Abstract CT027: A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1)

Abstract

Background: OX40 (CD134) belongs to the tumor necrosis factor receptor (TNFR) family, and transduces a costimulatory signal during T-cell activation. In the periphery, OX40 expression is limited to recently activated CD4+ and CD8+ cells. In tumors, infiltrating T lymphocytes are enriched for OX40, where it augments T-cell activation, proliferation and survival. OX40 is also expressed on tumor infiltrating regulatory T cells (Tregs). Intratumoral Treg depletion is critical for the in vivo antitumor activity of immune checkpoint antibodies. OX40 can also be found on natural killer (NK) cells, mediating antibody-dependent cellular cytotoxicity. Together, these mechanisms make stimulation of OX40 with agonistic agents an attractive target for a novel anti-cancer immunotherapy. GSK3174998 is a humanized IgG1 anti-OX40 agonistic monoclonal antibody identified through collaboration with MD Anderson Cancer Center and is currently in phase I development. Methods: The primary objective of this open-label non-randomized multicenter phase I study is to evaluate the safety of GSK3174998, as monotherapy in escalating doses every 3 weeks IV for up to 48 weeks (Part 1) or in combination with 200 mg pembrolizumab administered every 3 weeks IV for up to 2 years (Part 2). Secondary objectives include assessment of antitumor activity, pharmacokinetics, pharmacodynamics and immunogenicity. Adverse events will be monitored using NCI CTCAE v. 4.0. Radiographic imaging will be obtained every 12 weeks to assess clinical response defined by immune-related RECIST. Exploratory objectives include examination of changes in genomic DNA, RNA, protein, measures of immune function in tumor, and the association of these with antitumor activity. The study will enroll up to approximately 180 pts; eligible pts will have measurable disease with documentation of metastatic non-small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma, bladder, soft tissue sarcoma, triple-negative breast cancer, and colorectal carcinoma displaying microsatellite instability that has progressed after standard therapy, or for which standard therapy is ineffective, intolerable, or inappropriate. A pre-treatment biopsy is requested of all pts. Matched pre-treatment and on-treatment biopsies will be performed in expansion cohorts to allow investigation of candidate biomarkers which may predict clinical response. As of Feb 1, 2016, monotherapy cohorts 1 and 2 have completed without DLT and enrollment to Cohort 3 is ongoing. This study (NCT02528357) is funded by GlaxoSmithKline. Citation Format: Jeffrey Infante, Christoph M. Ahlers, F Stephen Hodi, Sopie Postel-Vinay, Jan HM Schellens, John V. Heymach, Karen Autio, Mary Barnette, Herbert Struemper, Maura Watmuff, Elaine M. Paul, David R. Kaufman, Jeffrey S. Weber, Axel Hoos. A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT027.

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

“…In accordance with disappointing clinical trial results, [27][28][29] the clinical candidate human αOX40 IgG2 antibody failed to stimulate TIL proliferation or cytokine secretion in our in vitro expansion assay, while treatment with OX40L resulted in TIL expansion and increased secretion of proinflammatory cytokines. The clinical αOX40 antibody and OX40L differ with regard to their structure: αOX40 antibody is monomeric, whereas OX40L is of hexameric shape.…”

“…27 Besides, more phase I studies have been performed in which agonistic αOX40 antibody treatment showed low clinical efficacy in advanced solid tumors. 28 29 Hence, we wondered whether the reason for the limited clinical efficacy was due to (1) low OX40 expression on human TILs, (2) minor effects of OX40 costimulation on TIL functions and expansion, or (3) suboptimal performance of the currently used αOX40 antibodies. Therefore, we measured OX40 levels on distinct TIL subsets of colorectal and HCC tumor tissue, thus demonstrating that TI activated T-helper (aTh) and activated regulatory T cell (aTreg) do express high OX40 levels.…”

“…27 Besides, more phase I studies have been performed in which agonistic αOX40 antibody treatment showed low clinical efficacy in advanced solid tumors. 28 29 …”

Immune checkpoint inhibitors for bladder cancer treatment

“…Он трансдуцирует костимулирующий сигнал во время активации Т-клеток. Пациенты с мРМП активно включаются в несколько исследований фазы I, в которых изучаются антагонисты TIM-3 (NCT02608268) [42], ингибиторы LAG3 (NCT01968109) [43] и агонисты OX40 (NCT02528357) [44], с ингибиторами PD-1/PD-L1 и без них. В настоящее время анти-LAG3 mAb (BMS-986016) изучается в сочетании с ниволумабом в исследовании I фазы (NCT01968109) [43].…”

“…В настоящее время анти-LAG3 mAb (BMS-986016) изучается в сочетании с ниволумабом в исследовании I фазы (NCT01968109) [43]. Агонист OX40 (GSK3174998) исследуется совместно с пембролизумабом в испытании фазы I (NCT02528357) [44]. Еще один интересный подход к стимулированию иммунного ответа дополнительно нацелен на Т-клеточное микроокружение и связан с индоламин-2,3-диоксигеназой, которая является внутриклеточным ферментом, вырабатываемым опухолевыми клетками, и играет важную роль в путях, генерирующих иммуносупрессивные метаболиты [45].…”