Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. Methods: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). Results: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. Conclusion: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.
Cytokines play an important role in regulating the immune response. Although there is great interest in exploiting cytokines for cancer immunotherapy, their clinical potential is limited by their pleiotropic properties and instability. A variety of cancer cell-intrinsic and extrinsic characteristics pose a barrier to effective treatments including cytokines. Recent studies using gene and cell therapy offer new opportunities for targeting cytokines or their receptors, demonstrating that they are actionable targets. Current efforts such as virotherapy, systemic cytokine therapy, and cellular and gene therapy have provided novel strategies that incorporate cytokines as potential therapeutic strategies for glioblastoma. Ongoing research on characterizing the tumor microenvironment will be informative for prioritization and combinatorial strategies of cytokines for future clinical trials. Unique therapeutic opportunities exist at the convergence of cytokines that play a dual role in tumorigenesis and immune modulation. Here, we discuss the underlying strategies in pre- and clinical trials aiming to enhance treatment outcomes in glioblastoma patients.
Purpose: Trials of immunotherapy in diffuse glioma patients have been mostly unsuccessful. We therefore sought to determine the combined effects of the signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 and the STING agonist IACS-8803 in a preclinical model of glioma. Experimental Design: C57BL/6 mice (n=9-10/group) with orthotopically engrafted GL261 cells were treated orally with WP1066, a blood-brain-barrier penetrant inhibitor of STAT3, in combination with the STING agonist IACS-8803 administered directly into the tumor. Analysis of treatment effects included immunoblots, ubiquitination, multiplex immunohistochemistry, and NanoString immune phenotyping of glioma-infiltrating immune cells. Results: The STING agonist 8803 at 2.5µg/mouse, in combination with WP1066 dosed at 30mg/kg with a 12-hour delay, increased animal subject median survival (MS) to 58 days, in contrast to monotherapy (WP1066=25 days, 8803=29 days) or control (25 days) (p=0.002 of combo relative to all other groups). Dose escalation of WP1066 to 60 mg/kg, administered simultaneously with 8803, completely abrogated the therapeutic combinatorial effect. Five ubiquitin-binding domains were predicted on STING using the UbPred program; concentrations of 5µM or higher of WP1066 induced polyubiquitination of phosphorylated STING. Immune profiling during the therapeutic window demonstrated a multi-pathway induction of anti-tumor immunity. Conclusions: Co-administration of a reduced effective dose of WP1066 is necessary with STING agonist 8803 to effectively enhance the anti-glioma immune reactivity in the tumor microenvironment. Citation Format: Hinda Najem, Shashwat Tripathi, Moloud Sooreshjani, Lisa Hurley, Corey Dussold, Victor Arrieta, Martina Ott, Jun Wei, Michael Curran, Anantha Marisetty, Waldemar Priebe, Leondias C. Platanias, Maciej S. Lesniak, Charles D. James, Craig Horbinski, David M. Ashley, Amy B. Heimberger. Establishment of the effective dose of the STAT3 inhibitor WP1066 used in combination with STING activation for reprograming the preclinical glioma microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB335.
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