Lycera’s most advanced program in cancer immunotherapy focuses on oral, selective RORγ agonists. The retinoic acid-related orphan receptor-gamma t (RORγt) is a nuclear receptor transcription factor that acts as a immune cell master control switch driving the generation and function of Th17 (helper T-cells) and Tc17 (cytotoxic) T cells.
Lycera’s RORγ agonist, LYC-55716, combines multiple anti-tumor mechanisms into a single therapeutic by modulating gene expression to reprogram immune cells for improved function, as well as decrease immunosuppressive mechanisms. For instance, scientists at Lycera have demonstrated that RORγ agonists enhance cytokine production by both murine and human cells, T-effector to T-reg cell ratios and reduced PD-1 expression. When RORγ agonists are used in vivo, the integration of the mechanisms results in immune-dependent decreased tumor growth and enhanced survival in preclinical models of cancer. Essentially, Lycera’s RORγ agonist approach both “removes the brake” and “pushes on the accelerator” of immune function.
Based on the Company’s ground breaking research, Lycera initiated the ARGON trial (Trial of RORgamma Agonist LYC-55716 in Advanced Cancer) which is a Phase 1/2A study of LYC-55716 in patients with advanced, relapsed or refractory solid tumors. The initial Phase 1 portion of the study was designed to find the biologically active or maximum tolerated dose of LYC-55716. The study utilized a 3+3 study design, in which LYC-55716 will be administered orally in subjects with relapsed or refractory solid tumors. The primary endpoints are safety and tolerability, and the study is designed to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose.
In October 2017, Lycera announced that LYC-55716 was advancing to Phase 2A development. The study will enroll approximately75 patients in 6 tumor cohorts. Tumor cohorts were identified based on RORγ expression, biology and sensitivity to immunotherapies. Patients will be enrolled if they have failed standard therapies and have been diagnosed with advanced Non-Small Cell Lung Cancer, Squamous Cell Cancer of the Head & Neck, Ovarian Cancer, Bladder Cancer, Renal Cancer, and Gastro-esophageal Cancer. The trial is expected to be fully enrolled by mid-2018.
In January 2018, Lycera announced the initiation of a multi-center Phase 1B combination study in metastatic Non-Small Cell Lung Cancer in combination with pembrolizumab.
Furthermore, ex vivo treatment of anti-tumor T cells with Lycera’s RORγ agonists improves the cancer-fighting ability of these cells and increased persistence of T cells able to produce more cytokines. Thus, this approach has high potential for substantially improving adoptive cell therapy approaches.
Novel Immuno Oncology Targets
Publications for RORγ Agonists
2018 American Association of Cancer Researchers Annual Meeting (Poster): LYC-55716, a First-in-Class RORg Agonist: Rationale and Preclinical Data to Support Clinical Combinations with Established Immunotherapies. Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter
2018 American Association of Cancer Researchers Annual Meeting (Poster): Safety and Dose Selection for LYC-55716, a First-in-Class ROR-g Agonist to Treat Solid Tumors: Phase 1 Results from an Open-Label, Multicenter Phase 1/2a Trial. Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, Garry Weems, Marshall Schreeder, H. Jeffrey Wilkins
2018 Multidisciplinary Head and Neck Cancers Symposia (Poster): Novel Immunotherapy: LYC-55716, a Small-molecule RORγ Agonist, in Clinical Trials for Head and Neck Squamous Cell Carcinoma. Xiao Hu, Xikui Liu, Hongxiu Li, Madhumita Bogdan, Yilin Gao, Brian Fox, Garry Weems, H. Jeffrey Wilkins, Laura Carter
2018 ASCO-SITC Clinical Immuno-Oncology Symposium (Poster): RORg Agonist LYC-55716, a Novel, Small-Molecule Immunotherapy: Rationale for Clinical Evaluation in Non–Small Cell Lung Cancer Based on Translational and Bioinformatic Evaluation Laura Carter, Xikui Liu, Hongxiu Li, Elizabeth Zawidzka, Yilin Gao, Brian Fox, Garry Weems, H. Jeffrey Wilkins, Xiao Hu
2018 American Society of Clinical Oncology Genitourinary Cancers Symposium (Poster): Novel Small-Molecule RORγ Agonist Immuno-oncology Agent LYC-55716: Tumor Selection and Evaluation of Renal Cell and Bladder Cancer for Inclusion in Phase 2a Expansion. Xiao Hu, Xikui Liu, Hongxiu Li, Elizabeth Zawidzka, Garry Weems, Yilin Gao, Brian Fox, H. Jeffrey Wilkins, Laura Carter
2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (Poster): LYC-55716, A Novel Small-Molecule RORg Agonist Immuno-oncology Agent: Rationale for Tumor Selection and Clinical Evaluation of Gastric and Esophageal Carcinoma in Phase 2a Expansion Garry Weems, Xiao Hu, Xikui Liu, Hongxiu Li, Madhumita Bogdan, Yilin Gao, Brian Fox, H. Jeffrey Wilkins, Laura Carter
2017 Society for Immunotherapy of Cancer (Poster): Prioritizing tumor types for treatment with a novel immunotherapy: LYC-55716 a small-molecule RORg agonist Xiao Hu, Xikui Liu, Hongxiu Li, Madhumita Bogdan, Yilin Gao, Brian Fox, H. Jeffrey Wilkins, Laura Carter
2017 European Society for Medical Oncology (Poster): A First-in-human, Open-label, Multicenter Phase 1/2a Study to Evaluate the Safety and Efficacy of Increased Repeated Doses of the First-in-class RORγ Agonist LYC-55716 in Treating Locally Advanced or Metastatic Solid Tumors. Devalingam Mahalingam, Marshall Schreeder, John Nemunaitis, Judy S. Wang, H. Jeffrey Wilkins, Erika P. Hamilton
2016 OncoImmunology (Manuscript): Synthetic RORγ agonists regulate multiple pathways to enhance anti-tumor immunity. Xiao Hu, Xikui Liu, Jacques Moisan, Yahong Wang, Charles A. Lesch, Chauncey Spooner, Rodney W. Morgan, Elizabeth M. Zawidzka, David Mertz, Dick Bousley, Kinga Majchrzak, Ilona Kryczek, Clarke Taylor, Chad Van Huis, Don Skalitzky, Alexander Hurd, Thomas D. Aicher, Peter L. Toogood, Gary D. Glick, Chrystal M. Paulos, Weiping Zou & Laura L. Carter
2016 American Association for Cancer Research (Poster): RORgamma Agonists Regulate Immune Checkpoint Receptors to Enhance anti-Tumor Immunity. Xiao Hu, Xikui Liu, Jacques Moisan, Chrystal Paulos, Yahong Wang, Chauncey Spooner, Charles Lesch, Rodney Morgan, David Mertz, Dick Bousley, Clarke Taylor, Chad Van Huis, Don Skalitzky, Thomas Aicher, Peter Toogood, Laura Carter
2015 Society for Immunotherapy of Cancer (Poster): RORγ Agonists Enhance Survival and Memory of Type 17 T Cells and Improve Anti-tumor Activity. Xiao Hu, Jacques Moisan, Kinga Majchrzak, Chuck Lesch, Yahong Wang, Brian Sanchez, Xikui Liu, Rodney Morgan, David Mertz, Dick Bousley, Chad Van Huis, Don Skalitzky, Clarke Taylor, Thomas Aicher, Peter Toogood, WeipingZou, Gary Glick, Chrystal Paulos, Laura Carter
2015 Novel American Association of Immunologists – Oral Presentation and Poster Presentation. RORγ Agonists Enhance Anti-Tumor Activity of Adoptive T Cell Therapy. Jacques Moisan, Kinga Majchrzak, Xia Hu, Rodney W Morgan, Xikui Liu, Kellie M Demock, Yahong Wang, Chuck A Lesch, Brian M Sanchez, Dick Bousley, Clarke B Taylor, Chad A Van Huis, Don J Skalitzky, Tom D Aicher, Peter L Toogood, Weiping Zou, Gary D Glick, Chrystal M Paulos, Laura L Carter
2015 American Association for Cancer Research – Poster Presentation. RORγ Agonists as a Novel Immunotherapy Approach for Cancer. Xiao Hu, Jacques Moisan, Charles Lesch, Yahong Wang, Xikui Liu, Rodney Morgan, David Mertz, Brian Sanchez, Dick Bousley, Clark Taylor, Chad van Huis, Don Skalitzky, Thomas Aicher, Peter Toogood, Weiping Zou, Gary Glick, Laura Carter
2015 Keystone Symposia Conference – Tumor Immunology (Poster). Novel oral RORγ agonists demonstrate anti-tumor efficacy in the 4T1 breast cancer model. Jacques Moisan, Xiao Hu, Rod Morgan, Xikui Liu, Kellie Demock, Yahong Wang, Chuck Lesch, Brian Sanchez, Dick Bousley, Clarke Taylor, Chad Van Huis, Don Skalitzky, Tom Aicher, Peter Toogood, Weiping Zou, Gary Glick, Laura Carter
2015 Nature Chemical Biology. Sterol metabolism controls Th17 differentiation by generating endogenous RORγ agonists. Xiao Hu, Yahong Wang, Ling-Yang Hao, Xikui Liu, Chuck A. Lesch, Brian M. Sanchez, Jay M. Wendling, Rodney W. Morgan, Tom D. Aicher, Laura L. Carter, Peter L. Toogood and Gary D. Glick
2014 Society for Immunotherapy of Cancer (Poster). Novel synthetic RORγ agonist compounds as a potential anti-tumor therapeutic approach. Xiao Hu, Xikui Liu, Rod Morgan, Jacques Moisan, Ling-Yang Hao, Yahong Wang, Brian Sanchez, Charles Lesch, Dick Bousley, Clark Taylor, Chad van Huis, Thomas D. Aicher, Peter Toogood, Weiping Zou, Gary Glick, Laura Carter