Abstract
BackgroundWhile 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.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 of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays.ResultsThe 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.ConclusionsThese 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.
Highlights
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
adenoviral p53 (Ad-p53) has local and abscopal effects with reversal of anti-PD1 resistance We evaluated the ability of Ad-p53 to reverse resistance to immune checkpoint inhibitor therapy in the B16F10 melanoma
Anti-PD-1 treatment Animals were treated with intraperitoneal anti-PD-1(10 mg/kg) every 3 days starting on Day 1, over a 30-day period following implantation of the primary tumor
Summary
Immune checkpoint inhibitor therapy has become a new standard of care for multiple recurrent and metastatic cancers. Various approaches are being tested to increase immune checkpoint blockade efficacy, including a combination with immune-stimulating cytokines [2, 3]. Interleukin 2 (IL2) and interleukin 15 (IL15) belong to a family of immune-stimulating cytokines sharing a common beta chain (CD122) and gammachain (CD132) receptor known to drive the proliferation and cytolytic activity of CD8 + T cells and natural killer (NK) cells. We evaluated Ad-p53 tumor suppressor therapy in a murine tumor model known to be highly resistant to immunotherapy in combination with IL2/IL15 CD122/132 agonists and immune checkpoint blockade. We observed substantial synergy supporting further development of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
