bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4577: Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia
Authors: Mukherjee Sumit , Fried Angela , Hussaini Rahman , White Richard , Chatterjee Aheli , Banerjee Probal 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most insidious form of primary adult brain tumor with a mean life expectancy of 12-24 months. Previously, we have used the non-invasive strategies of (1) intranasal delivery of a glioblastoma-directed curcumin (CC) adduct (CC-CD68Ab) and (2) the intraperitoneal (i.p.) infusion of a lipid-encapsulated formulation of CC-phytosome to rescue orthotopically GL261-implanted GBM mice and study the effect of CC on the phenotype of the tumor-associated microglial cells (TAMs). Both treatment regimens not only caused tumor remission in 50-60% of GL261-implanted GBM mice, but also induced a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high, IL10high, iNOSlow, IL12low M2-type TAMs, while simultaneously inducing the Arginase1low, IL10low, iNOShigh, IL12high M1-type TAMs. Concurrently, we observed a marked induction and phosphorylation-mediated activation of microglial p65 NF-kB and STAT1, with concomitant suppression and inactivation of STAT3. p-STAT1high, p-STAT3low M1 microglia are known to cause IL12-dependent recruitment/activation of tumoricidal NKp46high natural killer (NK) cells. In determining the kinetics of CC-induced M1 repolarization of M2-TAMs, we observed that five days of CCP treatment (i.p.) was sufficient to induce a dramatic change in the tumor-associated Iba1+ TAMs, inhibiting the tumor-promoting M2-type TAM population, while activating M1-type microglia. As expected, we observed a concomitant recruitment of NKp46high NK cells into the GBM tumor. Cognizant of the fact that NK cells activate and stabilize the M1-microglia, we eliminated the NK cells in these GBM mice using the NK cell-targeted antibody NK1.1 Ab to observe a significant reduction in CC-evoked repolarization of TAMs. Our results demonstrate a unique oncoimmunotherapeutic function of CC, which when appropriately delivered, not only eliminates GBM directly, but also indirectly elicits recruitment and activation of tumoricidal NK cells and M1-TAMs. Furthermore, maintenance of this CC-evoked M1 phenotype is contingent upon CC-induced recruitment and activation of NK cells. Thus, when delivered appropriately, CC functions on GBM both directly as well as by stimulating and recruiting an army of immune cells that eliminate both GBM and GBM-initiating cells.
Citation Format: Sumit Mukherjee, Angela Fried, Rahman Hussaini, Richard White, Aheli Chatterjee, Probal Banerjee. Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia [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 4577. doi:10.1158/1538-7445.AM2017-4577
Abstract 4583: Heterogeneity in immune biomarker expression: Detailed analysis of a case with SCLC transformation after EGFR-TKI treatment
Authors: Suda Kenichi , Murakami Isao , Yu Hui , Kim Jihye , Ellison Kim , Rivard Christopher J. , Mitsudomi Tetsuya , Hirsch Fred R. 
Published: July 2017

Abstract
Introduction: The expression status of immune markers are of current research interest due to their potential roles as predictive biomarkers for immunotherapy in cancers. Currently there is little information on how the microenvironment of tumors and/or therapy-inducible histological transformation may affect the expression of these immune markers. Methods: A 76-year-old never-smoking female with epidermal growth factor receptor (EGFR) mutated lung adenocarcinoma (AC) acquired resistance to gefitinib. After her death, autopsy revealed small-cell lung cancer (SCLC) transformation and EGFR T790M secondary mutation as mutually exclusive resistance mechanisms. Two liver metastases (SCLC vs. AC with T790M) and two lymph node metastases (SCLC vs. AC with T790M) were analyzed to compare the expression status of immune markers by immunohistochemistry (IHC) and an immune-oncology gene expression panel (HTG EdgeSeq Immuno-Oncology Assay). Results: IHC analysis revealed that PD-L1 was expressed in 5% of tumor cells with AC histology (T790M) but not in tumor cells with SCLC transformation (Table 1). The liver metastasis with SCLC transformation showed negative stromal PD-L1 expression and scant tumor infiltrating lymphocytes, while the other lesions demonstrated stromal PD-L1 staining and infiltration of CD8-positive T cells. PD-1 was positive in lymphocytes from lymph node metastases, but not in those from liver metastases. Data generated using an IO panel indicated higher expression of galectin 9 and higher level of T cell stimulatory checkpoints in lesions with SCLC transformation. Bioinformatic analysis also demonstrated lower expression of type I interferon regulated genes in lesions with SCLC transformation. Conclusion: These data highlight the heterogeneity of expression of immune markers depending on the metastatic sites and histological transformation, and indicate that a biopsy from one lesion may not be representative of immune marker status for all lesions.
Summary of immune marker IHC staining in all specimensSpecimensPD-L1 (tumor)PD-L1 (stroma)TILsCD8 (T cells)PD-1 (T cells)Liver metastasis (AC / T790M)5%5%+++negativeLiver metastasis (SCLC)negativenegativescantn.a.n.a.Lymph node metastasis (AC / T790M)5%5%++++Lymph node metastasis (SCLC)negative10%++++
Citation Format: Kenichi Suda, Isao Murakami, Hui Yu, Jihye Kim, Kim Ellison, Christopher J. Rivard, Tetsuya Mitsudomi, Fred R. Hirsch. Heterogeneity in immune biomarker expression: Detailed analysis of a case with SCLC transformation after EGFR-TKI treatment [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 4583. doi:10.1158/1538-7445.AM2017-4583
Abstract 4596: Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies
Authors: Rios-Doria Jonathan , Harper Jay , Rothstein Raymond , Wetzel Leslie , Chesebrough Jon , Marrero Allison , Chen Cui , Strout Patrick , Mulgrew Kathy , McGlinchey Kelly , Fleming Ryan , Bezabeh Binyam , Meekin John , Stewart David , Kennedy Maureen , Martin Philip , Buchanan Andrew , Dimasi Nazzareno , Michelotti Emil , Hollingsworth Robert 
Published: July 2017

Abstract
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether ADCs conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induced ICD, modulated the immune microenvironment, and could combine with IO drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADCs had greater antitumor activity in immunocompetent vs. immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. These ADCs also induced immunological memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of these ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in the antitumor activity. Combinations of ADCs in different tumor models with IO drugs including PD-1 or PD-L1 antibodies, or OX40 ligand or GITR ligand fusion proteins produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADCs, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity. Immunophenotyping studies in different tumor models revealed broad immunomodulation of lymphoid and myeloid cells by ADCs and ADC/IO combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADCs and IO drugs that may increase clinical responses.
Citation Format: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil Michelotti, Robert Hollingsworth. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies [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 4596. doi:10.1158/1538-7445.AM2017-4596
Abstract 4597: A novel immuno-oncology approach: targeting cell-surface mesothelin with a fusion construct containing human granzyme B
Authors: Cheung Lawrence H. , Tijani Rasheed , Khan Nasir , Thuning-Roberson Claire , Rosenblum Michael G. 
Published: July 2017

Abstract
Immunological approaches to target tumors have gained considerable traction recently because of excellent clinical results. In addition, targeted treatment with antibody-drug conjugates (ADCs) can also be effective in achieving regression of solid tumors. The challenge for ADCs continues to be efficacy, stability of the construct and development of resistance. We have developed a unique fusion protein composed of 1) a novel human single-domain antibody (SD1) that uniquely targets Region III of the mesothelin glycoprotein and 2) an engineered version of the human serine protease Granzyme B (GrB). Mesothelin is highly expressed in aggressive cancers such as malignant mesothelioma, pancreatic and ovarian cancers, and NSCLC. Granzyme B generates an intense, irreversible pro-apoptotic effect through direct cleavage of caspases, release of cytochrome C from mitochrondria, and cleavage of nuclear matrix. Previous ADCs targeting mesothelin have faced the drawbacks of toxic payloads, formation of neutralizing antibodies, and competition with the serum protein MUC16/CA125. SD1-GrB represents a new class of completely human immunotoxins containing a payload with a unique mechanism of action. Additionally, because of its unique binding properties, SD1 does not compete with circulating CA125 and is not subject to cleavage. The SD1-GrB construct was designed as a homodimer (~200kDa) containing an IgG Fc domain and was expressed using transient-transfection of HEK293E cells. The soluble SD1-GrB was isolated from conditioned media and purified to homogeneity as assessed by SDS-PAGE and Western. Enzymatic activity of the GrB component was assessed by IEPD and found to be similar to authentic, native GrB. Binding to mesothelin was confirmed by surface plasmon resonance. Additionally, binding to the human lung adenocarcinoma cell lines H460 and HCC1703 was demonstrated by ELISA. Initial cytotoxicity (IC50) of SD1-GrB against H460 and HCC1703 was in the 30 nM range. Assessment against a larger panel of cell lines is ongoing followed by in vivo efficacy in a human tumor xenograft model. Our preliminary evaluation of SD1-GrB ADC suggests this construct has a unique mechanism of action and is highly cytotoxic against target cells. This molecule appears to be an excellent candidate for further pre-clinical development as a therapeutic agent. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Lawrence H. Cheung, Rasheed Tijani, Nasir Khan, Claire Thuning-Roberson, Michael G. Rosenblum. A novel immuno-oncology approach: targeting cell-surface mesothelin with a fusion construct containing human granzyme B [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 4597. doi:10.1158/1538-7445.AM2017-4597
Abstract 4598: Triggering of OX40 on T cells by a novel monoclonal antibody elicits robust antitumor immunity&lt;!–EndFragment–&gt;
Authors: Long Hua , White Ann , Wei Jie , Jiang Brittany , Feldman Reid , Pappas Danielle , Al-Shamkhani Aymen , Lin John 
Published: July 2017

Abstract
T cell costimulation is an attractive strategy for cancer treatment in addition to check point inhibitors. Costimulatory molecule OX40 is a member of the TNF receptor superfamily that is transiently expressed on activated T cells. Activation of OX40 leads to enhanced T cell proliferation and cytokine secretion and in turn results in better anti-tumor efficacy as shown by multiple mouse syngeneic tumor models. PF-04518600 (PF-8600) is a fully human IgG2 agonist antibody to human OX40 with high affinity and specificity. We used in vitro and in vivo methods to evaluate the co-stimulatory functions of PF-8600. PF-8600 demonstrated better agonist activity in a luciferase reporter cell line expressing OX40 and NFκB as compared to a human IgG1 antibody. In human primary T cells, PF-8600 dose dependently increased T cell proliferation and cytokine secretion in vitro. Furthermore in a mouse line expressing human OX40, PF-8600 in a mouse IgG1 framework increased the proliferation of OT1 cells and inhibited EG7 tumor growth as compared to isotype control antibody, further confirming the mechanism of action as an OX40 agonist. As regulatory T cells are a major inhibitory population in the tumor microenvironment, their specific depletion in the tumor is highly desirable. In an in vitro assay using monocyte derived macrophages as effector cells, PF-8600 mediated the depletion of OX40 expressing cells similar to a human IgG1 antibody, and this activity is dependent on the binding to hFcγRIIA. In human FcγR knock-in mice, anti-OX40-hIgG1 showed increased Treg reduction in the tumor comparing to anti-OX40-hIgG2, but less T cell proliferation and activation in the periphery. In combination with an anti-PD-L1 antibody, both anti-OX40-hIgG1 and hIgG2 showed similar enhanced anti-tumor activity in the MC38 colon carcinoma model as comparing to anti-PD-L1 alone. Both in vitro and in vivo results demonstrated PF-8600 enhanced T cells functions and inhibited tumor growth in a mouse syngeneic tumor model. The activity of the hIgG2 antibody is similar to that of an hIgG1 in both phagocytosis assays and hFcγR KI in vivo assays. Based on the mechanism of action and robust anti-tumor efficacy in preclinical models, PF-8600 is currently in clinical development in a broad spectrum of malignancies.
Citation Format: Hua Long, Ann White, Jie Wei, Brittany Jiang, Reid Feldman, Danielle Pappas, Aymen Al-Shamkhani, John Lin. Triggering of OX40 on T cells by a novel monoclonal antibody elicits robust antitumor immunity&lt;!–EndFragment–&gt; [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 4598. doi:10.1158/1538-7445.AM2017-4598
Abstract 4599: Antibody targeting PDZ domain of TIP-1 induces proliferation arrest through AKT/mTOR signaling inhibition in lung cancer and glioblastoma
Authors: Kapoor Vaishali , Dadey David , Hoye Kelly , Collins Andrea , Thotala Dinesh , Hallahan Dennis 
Published: July 2017

Abstract
Antigens that are over-expressed in cancer in response to radiation are being used as novel targets. We showed tax interacting protein 1 (TIP-1) to be radiation-inducible that translocated to the surface of the cancer cell following irradiation. TIP-1, which consists of a single PDZ domain plays an important role in cell signaling, cancer development, and progression. TIP-1’s involvement in various survival pathways makes it an attractive target for anticancer therapeutics. We used antibodies specific to this PDZ domain to determine its role in cancer cell survival. We monitored proliferation in lung cancer (A549 and H460) and glioblastoma (D54 and U251) cells after 24, 48, 72 and 96h treatment with the anti-PDZ antibody. We observed a time-dependent proliferation arrest with anti-PDZ antibody treatment which was associated with increased apoptosis. The anti-PDZ antibody when combined with radiation (3Gy) led to reduced proliferation and colony formation. Anti-PDZ antibody had no effect on the proliferation of normal lung (MRC-5) and endothelial (HUVEC) cells. Cells treated with anti-PDZ antibody showed decreased levels of the phosphorylated forms of AKT, mTOR, and a downstream substrate of mTOR, 4EBP1. Anti-PDZ antibody treatment also led to an overall reduction in basal levels of AKT, mTOR, and 4EBP1. Further, we evaluated the effect of the anti-PDZ antibody on tumor growth in heterotopic mouse models of lung cancer (A549) and glioma (U251). We observed significant growth delay in mice treated with anti-PDZ antibody treatment when compared to mice treated with the isotype control. The combination of the anti-PDZ antibody with radiation showed an additive effect. Immunoblot analysis of tumor tissues also showed downregulation of phosphorylated and total levels of AKT, mTOR and 4EBP1 in the tumors treated with anti-PDZ antibody. Overall, our results suggest that TIP-1 is a promising therapeutic target for treatment of lung cancer and glioblastoma. Antibodies specific to the PDZ domain of TIP-1 enhance the efficacy of radiotherapy. The anti-PDZ antibodies need to be optimized further before translating it into the clinic.
Citation Format: Vaishali Kapoor, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan. Antibody targeting PDZ domain of TIP-1 induces proliferation arrest through AKT/mTOR signaling inhibition in lung cancer and glioblastoma [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 4599. doi:10.1158/1538-7445.AM2017-4599
Abstract 461: Dichotomous roles of Dicer1 in rhabdomyosarcoma and angiosarcoma
Authors: Hanna Jason A. , Garcia Matthew R. , Drummond Catherine J. , Go Jonathon C. , Finkelstein David , Rehg Jerold E. , Hatley Mark E. 
Published: July 2017

Abstract
Pediatric and adult angiosarcomas are rare and highly aggressive soft tissue sarcomas with an extremely poor prognosis. Due to the rarity of this disease especially in children, the molecular drivers and optimized treatment strategies for patients are lacking, highlighting the need for genetic and in vivo animal models. MicroRNAs are a class of small RNAs that regulate gene expression and are often dysregulated in cancers including sarcomas. DICER1 is required for microRNA biogenesis and germline DICER1 mutations result in a cancer predisposition syndrome associated with increased risk of benign and malignant tumors including rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma resembling developmentally arrested skeletal muscle. Here we show Dicer1 expression is required for tumorigenesis in a mouse model of RMS driven by activation of oncogenic Smoothened by Cre recombinase expressed from the adipose protein 2 (aP2) promoter (aP2-Cre). Unexpectedly, in studying the role of Dicer1 in RMS, we found that Dicer1 deletion with aP2-Cre leads to aggressive angiosarcoma. Angiosarcoma development was independent of the Smoothened oncogene and other genetically engineered oncogenes or tumor suppressor loss, providing the first in vivo mouse model of biallelic Dicer1 loss alone driving tumorigenesis. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma and were enriched for microRNA-23 target genes including the oncogene Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis. The aP2-Cre;Dicer1Flox/- model provides a simple in vivo animal model to study angiosarcoma for novel therapeutics and the molecular mechanisms of cancer initiation, progression, and metastasis. In addition, our results demonstrate DICER1 and microRNAs play major and opposing roles in sarcomagenesis.
Citation Format: Jason A. Hanna, Matthew R. Garcia, Catherine J. Drummond, Jonathon C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Dichotomous roles of Dicer1 in rhabdomyosarcoma and angiosarcoma [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 461. doi:10.1158/1538-7445.AM2017-461
Abstract 4611: A 3D in vitro culture-based method to visualize and quantify effects of immuno-modulatory drugs
Authors: Daszkiewicz Lidia , Yan Kuan , Klop Maarten , Price Leo 
Published: July 2017

Abstract
BACKGROUNDUnleashing the full potential of cancer immunotherapy is hampered by a lack of effective in vitro testing methods. 2D cultured cells poorly reflect the in vivo situation and lack the tumour microenvironment whereas humanized animal models are slow, have low throughput and are expensive. 3D cultures, on the other hand, more faithfully reproduce the organization of a tissue, recapitulating the cell-cell connections and cellular heterogeneity found in the tumour and allow for a cost-efficient testing of drug candidates. To address the unmet need of immunotherapy cancer drug developers for robust assays that incorporate the human immune system, with functional read-outs in a high throughput (384well plate) format, we developed an in vitro platform based on 3D co-cultures of cancer tumoroids and immune cells. This assay is designed to test the capacity of small molecules, bi-specific antibodies, checkpoint modulators, vaccines and combinations of thereof to enhance anti-cancer immune responses. METHODSCancer cells of different sources were grown in a hydrogel to form tumoroids and then HLA-matched PBMCs pre-conditioned via different protocols to achieve activated or exhausted T cells, were added in the presence or absence of immune-modulatory drugs. T cell infiltration and subsequent tumoroid killing was quantified using 3D high-content imaging. After ‘optical sectioning’ 3D image stacks were reconstituted and morphometric analysis was performed with OMiner software. RESULTS AND CONCLUSIONS Addition of immune checkpoint inhibitors, pembrolizumab and ipilimumab, led to enhanced T cell infiltration and cytotoxicity of exhausted T cells. These results showed that automated 3D image and data analysis enables discrimination of immune-tumour cell interactions depending on activation status of T cells and permits the visualization of T cell re-gain of function in the presence of checkpoint modulators. A 3D environment allows the different cell types to engage in a more realistic setting than when cells are grow in a monolayer and enables the quantification of spatially resolved information, which is of an utmost importance when studying tumor-immune cell relationships. This new and innovative platform empowers immunotherapy drug developers with a powerful tool to evaluate drug performance. Furthermore, drug combinations can be studied to determine synergistic effects with other checkpoint inhibitors of standard of care compounds in an efficient manner.
Citation Format: Lidia Daszkiewicz, Kuan Yan, Maarten Klop, Leo Price. A 3D in vitro culture-based method to visualize and quantify effects of immuno-modulatory drugs [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 4611. doi:10.1158/1538-7445.AM2017-4611