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Immunotherapy represents an extremely promising treatment approach for cancer patients. The success in this field has been signified by multiple recent approvals of checkpoint inhibitors across a range of cancer types. Subsequently, there is an increasing need to understand why certain patients and diseases benefit from these treatments while others do not, as well as how to maximize the benefits from these treatments. To address some of these questions, we used an in vivo screening platform, MuScreen, which allows for evaluation of multiple syngeneic models and treatment modalities.We have characterized baseline and treated tumor immune infiltrates for a panel of syngeneic models using flow cytometry. The correlation between responsiveness and effects of checkpoint inhibitors (e.g., anti-PD-1), and macrophage targeted agents (e.g., CSF1R inhibition) on immune infiltrates including tumor-associated macrophages (TAMs) were investigated in 6 syngeneic models. Furthermore, M1/M2 polarization of macrophages was investigated to explore the potential role of these cells in establishing an immunosuppressed tumor microenvironment that may affect response to therapy. Here, we show that the baseline immune cell population varies across models, and that immune checkpoint inhibitors and macrophage-targeted agents had variable efficacy across different tumor models. We also present the correlation of immune cell infiltration, including tumor infiltrating lymphocytes (TILs), TAMs, and responsiveness to immunotherapy intervention. Having an in-depth understanding of the immune make up of a model in which an immunomodulatory compound is screened is paramount for successful translation into the clinic. A well-characterized and fully profiled panel of syngeneic models such as the MuScreen platform allows for finding the right model for screening test compounds to be used alone or in combination with immunotherapy. Citation Format: Yuki Kato Maves, Hooman Izadi, Elvira C. Talaoc, Deborah Yan, Charlene Echegaray, Andrew Calinisan, Krystal Moya, Heather Venant, Mitchell Garland, Radhika Iyer, Shounak Gosh, Stephanie Songco, Jayant Thatte, Tommy Broudy. Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor models [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 2811. doi:10.1158/1538-7445.AM2017-2811

Purpose: Neuroblastoma (NB) is one of the most common and deadly solid tumors of childhood. The Trk family of neurotrophin receptors plays an important role in clinical behavior of NBs. Overexpression of TrkB and its ligand, BDNF, is associated with poor prognosis. We wanted to determine if RXDX-101, an oral pan-TRK, ROS1 and ALK inhibitor, would be effective in our NB xenograft model, either alone or in combination with conventional chemotherapy. Experimental Design: We tested the in vitro effects of RXDX-101 as a single agent, or in combination with the chemotherapeutic agents irinotecan and temozolomide (Irino-TMZ), using a subclone of the SH-SY5Y NB cell line transfected with TrkB. We also examined in vivo growth inhibition of TrkB-expressing NB xenografts with RXDX-101 alone or in combination with Irino-TMZ. Results: RXDX-101 significantly inhibited growth of TrkB-expressing NB cells in vitro. Enhanced in vitro inhibition was observed when RXDX-101 was used in combination with Irino-TMZ. Single agent therapy with RXDX-101 resulted in significant tumor growth inhibition compared to control animals [p Conclusions: We show that RXDX-101 inhibits growth of TrkB expressing NB cells in vitro and in vivo. Furthermore, RXDX-101 cotreatment enhanced the efficacy of conventional chemotherapy in our NB xenograft model. Our data suggest that RXDX-101 has potential for incorporation in clinical trials for NB and other Trk expressing tumors. Citation Format: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur. The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2015-5390

Purpose: Neuroblastoma (NB) is the most common and deadly solid tumor in childhood. The majority of NB patients have advanced stage disease and a poor prognosis, so more effective, less toxic therapy is needed. We wanted to determine if more targeted delivery of chemotherapeutic agents would improve efficacy and reduce systemic toxicity. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. Experimental Design: We formulated ultrasmall-sized ( Results: All SN38-TS NP regimens were far superior to irinotecan, and “cures” were obtained in all NP arms (no cures with irinotecan). SN38-TS NP delivery resulted in 200x the amount of SN38 in NB tumors at 4 hr post-treatment, and 25% of the 4-hr SN38 level remained at 72 hr post-treatment, compared to no SN38 detected at 24 hr post-treatment for the irinotecan arm; no toxicity was seen with NPs. Conclusions: We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity. Citation Format: Radhika Iyer, Jamie L. Croucher, Michael Chorny, Jennifer L. Mangino, Ivan S. Alferiev, Robert J. Levy, Venkatadri Kolla, Garrett M. Brodeur. Nanoparticle delivery of an SN38 conjugate is more effective than Irinotecan in a mouse model of Neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2015-5537