Search

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

Background: Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted next-generation sequencing-based approaches offer promising diagnostic capabilities, there are still limitations. There is a pressing clinical need for a well-validated, rapid, cost-effective mutation profiling system in patient specimens. Given their speed and cost-effectiveness, quantitative PCR mutation detection techniques are well suited for the clinical environment. The qBiomarker mutation PCR array has high sensitivity and shorter turnaround times compared with other methods. However, a direct comparison with existing viable alternatives are required to assess its true potential and limitations. Methods: In this study, we evaluated a panel of 117 patient-derived tumour xenografts by the qBiomarker array and compared with other methods for mutation detection, including Ion AmpliSeq sequencing, whole-exome sequencing and droplet digital PCR. Results: Our broad analysis demonstrates that the qBiomarker's performance is on par with that of other labour-intensive and expensive methods of cancer mutation detection of frequently altered cancer-associated genes, and provides a foundation for supporting its consideration as an option for molecular diagnostics. Conclusions: This large-scale direct comparison and validation of currently available mutation detection approaches is extremely relevant for the current scenario of precision medicine and will lead to informed choice of screening methodologies, especially in lower budget conditions or time frame limitations.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Background: The role of B cells and antibodies in anticancer immune responses may correlate with improved prognosis in several types of cancer. Indeed, tumor-reactive antibodies are detected in the blood of cancer patients, tumor-infiltrating B cells have been shown to produce tumor-reactive antibodies, and tumor-reactive antibodies can cause tumor regression in several mouse models. Taken together, these observations support further identification, isolation and characterization of antitumor antibodies from patients demonstrating effective anticancer responses and defining the cognate targets and mechanisms whereby they contribute to tumor control. Methods: We identified cohorts of patients with nonprogressing metastatic cancer who had received checkpoint immunotherapy and isolated their circulating plasmablasts. Antibody heavy and light chain paired sequences were obtained from individual cells using Atreca's Immune Repertoire Capture (IRCTM) technology. The expressed antibodies were then analyzed for their ability to bind to tumor cells as well as tumor tissue and their ability to mediate antitumor activity was explored in syngeneic mouse tumor models. Results: Elevated plasmablast levels were observed in individuals with nonprogressing metastatic cancer, and analysis of plasmablast antibody sequences revealed clonal families of B cells that persisted over time with hallmarks of affinity maturation and class switching. We also identified antibody sequences with features common to more than one patient, consistent with convergent antibody selection. In particular, one antibody (AB-213) isolated from a NSCLC patient was found to demonstrate binding to unrelated human tumors as well as the mouse EMT6 tumor. When AB-213 was expressed with a mouse IgG2a constant region the chimeric antibody showed efficacy in vivo by reducing tumor volume and increasing survival in Balb/c mice harboring the syngeneic EMT6 model. Antitumor activity of the chimeric antibody was observed to be dose-dependent when administered as monotherapy or in combination with checkpoint inhibitors. We feel, based on these data, AB-213 could become a very important clinical therapeutic. Citation Format: Gilson Baia, Amy Manning-Bog, Alexander Scholz, Jeff DeFalco, Michael Harbell, Danhui Zhang, Felix Chu, Beatriz Millare, May Sumi, Patricia Zuno, Judevin Lugar Sapugay, Dongkyoon Kim, Yvonne Leung, Shuwei Jiang, Xiaobin Tang, Kevin Williamson, Xiaomu Chen, Sean Carroll, Christine Dowd, Ish Dhawan, Jonathan Benjamin, Gregg Espiritu Santo, Nicole Haaser, Ngan Nguyen, Eldar Giladi, David Minor, Yann Chong Tan, Jeremy B. Sokolove, Lawrence Steinman, Tito Serafini, Guy Cavet, Norman M. Greenberg, Jacob Glanville, Wayne Volkmuth, Daniel E. Emerling, William H. Robinson. Mining the cancer immuno-responsome: The identification of functional antitumor antibodies from patients receiving checkpoint inhibitors [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 3966.

e15015Background: It is unclear exactly how B cells and their antibodies (Abs) influence the anti-cancer immune response. We've proposed that anti-tumor Abs drive or amplify anti-tumor immune effec...

Background: Therapeutics reactivating the immune system have demonstrated promise, with durable objective responses in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify immunotherapeutic targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, development of robust preclinical tools to test such drugs against human tumors in the context of an allogeneic immune system remains an imperative. We have previously demonstrated the generation of its ImmunoGraft platform, whereby two technologies, the patient-derived xenograft (PDX) and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. We now report on the utility of the ImmunoGraft for assessing the effect of immune-modulating agents in solid tumors. Materials and Methods: Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted with human CD34+ cells and monitored for the expansion of human immune cells (humanized). Humanized mice were engrafted with solid tumors that had been subjected to histocompatibility typing and characterized for a number of molecular markers, including PD-L1 expression. Tumor growth in the ImmunoGrafts was compared against non-humanized counterparts, as well as the level of immune reconstitution. Finally, ImmunoGrafts were treated with drugs blocking the immune checkpoints CTLA4 and PD1 and human immune activation and tumor growth inhibition evaluated. Results: Mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and lymphoid organs of humanized mice. Solid tumors, including NSCLC, melanoma, and head and neck cancer, were successfully engrafted in the humanized mice. Moderate to high expression of PD-L1 was found in approximately 80% of these tumors. ImmunoGrafts treated with anti-CTLA4 or anti-PD1 antibodies exhibited systemic immune responses characterized by robust proliferation of splenic and circulating huCD3+ T cells, as well as activated huCD4+ Th1 cells. There was also an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes and huCD68+ macrophages, along with elevated secretion of human-specific cytokines. Tumor growth inhibition, and in some instances tumor regression, was demonstrated in treated ImmunoGrafts. The magnitude of growth inhibition correlated with the level of immune activation. Conclusion : The ImmunoGraft is an innovative pre-clinical model enabling immunotherapeutic agents to be evaluated for efficacy in solid tumors. This platform is more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and may be one of the most translationally-relevant models to date for screening therapies targeting the immune system. To gauge the clinical potential of the ImmunoGraft, a retrospective analysis is currently ongoing using PDX models developed from patients treated with immuno-oncology drugs. The ImmunoGraft has the potential to revolutionize translational drug discovery and development for immunotherapeutic agents in oncology. Citation Format: Gilson Baia, David Vasquez, David Cerna, Daniel Ciznadija, David Sidransky, Jennifer Jaskowiak, Lindsay Ryland, Angela Davies, Amanda Katz, Keren Paz. The ImmunoGraftTM: A humanized mouse model for translational assessment of immunotherapy in solid tumors. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A40.

Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted Next Generation Sequencing (NGS) - based approaches provide accurate results and offer promising diagnostic capabilities, there are still limitations which impede their adoption for large-scale population-based screening. There is a pressing clinical need for a well-validated, rapid, cost-effective and accurate mutation profiling system with optimal analytical performance in patient specimens. Given their speed, and cost-effectiveness, real-time, quantitative qPCR mutation detection techniques are well suited for the clinical environment. The novel qBiomarker somatic mutation PCR array has high sensitivity and shorter turnaround times compared to other methods. However a direct comparison to existing viable alternatives is required to assess its true potential and limitations. In this study, we extensively evaluated a panel of 117 patient-derived tumor xenografts (PDX) by the qBiomarker array and directly compared its efficacy with that of other routinely used methods for mutation detection, including Ion AmpliSeq sequencing, whole exome sequencing (WES), and ultra-sensitive droplet digital PCR (ddPCR) genotyping. Our comprehensive analysis demonstrates that qBiomarker's performance is on par with that of other routinely used but more complex, labor-intensive and expensive methods of cancer mutation detection, and provides a foundation for advancing the adoption of qBiomarker assay for cancer driving mutation profiling in clinical diagnostics. Furthermore, a large-scale direct comparison of different mutation detection approaches will lead to informed choice of screening methodologies, especially in lower budget conditions or timeframe limitations. Citation Format: Mariana Brait, Evgeny Izumchenko, Luciane Kagohara, Samuel Long, Piotr Wysocki, Brian Faherty, Elana Fertig, Tin Khor, Elizabeth Bruckheimer, Gilson Baia, Daniel Ciznadija, Ido Sloma, Ido Ben-Zvi, Keren Paz, David Sidransky. Validation of qBiomarker as an accurate and efficient mutation detection method in a comprehensive analysis of patient-derived tumor xenografts. [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 3640.

The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals, and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are composed of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4, and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers, and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas, and the NF2 gene product, Merlin, acts upstream of the Hippo pathway. Here, we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using an siRNA transient knockdown of YAP1 in NF2-mutant meningioma cells, we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas, deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis. Mol Cancer Res; 10(7); 904–13. ©2012 AACR.

Background: Therapeutics reactivating the immune system have demonstrated promise, with durable objective responses in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify immunotherapeutic targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, development of robust preclinical tools to test such drugs against human tumors in the context of an allogeneic immune system remains an imperative. We have previously demonstrated the generation of its ImmunoGraftTM platform, whereby two technologies, the patient-derived xenograft (PDX) and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. We now report on the utility of the ImmunoGraftTM for assessing the effect of immune-modulating agents in solid tumors. Materials and Methods: Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted with human CD34+ cells and monitored for the expansion of human immune cells (humanized). Humanized mice were engrafted with solid tumors that had been subjected to histocompatibility typing and characterized for a number of molecular markers, including PD-L1 expression. Tumor growth in the ImmunoGraftsTM was compared against non-humanized counterparts, as well as the level of immune reconstitution. Finally, ImmunoGraftsTM were treated with drugs blocking the immune checkpoints CTLA4 and PD1 and human immune activation and tumor growth inhibition evaluated. Results: Mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and lymphoid organs of humanized mice. Solid tumors, including NSCLC, melanoma, and head and neck cancer, were successfully engrafted in the humanized mice. Moderate to high expression of PD-L1 was found in approximately 80% of these tumors. ImmunoGraftsTM treated with anti-CTLA4 or anti-PD1 antibodies exhibited systemic immune responses characterized by robust proliferation of splenic and circulating huCD3+ T cells, as well as activated huCD4+ Th1 cells. There was also an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes and huCD68+ macrophages, along with elevated secretion of human-specific cytokines. Tumor growth inhibition, and in some instances tumor regression, was demonstrated in treated ImmunoGraftsTM. The magnitude of growth inhibition correlated with the level of immune activation. Conclusion: The ImmunoGraftTM is an innovative pre-clinical model enabling immunotherapeutic agents to be evaluated for efficacy in solid tumors. This platform is more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and may be one of the most translationally-relevant models to date for screening therapies targeting the immune system. To gauge the clinical potential of the ImmunoGraftTM, a retrospective analysis is currently ongoing using PDX models developed from patients treated with immuno-oncology drugs. The ImmunoGraftTMhas the potential to revolutionize translational drug discovery and development for immunotherapeutic agents in oncology. Citation Format: Gilson Baia, David Vasquez, David Cerna, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. The ImmunoGraft: A humanized mouse model for translational assessment of immunotherapy in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A8.

Triple negative breast cancer has an extremely poor prognosis when chemotherapy is no longer effective. To overcome drug resistance, novel drug delivery systems based on nanoparticles have had remarkable success. We produced a novel nanoparticle component 'MDC' from milk-derived colloid. In order to evaluate the anti-cancer effect of MDC, we conducted in vitro and in vivo experiments on cancer cell lines and a primary tumor derived breast xenograft. Doxorubicin (Dox) conjugated to MDC (MDC-Dox) showed higher cancer cell growth inhibition than MDC alone especially in cell lines with high EGFR expression. In a mouse melanoma model, MDC-Dox significantly suppressed tumor growth when compared with free Dox. Moreover, in a primary tumor derived breast xenograft, one of the mice treated with MDC-Dox showed partial regression, while mice treated with free Dox failed to show any suppression of tumor growth. We have shown that a novel nanoparticle compound made of simple milk-derived colloid has the capability for drug conjugation, and serves as a tumor-specific carrier of anti-cancer drugs. Further research on its safety and ability to carry various anti-cancer drugs into multiple drug-resistant primary breast models is warranted.

The blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, robust preclinical tools to test these drugs directly against human cancers in the context of a human immune system are required. Champions Oncology has now developed the ImmunoGraft, whereby two innovative technologies, the patient-derived xenograft and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells and twelve weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the now humanized animals. Growth of NSCLC tumors implanted into humanized NOG animals was comparable to those in non-humanized counterparts, and when humanized animals harboring NSCLC tumor implants were treated with ipilimumab, tumor growth was slowed, exhibiting marked regression. Systemic immune activation was observed in humanized mice following treatment with ipilimumab, characterized by robust proliferation of huCD3+ T cells and activated huCD4+ Th1 cells, as well as an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes (all relative to vehicle controls). We have developed an innovative new preclinical cancer model, the ImmunoGraft, which will enable novel immunotherapeutic agents to be accurately evaluated for efficacy against virtually any cancer indication that can be engrafted. As a proof-of-concept of the utility of the ImmunoGraft, we demonstrated how effectively ipilimumab restricted the growth of NSCLC implants engrafted in humanized animals. This translational platform is, therefore, more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and is the most clinically-relevant model for screening immune system-targeting therapies, as single agents or in combination with standard-of-care drugs and other immuno-modulators. The ImmunoGraft has strong potential to revolutionize the application of immunotherapy to both personalized oncology and translational drug discovery. Citation Format: Gilson Baia, David Vasquez-Dunddel, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. A humanized mouse model for translational assessment of targeted immune checkpoint blockade. [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 5031. doi:10.1158/1538-7445.AM2015-5031

TumorGrafts (also known as patient-derived xenografts) are a valuable tool for the personalization of oncology treatment, as well as development of new cancer therapeutics. Tumor explants are engrafted into immunodeficient mice and allowed to develop prior to screening against a panel of drugs or drug combinations to assess which best inhibit tumor growth. These models capture the chaotic heterogeneity, histopathology, and biology of the original tumor, as well its 3-dimensional interaction with the surrounding stroma and other cells migrating into the tumor environment. TumorGrafts will serve basic and clinical research groups as an increasingly valuable preclinical model of cancer. One important variable governing the generation of these models is the take rate, or the percentage of patient tumors that successfully engraft and grow in the mice. This is a potentially critical limitation to applying these preclinical models for improving patient treatment and advancing novel drug regimens to the clinic. Hence, there is a need to understand and exploit the mechanisms that influence take rate in order to ensure that the majority of tumor explants readily engraft and expand. We describe here our experience in optimizing the engraftment of patient tumor tissue in immunodeficient mice. We found a number of factors contribute to take rate including tumor type, tissue quantity and quality, engraftment site, oxygenation state, neovascularization and the presence of extracellular stromal components and cells. We have also uncovered a correlation between the growth rate of tumors in the mice and the clinical aggressiveness of the original malignancy, information that may be useful in guiding clinical management. Moreover, we describe how we are now able to consistently use biopsy material rather than surgical explants to establish TumorGrafts, a crucial step forward that allows this technology to benefit patients diagnosed with early-stage cancers or where surgery is not indicated. Although engraftment of patient tumor tissue in immunodeficient mice is a complex process, with multiple factors impacting success, we have effectively optimized this process, improving our take rate and at the same time, reducing the time to obtaining drug screening results, all without compromising tumor integrity. Citation Format: David M. Vasquez-Dunddel, Gilson Baia, Amanda Katz, Daniel Ciznadija, David Sidransky, Keren Paz. Multifactorial biological processes govern engraftment of patient-derived tumor tissue in immunodeficient mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2014-1190

The blockade of immune checkpoints with monoclonal antibodies (mAbs) is a promising therapeutic avenue, with durable objective responses observed in patients with solid tumors, particularly melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Preclinical models that recapitulate a functional human immune system will therefore be essential tools for the continued investigation of immunotherapy approaches. Champions Oncology is engaged in advanced personalized solutions and our TumorGraft models have been developed and extensively characterized as a platform for use in personalizing cancer patient care, as well as pharmaceutical development. However, because TumorGrafts are established by engrafting patient tumors into immune-deficient mice, the therapeutic efficacy of immune-modulatory drugs cannot be directly examined. To circumvent this limitation, we reconstituted the human immune system by engrafting human hematopoietic cells (HLA-A2; CD34+) into immune-compromised mice (PrkdcscidIl2rgtm1Sug) carrying the scid mutation and a targeted mutation of the Il2r-gamma gene. Ten to twelve weeks later, mature CD45+ human T cells could be detected in these mice, at which time TumorGrafts were established, followed by drug-sensitivity testing with various mAbs targeting the immune system. Fifty six well-established melanoma, colorectal, breast and lung TumorGraft models were characterized and selected with regard to their HLA type and other molecular characteristics such as BRAF mutation status (in melanoma) and KRAS mutation status (in colorectal and lung cancer) as well as expression of PD-L1. With the present study, we demonstrated the potential of combining the humanized mouse with Champions TumorGraft to generate a preclinical platform for assessing the therapeutic value of mAbs targeting immune checkpoints in various solid tumors. Citation Format: Gilson S. Baia, David Vasquez, Daniel Ciznadija, Brandy Wilkinson, David Sidransky, Amanda Katz, Keren Paz. Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2014-1674

Meningiomas are common tumors of the central nervous system and are the second most prevalent tumors in Neurofibromatosis type 2 patients. Despite their high frequency, currently there are no chemotherapeutic options for these tumors and treatment is limited to surgery and various forms of radiation therapy either as adjuvant or primary therapy. Some tumors are unresectable due to location and have histhopathologic aggressive features (designated as WHO grade II and III) with higher recurrence rates. When treatment is recommended, these tumors almost uniformly receive some form of radiation therapy. The aim of this study was to find new therapeutic options to couple with radiation, given its common use with non-surgical meningiomas. We are interested in targeting oncogenic pathways in the context of loss of the NF2 gene, which represents the most common genetic alteration in meningiomas, present is 50-70% of sporadic tumors and all of NF2 cases. We used cell-based assays searching for small molecule inhibitors that showed prevalent efficacy against NF2-deficient cells. Cell proliferation and clonogenic assays were employed to investigate the potential synergy effect of drugs and radiation combinations. Three pairs of NF2 isogenic meningioma cells (AC1, SF6717 and KT21MG1) were used to screen libraries of FDA approved compounds. The primary screen was performed using KT21MG1 cells. The top 5% compounds (86 compounds) showing preferential inhibition of NF2-deficient cells were selected for further validation. The secondary screen was used to validate useful targets with AC1 and SF6717 cells. Twelve compounds (∼15%) showed prevalent inhibitory activity on these cells. Small molecules targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor receptor (VEGFR) showed preferential synergistic inhibition of NF2 cells with radiation, compared to either radiation or drug treatment alone. Currently, preclinical testing is in progress to investigate the efficacy of these inhibitors in combination with radiation in a meningioma mouse model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2759. doi:1538-7445.AM2012-2759