Abstract:Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172HΔg/+K-rasLA1/+) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PDL1 (CD274) expression did n… Show more
“…Type I IFN promotes antigen presentation and priming of antitumor T cells, and expression of type I IFN genes has been linked to positive prognosis in response to chemotherapy and radiation (30,59,60). ICD-inducing agents, including anthracyclines, radiation therapy, and oncolytic viruses, have been shown to upregulate type I IFN response genes within the tumor cell (30,50,(60)(61)(62)(63)(64). Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53).…”
Section: Discussionmentioning
confidence: 99%
“…Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53). Recently, induction of a type I IFN response via radiation therapy was shown to overcome tumor resistance to anti-PD1 (64). However, persistent type I IFN signaling can be immunosuppressive and lead to checkpoint blockade resistance (52).…”
“…Type I IFN promotes antigen presentation and priming of antitumor T cells, and expression of type I IFN genes has been linked to positive prognosis in response to chemotherapy and radiation (30,59,60). ICD-inducing agents, including anthracyclines, radiation therapy, and oncolytic viruses, have been shown to upregulate type I IFN response genes within the tumor cell (30,50,(60)(61)(62)(63)(64). Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53).…”
Section: Discussionmentioning
confidence: 99%
“…Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53). Recently, induction of a type I IFN response via radiation therapy was shown to overcome tumor resistance to anti-PD1 (64). However, persistent type I IFN signaling can be immunosuppressive and lead to checkpoint blockade resistance (52).…”
“…21 The increased expression of MHC I molecules could also be linked to the increased type I IFN responses. 35 Importantly, resistance to anti-PD1 therapy could be mediated by suppression of type I IFN signaling in a preclinical model of Kras-mutated p53-deficient lung cancer. 35 In this model, induction of IFNβ by radiotherapy was able to elevate MHC I expression and restore the responsiveness of resistant tumors to anti-PD1 therapy.…”
Section: Discussionmentioning
confidence: 99%
“…35 Importantly, resistance to anti-PD1 therapy could be mediated by suppression of type I IFN signaling in a preclinical model of Kras-mutated p53-deficient lung cancer. 35 In this model, induction of IFNβ by radiotherapy was able to elevate MHC I expression and restore the responsiveness of resistant tumors to anti-PD1 therapy. Increased FAS expression with SGT-53 treatment could also increase CTL-mediated apoptosis of tumor cells since CTLs use FAS/FAS ligand binding to induce apoptosis of target cells during the CTL-tumor cell interaction.…”
The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.
“…Other effects provoked by radiation include increased expression of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells 15 and radiation-induced type I interferon (IFN) production, upregulated MHC class I expression, and restored response to anti-PD-1 in anti-PD-1-resistant rat models. 16 These molecular mechanisms open the possibility of a synergistic effect when used in conjunction with immunotherapy. …”
Section: The Rationale Of Immune-radiotherapy In Nsclcmentioning
impressive significantly longer progression-free survival in patients with untreated metastatic NSCLC and PD-L1 expression on at least 50% of tumor cells.Median progression-free survival was 10.3months (95% CI 6.7 to not reached) in the pembrolizumab group versus 6.0months (95% CI, 4.2 to 6.2) in the control group (HR 0.50; 95% CI, 0.37 to 0.68; P<0.001). Results for overall survival are not mature yet, but the estimated rate of overall survival at 6months also favored pembrolizumab. Previous studies 4,5 reported the benefit of immunotherapy in patients who progressed after a first line of chemotherapy. Although promising results are being reported, the response rate of immunotherapy is still sub-optimal, 4-6 this could be explained by underlying mechanisms that are currently under study.Several strategies are under development to improve the published results of immunotherapy, including dual checkpoint blockade with anti-CTLA-4 antibodies and combination with cytotoxic chemotherapy or anti-VEGF antibodies.
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