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RORγ Agonists Enhance the Sustained Antitumor Activity through Intrinsic Tc17 Cytotoxicity and Tc1 Recruitment.

Activation of RORγ with synthetic small-molecule agonists has been shown to enhance type 17 effector (CD4+ Th17 and CD8+ Tc17 cells) cell functions and decrease immunosuppressive mechanisms, leading to improved antitumor efficacy in adoptive cell transfer and syngeneic murine tumor models. However, whether Tc17 cells possess intrinsic cytotoxicity and the mechanism they use to lyse target cells is controversial. We report here that Tc17 cells were lytic effectors dependent on perforin and granzyme A. In contrast to Tc1 cells, Tc17 cells resisted activation-induced cell death and maintained granzyme A levels, which conferred the ability to lyse target cells in serial encounters. Thus, although the acute lytic capacity of Tc17 cells could be inferior to Tc1 cells, comparable lysis was achieved over time. In addition to direct lytic activity, Tc17 cells infiltrated early into the tumor mass, recruited other CD8+ T cells to the tumor, and enhanced the survival and lytic capability of these cells during repeated target encounters. Synthetic RORγ agonists further augmented Tc17 survival and lytic activity in vitro and in vivo, controlling tumor growth not only through direct cytotoxicity, but also through recruitment and improved function of other effector cells in the tumor microenvironment, which suggests complementary and cooperate activities for effective immunotherapy.

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Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Transcription factor retinoic acid receptor-related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer. Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment). These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

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In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo.

Adoptive T-cell transfer therapy is an FDA- approved treatment for leukemia that relies on the ex vivo expansion and reinfusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during ex vivo expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion in vitroIn vivo, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells in vivoSignificance: RORγ agonists can be used in vitro during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3888/F1.large.jpg Cancer Res; 78(14); 3888-98. ©2018 AACR.

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Abstract 3762: Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME

Abstract RORγt is a master transcription factor, which regulates the proliferation and functionality of Type 17 T-cells (TH17 and Tc17). Recent nonclinical studies have shown that in addition to promoting effector differentiation, stemness and plasticity, RORγt also inhibits Treg differentiation, an important component of suppressive tumor microenvironment (TME). Therefore, stimulation of RORγt by synthetic, small-molecule agonists holds promise as an immunotherapy. We tested the effects of a RORγ agonist (LYC-54143; 100 mg/kg BID given continuously till the end of study) on the tumor growth and survival in mice in combination with a tumor antigen-specific vaccine (3 doses, one week apart), which is required for proper priming in this model. We found that the RORγ agonist resulted in a highly significant enhancement of the antitumor effect delaying the tumor growth (p≤0.001 at day 21 compared to vaccine alone treatment) and prolonging survival. At day 36 after tumor implantation, 80% of mice survived in the RORγ agonist + vaccine treatment group compared to 0% survival following RORγ agonist or vaccine alone treatments. Immunologically, we found that RORγ agonist treatment led to a significant decrease in the numbers of Tregs and a significant increase in IL-17+ IFNγ+ T cells in the TME. Moreover, RORγ agonist treatment led to a significant increase in the numbers of T cells including increased antigen-specific CD8+ T-cells in the TME. Interestingly, scheduling RORγ agonist before or with the vaccine demonstrated comparable antitumor activity, suggesting that the scheduling of RORγ agonist treatment does not affect the therapeutic outcomes. These results show that an RORγ agonist can enhance the antitumor immune response by enhancing effector functions and by decreasing immune suppression in the TME by increasing cytokine production and switching the differentiation of immune-suppressive Tregs to effector Th17 cells and support that RORγ agonists are promising immune-modulatory agents in cancer. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3762.

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Abstract 5566: LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies

Abstract The retinoic acid-related orphan receptor γt (RORγt) is a nuclear receptor transcription factor that acts as an immune cell master control switch driving the generation and function of Th17 (helper) and Tc17 (cytotoxic) T cells. Preclinical data show that synthetic RORγ agonists modulate immune cell gene expression to both increase immune activity and decrease immunosuppressive mechanisms in the tumor microenvironment. Because RORγ agonists impact multiple antitumor mechanisms, these compounds have the potential to combine with other agents to enhance tumor immunity. In addition to preclinical data supporting a biologic rationale, bioinformatic and machine learning approaches based on the RORγ pathway were undertaken to prioritize possible clinical combinations. This work highlighted other immuno-oncology agents as well as targeted therapies and more conventional treatments. Preclinical, syngeneic mouse cancer models were used to test some of the hypotheses. Based on the finding that RORγ agonists decrease PD-1 expression and that anti-CTLA4 induces ICOS, which stabilizes RORγ expression, anti-PD1 or anti-CTLA4 agents were combined with the RORγ agonist LYC-54143 in 12 syngeneic murine models. Compared with individual agents, combination treatments elicited superior tumor growth inhibition in 6 of the models (Table). RORγ agonist treatment was also able to augment antitumor activity of doxorubicin. In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule RORγ agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer. Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine modelAnti-PD1 aloneAnti-CTLA4 aloneRORγ agonist aloneRORγ agonist + anti-PD1RORγ agonist + anti-CTLA4H22 (Liver)30-50%>50%*10-30%>50%*>50%*Pan02 (Pancreas)<10%10-30%<10%10-30%*10-30%*CT26 (Colon)10-30%<10%<10%<10%30-50%B16F10 (Melanoma)10-30%10%10-30%10-30%30-50%A230 (Lymphoma)<10%<10%10-30%30-50%10%Renca (Renal)<10%10-30%30-50%*30-50%*30-50%*P<.05 vs vehicle. Citation Format: Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter. LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5566.

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Abstract CT132: Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial

Abstract Background: LYC-55716, a first-in-class, oral, small-molecule agonist of the retinoic acid receptor-related orphan receptor γ (RORγ), is under development as a novel immuno-oncology agent for solid tumors. Preclinical data show that LYC-55716 modulates gene expression to reprogram immune cells for improved anti-tumor effector function as well as decreased immunosuppressive mechanisms, resulting in slower tumor growth and enhanced survival. An ongoing, open-label, Phase I/IIa trial is evaluating the safety and tolerability of the investigational agent LYC-55716 in patients with advanced solid tumors. Methods: The Phase I portion of the trial (NCT02929862) enrolled adults with locally advanced or metastatic solid tumors (no specific exclusions) who had progressed on standard therapy. Patients received 28-day treatment cycles of LYC-55716 in which dose and dosing regimen were determined according to PK profile and safety. Primary endpoints were safety (monitoring of adverse events [AEs], physical examination, lab results) and incidence of dose-limiting (Grade 3-4) toxicities during the first treatment cycle. Secondary endpoints included pharmacokinetics (PK) and response assessment. Pharmacodynamic markers of RORγ activation were also evaluated. Results: Data to date: Thirty-two patients were enrolled (23-79 y; 63% female); 27 completed ≥1 (28-day) treatment cycle. Treatment-related AEs occurring in ≥3 patients included diarrhea (n=7 [22%]); fatigue (n=5 [16%]); and anemia, poor appetite, and dry mouth (n=3 [9%] each). No dose-limiting toxicities were observed during Phase 1. The majority of treatment-related AEs were Grade 1-2; Grade 3 treatment-related AEs were reported only for anemia, elevated gamma-glutamine transferase, and hypophosphatemia; no Grade 4 treatment-related AEs occurred. None of the 5 deaths or 14 serious AEs (in 11 patients) were considered treatment-related, and no subjects withdrew due to AEs. LYC-55716 demonstrated an estimated elimination half-life of ~12 h. Twice daily dosing resulted in minimum plasma concentrations that were consistently higher than QD dosing and the highest BID dose resulted in a median minimum plasma concentration that exceeded by ~24-fold the 50% effective concentration that preclinical studies had indicated was required for target gene regulation. Pharmacodynamic data indicated target engagement, consistent with PK evidence of exposure levels in the predicted efficacious range. Updated data, including details of Phase II dose selection and response assessment, will be presented. Conclusion: Phase I data support the safety of LYC-55716 and selection of a BID dosing regimen for the ongoing Phase 2a phase of the trial in patients with non-small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers. Citation Format: Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, Garry Weems, Marshall Schreeder, H. Jeffrey Wilkins. Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT132.

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Abstract 3773: RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody

Abstract Combination immunotherapy strategies are being developed to improve the clinical outcome in cancer patients. T-cell costimulation through OX40 has been shown to promote expansion and proliferation of effector T-cells leading to enhanced effector functions, memory generation and immune inflammatory antitumor responses. However, treatment with anti-OX40 as a single agent has not led to major positive clinical outcomes. Therefore, anti-OX40 is an ideal candidate for combination immunotherapy. In preclinical models, we have recently shown that combining anti-PD-1 concurrently with anti-OX40 negates the effects of agonist anti-OX40, making identification of combination partners crucial for antitumor therapy. RORγt, a master transcription factor, is known to drive Type 17 T-cell differentiation. Synthetic, small-molecule RORγ agonists have been shown to enhance Type 17 T-cell effector functions and survival, decrease immune suppressive mechanisms and modulate expression of a number of costimulatory and coinhibitory molecules. We hypothesized that combining RORγ agonist could enhance the antitumor effects of anti-OX40. Using a murine model where vaccine is used to prime the immune system, we assessed the effects of anti-OX40 antibody combined with a RORγ agonist (LYC-54143) on growth of established tumors and survival. We found that the combined treatment resulted in a significantly delayed tumor growth and prolonged mice survival. Analysis of the tumor microenvironment revealed that combination therapy significantly increased the numbers of total CD4+ T-cells including RORγt+ and highly activated INFγ+ cells, decreasing Treg numbers. Moreover, we found that RORγ agonist resulted in an increase in the numbers of total, antigen-specific, granzyme B+, and IFNγ+ CD8+ T-cells in the TME. These results show that inducing Th17 cells within the TME produces better anti-OX40 effect, suggesting that agonist anti-OX40 and RORγ agonist treatment is a novel potent combination for cancer immunotherapy. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3773.

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