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.

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 Tumor Suppressor Immune Gene Therapy to Reverse Immunotherapy Resistance

2021 ◽  
Author(s):  
Sunil Chada ◽  
Dora Wiederhold ◽  
Kerstin B. Menander ◽  
Beatha Sellman ◽  
Max Talbott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Type I ◽  
Immune Gene ◽  
Gene Signatures ◽  
Complete Tumor

AbstractBackgroundWhile immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required overcome resistance to immunotherapies.MethodsWe investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms action, pre and post Ad-p53 treatment biopsies were evaluated for changes in gene expression profiles by Nanostring IO 360 assays.ResultsSubstantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with complete tumor remissions of both primary and contralateral tumors. Interestingly, contralateral tumors which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p<0.001). None of the monotherapies or doublet treatments induced complete tumor regressions. Ad-p53 treatment increased Type I Interferon, CD8+ T cell, immuno-proteosome antigen presentation and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 down regulated genes associated with stromal pathways and IL10 expression identified novel anti-cancer therapeutic applications.ConclusionsThese results imply the ability of Ad-p53 to induce efficacious local and systemic anti-tumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complimentary immune mechanisms of action which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist and immune checkpoint inhibitor combination treatment.

scholarly journals Tumor suppressor immune gene therapy to reverse immunotherapy resistance

2021 ◽  
Author(s):  
Sunil Chada ◽  
Dora Wiederhold ◽  
Kerstin B. Menander ◽  
Beatha Sellman ◽  
Max Talbott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mechanisms Of Action ◽  
Immune Gene ◽  
Gene Signatures ◽  
Complete Tumor

Abstract Background While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies. Methods We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays. Results The substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p < 0.001). None of the monotherapies or doublet treatments induced the complete tumor regressions. Ad-p53 treatment increased interferon, CD8+ T cell, immuno-proteosome antigen presentation, and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune-suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 downregulated genes associated with stromal pathways and IL10 expression identified novel anticancer therapeutic applications. Conclusions These results imply the ability of Ad-p53 to induce efficacious local and systemic antitumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complementary immune mechanisms of action, which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment.

Patient reported toxicities: Development and validation of patient-reported symptom measure for lung cancer patients receiving immunotherapy.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 93-93 ◽  
Author(s):  
Sandra S. Shaw ◽  
Heather S.L. Jim ◽  
Sarah Eisel ◽  
Aasha Hoogland ◽  
David LeDuc ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Interim Analysis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Lung Cancer Patients ◽  
Patient Reported

93 Background: There is increasing clinical and research interest in patient-reported outcomes (PROs) which provide unique and complementary information to provider-rated adverse events. While several studies have been published of PROs in lung cancer patients receiving immune checkpoint blockade, to our knowledge all have focused on PROs collected as part of a clinical trial. This interim analysis describes PROs outside the context of a clinical trial. Methods: The Addario Lung Cancer Foundation (ALCF) international patient registry was used to collect patient-reported clinical and PRO information. Patients who reported current or past treatment with an FDA-approved immune checkpoint inhibitor were asked to complete a second survey of symptomatic toxicities of these therapies. Patients rated 40 symptoms on a five-point scale. The Charlson Comorbidity Index and Functional Assessment of Cancer Therapy General (FACT-G) were administered to assess comorbidities and quality of life, respectively. Results: A total of 116 patients (mean age 61, 75% female) who reported treatment with nivolumab (52%) or pembrolizumab (47%) were included in analyses. The majority of patients (70%) had been treated for 6 months or less. The most commonly reported symptoms were fatigue (72%), aching joints (52%), aching muscles (35%), insomnia (34%), back pain (30%), itching (27%), bone pain (26%), and skin dryness (25%). A total of 26% of patients had experienced a treatment delay, 10% had been to the emergency room, and 6% had been hospitalized due to toxicity. Participants reported a mean score of 75.88 (SD=17.59) on the FACT-G, significantly lower than previously-published normative data for cancer patients. Conclusions: This study is among the first to evaluate patient-reported toxicities of immune checkpoint inhibitor outside the context of a clinical trial. Results from this interim analysis indicate patient reported toxicities of immune checkpoint inhibitors are common in lung cancer patients. Additional research is needed to better understand the longitudinal course of symptomatic toxicities. Acknowledgements: ALCF, IASLC, American Lung Association.

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

scholarly journals Influence of Tumor Immune Infiltration on Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Liu ◽  
Fang Yang ◽  
Ji-Ye Yin ◽  
Ying-Zi Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Cytolytic Activity ◽  
Consensus Clustering ◽  
Tfh Cells

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.

scholarly journals Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer

2018 ◽  
Vol 24 (7) ◽  
pp. 1617-1628 ◽  
Author(s):  
Tamara Muliaditan ◽  
James W. Opzoomer ◽  
Jonathan Caron ◽  
Mary Okesola ◽  
Paris Kosti ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Preclinical Models
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