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Goal: To evaluate Notch inhibitor monotherapy and combination (combo) therapy in Adenoid Cystic Carcinoma (ACC) Patient Derived Xenograft (PDX) models with and without activating Notch mutations (mt). ACC is a rare salivary gland malignancy with no standard of care. Chemotherapy resistance limits treatment to surgery/radiation and ~60% of patients (pts) will recur. ~22% of ACC pts have Notch activating mutations that are associated with a distinct phenotype, aggressive disease and poor prognosis. In a P1 solid tumor study, 2 ACC pts were treated with AL101, an investigational gamma secretase inhibitor (J Clin Oncol 36, 2018 abstract 2515). One pt with an NRR (Negative Regulatory Region) activating mutation had a prolonged partial response, the 2nd pt with a PEST mutation had stable disease. Both had an extended PK profile with a sustained pharmacodynamic response (>50% inhibition of HES1 in peripheral blood). These results prompted us to evaluate the effect of AL101 in tumors that harbor/lack Notch activating mutations. Design: 4 ACC PDX models were evaluated: ACCx9 (Notch1 mt: NRR activating mutation), ACCx11 (Notch1 mt, tandem duplication), ACCx6 (Notch1 wt), ACCx5M1 (Notch1 VUS, not predicted to be activating). Activated Notch1 (nuclear IHC stain) was confined to the Notch mt models. Tumors were implanted into 6-12 week old athymic nude female mice. Upon reaching 150-300 mm3 tumor volume, mice were randomized to treatment (N=5), or vehicle (N=10) arms. AL101 was dosed at 7.5 mg/kg po (days 1-4 of Q7D) as single agent or in combo with cisplatin (3 mg/kg ip; qw) or everolimus (10 mg/kg; po; qd). Results: Significant tumor growth inhibition (TGI) was seen with AL101 monotherapy compared to vehicle treatment in both Notch mt models (ACCx9; 110% TGI P0.99, ACCx5M1: 60% TGI P=0.26). Cisplatin and everolimus monotherapy had no significant effect on Notch mt models (cisplatin: ACCx9; 43% TGI P=0.98, ACCx11; 50% TGI P=0.99, everolimus: ACCx9; 51% TGI P=0.6, ACCx11; 54% TGI P=0.99). AL101 with cisplatin or everolimus had no further benefit in the ACCx9 model (both 106% TGI P=0.98 or P>0.99 respectively). The ACCx11 model had a non-significant benefit (104% TGI P=0.17 for cisplatin combo and 107% TGI P=0.18 for everolimus combo). Interestingly, the ACCx6 Notch wt model was sensitive to everolimus (75% TGI P=0.027) with no significant benefit of adding AL101. Conclusion: AL101 monotherapy had a significant anti-tumor effect in ACC PDX tumors with Notch activating mutations and lacked effectiveness in tumors lacking such mutations. Neither cisplatin nor everolimus monotherapy treatment had a significant effect in Notch mt models, alone or in combination with AL101. These data support the clinical development of AL101 as a targeted monotherapy for ACCs with Notch activating mutations. Citation Format: Renata ferrarotto*, Genia Alpert*, Udi Gluschnaider, Rami Rauch, Adi Mondshine, Oz Solomon, Bill Kramer, Evgeny Izumchenko, John Heymach, Andrea Vergara-Silva, Jon Aster, Matti Davis. AL101 mediated tumor inhibition in Notch mutated ACC PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4885.

Cancer immunotherapies are revolutionizing cancer treatment. Unfortunately, a large proportion of patients with solid tumors do not respond to currently available immune-therapeutics. The lack of response is due to a variety of mechanisms tumors adopt to avoid immune mediated clearance. The multiplicity of immunosuppressive mechanisms operational in the tumor microenvironment may not be overcome by single agents and require interventions at multiple control points. However, systemic exposure to combinations of immunoregulators may result in severe, dose limiting, acute and chronic toxicities that might be prevented if the effect of these agents is focused to the tumor microenvironment. We are engaged in the discovery of a novel class of immuno-oncology drugs aimed at maximizing the effect of immunoregulatory molecules in the tumor microenvironment and minimizing systemic adverse effects. These drugs incorporate plasmids, engineered to program tumor cells to produce and secrete immune-regulatory proteins, within hyaluronic acid (HA) coated lipid nanoparticles, called GAGomers, which specifically target tumor cells that overexpress activated HA receptors (GAG-pDNA). GAG-pDNA based therapeutics promise highly potent but localized activation of the immune system exclusively in the tumor microenvironment following systemic administration, leading to the destruction of tumor cells by activated immune cells without debilitating toxic side effects. To demonstrate the feasibility of the GAG-pDNA approach we have incorporated a plasmid directing the expression of murine IL-2 into GAGomers (GAG-pIL2) and assessed the anti-tumor activity of the construct after systemic delivery into tumor bearing mice. GAG-pIL2 administration resulted in statistically significant inhibition of tumor growth, which correlated with elevated IL-2 levels in the tumor and increased infiltration of T-cells into the tumor microenvironment. These experiments demonstrate the feasibility of programming tumor cells using GAG-pDNA to produce and secrete immunoregulatory molecules into the tumor microenvironment and trigger robust anti-tumor immune responses. Citation Format: Genia Alpert, David Altreuter, Sunil Anamandla, Arlyssa Birt, Guy Cinamon, Keren Cohen Merimi, Orli Even Or, Nir Gefen, Nadia Gurvich, Jeno Gyuris, Lorena Lerner, Adi Mondshine, Hong Wang. Anti-tumor effect of GAGomer-mediated intra-tumoral IL-2 expression following systemic administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1601. doi:10.1158/1538-7445.AM2017-1601