bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2532: Vemurafenib prodrugs suitable for oral and IV administration
Authors: Xi Ning , Zhang Yingjun , Wang Zhaohe , Lin Taoxi , Wang Qian 
Published: May 2015

Abstract
Background: The oral therapy vemurafenib was approved by the U.S. FDA in 2011 for first-line treatment of metastatic melanomas. Patients whose tumors carry the BRAF(V600E) mutation are treated with vemurafenib at recommended dose of 960mg twice daily. One reason for such a high dose is due to the poor oral bioavailability of vemurafenib. It was reported that the crystalline formulation of vemurafenib provided only modest drug exposures in animals and human (solubility limited absorption). To increase its oral bioavailability, vemurafenib was subsequently formulated as a micro-precipitated bulk powder (MBP). Despite this special formulation, vemurafenib displayed marked accumulation after repeat dosing at 960 mg BID with high inter-patient variability.
Methods and Results: To address the limitation of MBP formulation (e.g., high cost to manufacture and high doses to reach desired drug exposure), we developed prodrugs of vemurafenib, CT207 and CT317, with choices for both oral and i.v. administration. The prodrugs are homologues and freely soluble (&gt;1g/mL) in water as their sodium salts. Both drugs are well-absorbed in dogs and monkeys when dosed in 100% saline solution or in capsule. For example, CT317 reached AUC(0-24) = 256 µMh and 429 µMh (calculated in vemurafenib form) when dosed to dogs at 30 and 50 mg/kg QD (equivalent to 1120 and 1890 mg/day adult dosage). The absolute oral bioavailability of CT207 and CT317 in dogs was consistent at ∼80% in dosing range of 10 to 100 mg/kg, which was approximately 4-times higher than vemurafenib (formulated as MBP). Excellent drug exposure was also observed when CT207 was given to monkeys orally at doses of 50 and 100 mg/kg QD (equivalent to 1120 and 2240 mg/day adult dosage), providing AUC(0-24) = 506 µMh and 955 µMh, respectively. Both CT207 and CT317 showed the same potent antitumor activity as vemurafenib in COLO205 xenograft tumor model, demonstrating the equivalency of tumoricidal effects of the prodrugs to vemurafenib.
Conclusions: The consistent high oral bioavailability across wide dosing range and great aqueous solubility of CT207 and CT317 render them to have many advantages over vemurafenib: choices for oral or intravenous administration, reduced daily dose and frequency, and minimized inter-patient variability, among others. Therefore, the prodrugs described here have the potential to complement the clinic use of vemurafenib.
Citation Format: Ning Xi, Yingjun Zhang, Zhaohe Wang, Taoxi Lin, Qian Wang. Vemurafenib prodrugs suitable for oral and IV administration. [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 2532. doi:10.1158/1538-7445.AM2014-2532
Abstract 2541: Differential trafficking of dendritic cells after immunization determines establishment of systemic anti-tumor responses
Authors: Sato Noriko , Asiedu Kingsley , Choyke Peter L. 
Published: May 2015

Abstract
Systemic immune activation and memory cell generation is desired in dendritic cell (DC)-based therapies against cancers, especially with metastasis. Migration properties of DCs, however, could limit the responses regionally constrained. Clinically, DC-vaccines are often given subcutaneously (s.c.), intravenously (i.v.) or intradermally (i.d.), without monitoring the migration of DCs. In this study, we visualized trafficking of DCs labeled with In-111 oxine using a whole-body micro-SPECT imager after immunization via different routes and examined induction of immune activation and memory cell generation in mice. Bone marrow-derived DCs were used. Surprisingly, most of s.c. transferred DCs failed to migrate to the adjacent lymph nodes (LNs) and died at the injection site, irrespective of their maturation status. DCs injected i.v. were initially trapped in the lungs, but gradually migrated to the spleen, liver and, to a lesser extent, LNs. In contrast, DCs administered i.d. and intraperitoneally (i.p.) quickly entered lymphatic system and distributed to LNs. Proliferation of CMFDA labeled OT-1 CD8 T cells pre-transferred to mice receiving ovalbumin loaded DCs (OVA-DCs) indicated that i.v. and i.p. immunizations triggered stronger and more systemic expansion of effector T cells than s.c. and i.d. immunizations. To examine the establishment of long-term defense, we next immunized mice with OVA-DCs and challenged them with OVA-expressing tumors intramuscularly, contra-lateral to the s.c. and i.d. injection site. Intriguingly, i.v. immunization seemed less effective than the others in developing long-term antigen-specific immunity, despite its capability to induce an extensive acute responses. These results might suggest that difference in the microenvironment of organs where CD8 T cells encounter the antigen (i.e., spleen or LNs) controls the generation of long-lived memory cells. Collectively, immunization route would be a critical factor that determines the spatial distribution of immune activation and generation of functional memory cells in DC-based therapies.
Citation Format: Noriko Sato, Kingsley Asiedu, Peter L. Choyke. Differential trafficking of dendritic cells after immunization determines establishment of systemic anti-tumor responses. [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 2541. doi:10.1158/1538-7445.AM2014-2541
Abstract 2547: Peripheral immune signatures and survival in stage IV melanoma
Authors: Pawelec Graham P. , Martens Alexander , Garbe Claus , Weide Benjamin , Derhovanessian Evelyna , Schadendorf Dirk , Giacomo Anna Maria Di , Maio Michele , Vries Jolanda de , Zelba Henning 
Published: May 2015

Abstract
The presence of peripheral T-cells recognizing the melanoma-associated antigens NY-ESO-1 or Melan-A, as well as low frequencies of circulating CD14+ HLA-DR-/low myeloid-derived suppressor cells (MDSCs), is associated with prolonged survival in stage IV melanoma (n=94). In addition, the two of 12 patients with partial responses or stable disease in pilot studies of ipilimumab treatment both tended to have lower levels of MDSCs at baseline which decreased further on treatment. In contrast, two patients with progressive disease had high baseline MDSC levels, which increased further after treatment. These patients are being followed up to determine whether another mechanism of action of ipilimumab may be via an effect on MDSCs. A correlation was observed between the presence of antigen-reactive T cells and the frequency of MDSCs. Our results indicate that patients lacking antigen-reactive T cells had significantly higher levels of MDSCs. In addition, high frequencies of MDSCs correlated with lower frequencies of NY-ESO-1- and Melan-A-reactive T cells that also produced lower levels of IFN-gamma. NY-ESO-1 was recognized more frequently by CD4+ than by CD8+ T cells, whereas Melan-A more often stimulated CD8+ T cells. Possession of NY-ESO-1-reactive T cells conferred a survival advantage whether the response was mediated by CD4+ or CD8+ T cells or both. However, recognition of Melan-A by CD4+ T cells was associated with poorer clinical outcome even when the patient also possessed CD8+ reactive T cells. This negative effect was mediated by CD4+ T cells with a Th2- or Th17-type but not Th1-type cytokine response. Thus, tumor antigen-specificity and function of peripheral T cells and their interactions with MDSCs in advanced melanoma carries significant prognostic weight for predicting survival and may provide mechanistic insights into tumor immunosurveillance in such patients.
Citation Format: Graham P. Pawelec, Alexander Martens, Claus Garbe, Benjamin Weide, Evelyna Derhovanessian, Dirk Schadendorf, Anna Maria Di Giacomo, Michele Maio, Jolanda de Vries, Henning Zelba. Peripheral immune signatures and survival in stage IV melanoma. [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 2547. doi:10.1158/1538-7445.AM2014-2547
Abstract 2552: T cell apoptosis signaling biomarker of PD-1 engagement in cancer patients
Authors: Zhao Wei , Dong Haidong 
Published: May 2015

Abstract
Targeting membrane PD-1 molecules expressed by tumor-reactive T cells is gaining acceptance as a potentially effective anti-tumor immunotherapy. PD-1 blockade mediated by monoclonal antibodies has yielded promising therapeutic effects in treatment of melanoma, lung cancer and kidney cancers. Although detecting PD-1 expression by T cells is relatively straightforward, a simple and reliable method for determining whether PD-1 on T cells has engaged its ligand B7-H1 (PD-L1) is wanting. Our previous studies have revealed that engagement of PD-1 or B7-1 by B7-H1 results in alternations of apoptosis signaling pathway by up-regulating pro-apoptotic molecules among activated T cells and are correlated with B7-H1-mediated T cell death. Those observations suggest that intracellular levels of apoptosis-related Bcl2 family molecules among PD-1 positive CD8 T cells may be barometers of the extent to which PD-1 has been triggered by B7-H1. Using PD-1 and B7-H1 deficient animal models, we found that lower levels of intracellular pro-apoptosis molecules identify those activated T cells whose PD-1 molecules have not yet been extensively engaged, thus T cell function might be restored to their normal function once PD-1 signals from B7-H1 are blocked. Similarly, human PD-1 positive CD8 T cells engaged by B7-H1 also expressed higher levels of pro-apoptosis molecules during antigen stimulation. Our clinical data demonstrated that pro-apoptosis molecule expression by tumor-reactive T cell levels are higher among advanced melanoma and prostate cancers than healthy controls, reflecting chronic engagement with B7-H1. Thus, using pro-apoptosis status as signaling biomarkers for T cell PD-1 engagement, it may be possible to select patients who are most likely to have strong benefit from PD-1 or B7-H1 (PD-L1) blockade therapy.
Citation Format: Wei Zhao, Haidong Dong. T cell apoptosis signaling biomarker of PD-1 engagement in cancer patients. [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 2552. doi:10.1158/1538-7445.AM2014-2552
Abstract 2555: A cell based bioluminescent reporter assay for rapid measuring function of PD-1 or PD-L1 therapeutic antibodies
Authors: Cong Mei , Karassina Natasha , Cheng Jey , Fan Frank 
Published: May 2015

Abstract
Programmed death-1(PD-1) and its ligand (PD-L1) are important immunotherapy targets for cancer. PD-1 serves as a negative costimulatory receptor on various cell types, including T and B cells as well as myeloid-derived cells. Its ligand PD-L1 (B7-H1) is not expressed by normal epithelial tissues, but it is aberrantly expressed on a wide array of human cancers including melanoma, non-small cell lung carcinoma, breast cancer, pancreatic cancer, etc. Engagement of PD-1 by its ligands PD-L1 expressed on tumor cells associated with poorer prognosis by disabling the host antitumor response. The most recent investigational anti-PD-1 immunotherapy drugs such as nivolumab from BMS and lambrolizumab (MK-3475) from Merck have all demonstrated significant overall survival rate in patients with advanced melanoma.
Here we developed a cell based bioluminescent reporter assay that can be used for rapid quantifying function of PD-1 or PD-L1 therapeutic antibodies as measured by activation of NFAT signaling pathway. For this, Jurkat T-cell line stably expressing NFAT-luciferase reporter and human PD-1 was generated. Raji stably expressing human PD-L1 was generated as antigen presenting cells (APC). by co-cultivating the two cell lines in the present of CD3 and IgG, Raji cells fully activate Jurkat NFAT pathway via CD28 binding to CD80 (B7-1) and CD86 (B7-2) endogenously expressed on Raji cells. PD-1 signaling in Jurkat cells following engagement of PD-L1 ectopically expressed on Raji cells inhibits T cell function, and results in NFAT pathway inhibition. Blockade of PD-L1 using anti-PD-L1 mAb reversed NFAT pathway activation.
Citation Format: Mei Cong, Natasha Karassina, Jey Cheng, Frank Fan. A cell based bioluminescent reporter assay for rapid measuring function of PD-1 or PD-L1 therapeutic antibodies. [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 2555. doi:10.1158/1538-7445.AM2014-2555
Abstract 2566: Activation of tumor-initiated T cell priming and tumor destruction with potent STING-activating cyclic dinucleotide derivatives
Authors: Glickman Laura Hix , Kanne David B. , McWhirter Sarah M. , Leong Meredith L. , Lemmens Edward E. , Metchette Ken , Vance Russell E. , Pardoll Drew M. , Dubensky Thomas W. 
Published: May 2015

Abstract
Cyclic dinucleotides (CDNs) are bacterial messengers that are sensed by the host cytosolic surveillance pathway receptor, STING (Stimulator of Interferon Genes). CDN binding to STING initiates a TLR-independent signaling cascade through the TBK-1/IRF-3 axis, inducing type I interferon (IFN) and other co-regulated genes central to host innate defense. In response to binding cytosolic double-stranded DNA, a recently discovered mammalian enzyme, cyclic GMP-AMP synthase (cGAS), synthesizes CDNs that are structurally distinct from CDNs produced by bacteria. The mammalian CDN has a phosphate bridge with 2′-5′ and 3′-5′ linkages that increases its affinity for STING at least 10-fold. We show that mixed linkage (ML) CDNs were more potent activators of human PBMCs as compared to CDNs with canonical 3′-5′ phosphate linkages. Additionally, particular ML CDN derivatives with sulfur atoms at non-bridging oxygens of the internucleotide phosphate bridge were resistant to digestion by host cell phosphodiesterases, and R,R di-thio CDN diastereomers demonstrated increased potency in vitro and in vivo, as compared to either the R,S di-thio CDN diastereomer, or unmodified CDNs. Strikingly, direct injection of 2-week established flank B16 melanoma tumors with ML R,R dithio-CDN derivatives significantly and profoundly inhibited tumor growth, correlated with cytokine-mediated activation of NK and T lymphocytes, induction of antigen-specific T cell immunity and long-term survival. Anti-tumor efficacy was lost in mice encoding non-functional STING. Similar results were observed in other tumor models. These results demonstrate that CDNs have high translation potential for treatment strategies to induce activation of the tumor microenvironment, leading to effective tumor-initiated CD8+ T cell priming and anti-tumor efficacy.
Citation Format: Laura Hix Glickman, David B. Kanne, Sarah M. McWhirter, Meredith L. Leong, Edward E. Lemmens, Ken Metchette, Russell E. Vance, Drew M. Pardoll, Thomas W. Dubensky. Activation of tumor-initiated T cell priming and tumor destruction with potent STING-activating cyclic dinucleotide derivatives. [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 2566. doi:10.1158/1538-7445.AM2014-2566
Abstract 2568: Application of novel phospholipid conjugated Toll like receptor 7 ligands for cancer therapy by topical and systemic administration
Authors: Carson Dennis A. , Hayashi Tomoko , Crain Brian , Yao Shiyin , Cheng Jeffrey , Passini Nadia , Maj Roberto , Mura Emanuela , Cottam Howard , Holldack Johanna , Barberis Alcide 
Published: May 2015

Abstract
Introduction: Toll like receptor 7 (TLR7) activators are effective cancer immunotherapeutic drugs. However, the only clinically approved TLR7 ligand, imiquimod (IMQ), is absorbed into the systemic circulation inducing off-target adverse effects. To overcome this problem, we synthesized phospholipid-conjugated TLR7-specific activators. The objective of this project was to evaluate the safety and the anti-cancer activities of two TLR7 ligand-phospholipid conjugates, designated TMX-201 and TMX-202.
Procedures: In vitro immune activities of TLR7 agonists were compared in human and mouse leukocytes. Anti-malignant effects were evaluated using Inv-MycERTAM transgenic model of pre-malignant keratinocyte proliferation and murine models of 4T1 breast cancer and B16 melanoma.
Results: TMX-201 and TMX-202 were more potent cytokine inducers than IMQ in both mouse and human mononuclear cells. TMX-201 and TMX-202 showed less off-target binding compared to IMQ. The maximum tolerated doses of IMQ, TMX-201, and TMX-202 by i.v. administration were 15, 75 and 150 mg/kg, respectively. Topical administration of TMX-202 gel significantly reduced acanthosis in the Inv-mycERTAM model without inducing systemic cytokine production. Systemic administration of TMX-201 (4mg/kg) suppressed the growth of established subcutaneous B16 melanoma by 46%, without discernible adverse effects. Systemic or intra-tumor administration of TMX-201, in combination with anti-CTLA4 antibody, significantly suppressed lung metastasis formation in the 4T1 breast cancer model.
Conclusion: TMX-201 and TMX-202 displayed more potent immune stimulatory activity than IMQ with fewer off-target effects. These phospholipid-conjugated TLR7 agonists showed anti-cancer efficacy in three different mouse models. The new compounds may be useful topical and systemic therapeutic agents for cancer therapy, alone or in combination with checkpoint inhibitors.
Table 1.TMX-201 effect on lung metastases in the 4T1 breast cancer modelTreatmentMetastatic nodulesVehicle + isotype control33.5 ± 5.2TMX-20123.6 ± 4.9Anti-CTLA432.4 ± 13.6TMX-201 i.p. + anti-CTLA416 ± 2.7*TMX-201 i.t. + anti-CTLA413 ± 2.6**p&lt;0.05 vs vehicle+isotype control group
Citation Format: Dennis A. Carson, Tomoko Hayashi, Brian Crain, Shiyin Yao, Jeffrey Cheng, Nadia Passini, Roberto Maj, Emanuela Mura, Howard Cottam, Johanna Holldack, Alcide Barberis. Application of novel phospholipid conjugated Toll like receptor 7 ligands for cancer therapy by topical and systemic administration. [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 2568. doi:10.1158/1538-7445.AM2014-2568
Abstract 2572: CpG oligodeoxynucleotide enhances the efficacy of anticancer monoclonal antibody in an in vivo xenograft model using human endometrial cancer cell
Authors: Hiramatsu Kosuke , Serada Satoshi , Kobiyama Kouji , Morimoto Akiko , Kimura Toshihiro , Yoshino Kiyoshi , Fujimoto Minoru , Ishii Ken J. , Fujita Masami , Naka Tetsuji 
Published: May 2015

Abstract
Background: CpG oligodeoxynucleotides (ODN) has been shown to exhibit a potent immunostimulatory activity. Therefore, CpG ODN has been considered to be a promising material for enhancing the therapeutic effect of anticancer monoclonal antibody. We have previously identified bone marrow stromal antigen 2 (BST2) as a therapeutic target of endometrial cancer cells and also demonstrated that an anti-BST2 antibody showed a potent anti-tumor effect by antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against BST2 positive cells. The aim of this study was to evaluate the synergistic anti-tumor effect by combination of anti-BST-2 antibody and CpG ODN, and to clarify the mechanisms of its anti-tumor effect, using xenograft model of anti-BST2 positive endometrial cancer cells.
Material and Method: We implanted 7-8 week-old female SCID mice with 5×106 HEC-88 nu endometrial cancer cells subcutaneously. Mice with tumor were treated by intra-peritoneal injection of an anti-BST2 antibody alone (0 - 200 μg/mouse, twice a week for four weeks), intra-tumoral injection of CpG ODN alone (0 - 30 μg/mouse, twice a week for four weeks) or combination therapy (anti-BST2 antibody and CpG ODN). Anti-tumor effect was evaluated by monitoring the changes of tumor volume and also pathological analysis. In addition, activation of NK cells was evaluated.
Results: Intraperitoneal treatment of anti-BST2 antibody showed a significant anti-tumor effect, dose dependently. Similarly, intratumoral injection of CpG ODN showed a significant anti-tumor effect, in a dose dependent manner. Interestingly, the combination therapy was more effective than the single-agent therapy. In addition, the combination therapy also resulted in a high activity of NK cells.
Conclusion: We showed that CpG ODN increases the efficacy of anti-tumor effect of anti-BST2 antibody induced ADCC activity via potentiating NK cells mediated cancer cell injury. Combination of CpG ODN and anti-tumor monoclonal antibody is useful cancer therapy.
Citation Format: Kosuke Hiramatsu, Satoshi Serada, Kouji Kobiyama, Akiko Morimoto, Toshihiro Kimura, Kiyoshi Yoshino, Minoru Fujimoto, Ken J. Ishii, Masami Fujita, Tetsuji Naka. CpG oligodeoxynucleotide enhances the efficacy of anticancer monoclonal antibody in an in vivo xenograft model using human endometrial cancer cell. [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 2572. doi:10.1158/1538-7445.AM2014-2572
Abstract 2576: Polythymine oligonucleotides inhibit tumor growth through the induction of IFN alpha
Authors: Kobayashi Nobuaki , Shirota Hidekazu , Ichiki Yoko , Sakasai Kiyoshi , Ichikawa Yasushi , Kaneko Takeshi , Ishigatsubo Yoshiaki 
Published: May 2015

Abstract
IFNα is an immune-regulatory cytokine, used clinically for the treatment of various cancers. Administration of recombinant IFNα or IFNα-inducing agents in cancer patients induce the activation/expansion of NK cells and tumor-specific CTL responses, leading to tumor regression. Here, we find that the Polythymine (poly-T) oligonucleotides (ODN) induce the production of IFNα. Current results indicated the intratumoral injection of poly-T ODN could slow the growth of tumors and enhance the tumor specific CTLs. Our results shows a synthetic ODN containing Poly T motif have anti-tumor effect through the enhancement of IFNα production.
Citation Format: Nobuaki Kobayashi, Hidekazu Shirota, Yoko Ichiki, Kiyoshi Sakasai, Yasushi Ichikawa, Takeshi Kaneko, Yoshiaki Ishigatsubo. Polythymine oligonucleotides inhibit tumor growth through the induction of IFN alpha. [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 2576. doi:10.1158/1538-7445.AM2014-2576