were treated with either Ad- p53 or Ad-IL24 (p = 0.046, and p = 0.0021, respectively) or in combination with anti-PD-1 (p = 0.02 p53, and p < 0.0001 for IL-24) as compared to animals treated with anti-PD-1 alone. With respect to survival, combined tumor suppressor + anti-PD-1 therapy resulted in a statistically significant increase in survival compared to: a) tumor suppressor therapy alone (p = 0.01 for either Ad-p53 and or IL-24) and b) anti-PD-1 therapy alone (p < 0.001 for p53, and p = x for IL-24). Conclusions: Overall, these results indicate that IL-24 and p53 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance in primary tumors, and induce abscopal effects inferring the activation of systemic anti-tumor immune responses that reverse resistance to immune checkpoint inhibitor therapy.

scholarly journals Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingyu Chen ◽  
Haotian Chen ◽  
Dong He ◽  
Yaxin Cheng ◽  
Yuxing Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Checkpoint Inhibitor ◽  
Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

Immune modulation via epigenetic targeting to overcome immune checkpoint inhibitor resistance

Immunotherapy ◽  
2019 ◽  
Vol 11 (15) ◽  
pp. 1263-1266
Author(s):  
Thiru Prasanna ◽  
Fan Wu ◽  
Desmond Yip ◽  
Sudha Rao
Keyword(s):  
Immune Checkpoint ◽  
Immune Modulation ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Inhibitor Resistance

Safety and feasibility of immuno-cryotherapy.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 34-34
Author(s):  
Junaid Raja ◽  
Anish Ghodadra ◽  
Scott N. Gettinger ◽  
Harriet M. Kluger ◽  
Mario Sznol ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Metastatic Lesion ◽  
Image Guided ◽  
Progression Of Disease ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Inhibitor Resistance

34 Background: To investigate the safety and feasibility of image guided immuno-cryotherapy in patients with immune checkpoint inhibitor failure. Methods: Consecutive patients with primary or acquired failure to immune checkpoint inhibitor therapy were studied following treatment with concomitant image-guided cryotherapy and immune checkpoint inhibition. In addition to demographic features, type of malignancy, size of targeted metastatic lesion, number of cycles of cryotherapy, systemic immunotherapy, and adverse events in a 90 day post procedural window were extracted. The primary end point was safety and adverse events stratified by the common terminology for adverse events (CTCAE) criteria. As a secondary endpoint, efficacy of the cryotherapy was assessed by iRECIST. Results: Ten patients underwent combined image-guided cryotherapy and checkpoint immunotherapy between 2015 and 2017. Five patients received CTLA 4 blockade with cryotherapy, and 8 patients received PD1 axis blockade and cryotherapy. Six patients had metastatic non-small cell lung cancer and 4 had metastatic melanoma. Immunoprofiling demonstrated one patient each with a mutation in NRAS (G12C), NRAS (Q61R), KRAS (G12C), and ALK; and 2 with aBRAF V600E mutation. Cryotherapy was performed in immunotherapy failure sites, including liver (5) and adrenal glands (3), lymph node and muscle. The median size of targeted lesions was 4.5 cm (standard deviation 3.7cm). There were no grade 3 or higher adverse event, though 6 patients had grade 1 and 2 adverse effects in the periprocedural period which included fatigue, local pain, and poor appetite, isolated cases of diarrhea, colitis, pneumothorax, and procedural site hematoma. Regarding therapeutic response: 5 patients demonstrated partial response, 1 stable response, and 1 progression of disease. Two patients died in the followup period from non-treatment induced causes and 1 is awaiting follow-up. Disease control rate was 85.7%. Conclusions: Immuno-cryotherapy with immune checkpoint therapy in patients with immune checkpoint inhibitor resistance is safe and feasible in metastatic NSCLC and melanoma. There were no grade 3 or above adverse events.

Effect of adenoviral p53 (Ad-p53) tumor suppressor immune gene therapy on checkpoint inhibitor resistance and abscopal therapeutic efficacy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14610-e14610 ◽  
Author(s):  
Robert E. Sobol ◽  
Sunil Chada ◽  
Dora Bocangel Wiederhold ◽  
Chae-Ok Yun ◽  
Hyomin Ahn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Immune Therapy ◽  
Immune Gene ◽  
Inhibitor Resistance ◽  
Abscopal Effects

e14610 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 1012viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary

2021 ◽  
Author(s):  
Arthur Sillah ◽  
Scott S Tykodi ◽  
Evan T Hall ◽  
John A Thompson ◽  
Nathaniel F Watson ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Lifestyle Factors ◽  
Host Immune System

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

Analysis of tumor microenvironment characteristics in bladder cancer: implications for immune checkpoint inhibitor therapy

2021 ◽  
Author(s):  
Xingyu Chen ◽  
Haotian Chen ◽  
Dong He ◽  
YaXing Cheng ◽  
Yuxing Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cox Regression ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Inhibitor Therapy ◽  
Checkpoint Inhibitor Therapy

Abstract Background The tumor microenvironment (TME) has a significant influence on prognosis and immunotherapy. There are no studies on the systematic analysis of bladder cancer TME and its effect on immune checkpoint inhibitor therapy. Methods We comprehensively evaluated the TME infiltration pattern of bladder cancer in 1,889 patients and conducted extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TME of bladder cancer. The principal component analysis algorithm was used to calculate the immune cell (IC)score to quantify the level of IC infiltration. We used the receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), and Subnetwork Mappings in Alignment of Pathways (SubMAP) algorithms to evaluate whether the ICscore can predict the benefits of immune checkpoint inhibitors in bladder cancer patients. Results We identified three different TME phenotypes using unsupervised clustering methods. To explore the potential biological pathways that drive the formation of these microenvironmental phenotypes, we demonstrated the clinical and pathological characteristics, biological signaling pathways, cancer immune circulation, copy number, and somatic mutation differences among the different subtypes. In addition, univariate and multivariate Cox regression analyses showed that the ICscore is a reliable and independent prognostic marker. The ICscore can also predict immune checkpoint inhibitor responsiveness as patients with higher ICscores showed a significant therapeutic advantage in immunotherapy. Conclusions This study increases our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance on more effective personalized immunotherapeutic strategies.

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