bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2203: Targeting monoclonal antibodies to the tumor microenvironment for cancer immunotherapy
Authors: Hall Frederick L. , Chawla Sant P. , Chawla Neal S. , Gordon Erlinda M. 
Published: July 2016

Abstract
Therapeutic antibodies and immune checkpoint inhibitors can be delivered more efficiently to the tumor microenvironment (TME) by targeting the exposed collagenous (XC) proteins at the site/s of tumor invasion, stroma formation, and neoangiogenesis.Purpose: To assess the ability of bifunctional fusion polypepetides (mAb-Tropins) to selectively deliver monoclonal antibodies (mAbs) to the TME in tumor-bearing nude mice.Materials and Methods: Synthetic peptide probes and polypeptide aptamers (25-45 aa), fluorescein-labeled IgGs, and an anti-VEGF human mAb were tested in vitro in exposed collagen (XC)-agarose binding assays, in HUVEC cultures, and in vivo in a human xenograft model of pancreatic cancer in nude mice.Results: The XC-targeted mAb-Tropins, bound non-covalently to FITC-labeled IgGs [but not to truncated F(Ab’)2 fragments], exhibited selectivity for XC-agarose over control agarose matrices. Importantly, the biological activity of the XC/mAb-Tropin-bound anti-VEGF mAbs was fully preserved, as demonstrated by inhibition of endothelial cell proliferation in HUVEC cultures. In vivo, intense fluorescence was observed in tumors of mice injected with mAb-Tropin targeted IgGs at 15 and 60 minutes after intravenous injection, but not in non-targeted IgG-treated mice (see Figure below).Conclusions: Tumor XC-targeted mAb-Tropins are an effective method of delivering therapeutic mAbs precisely to the tumor compartments, with meaningful implications for cancer immunotherapy.
Figure
Figure Legend: The performance of mAb-Tropin 277 is evaluated in vitro in XC-binding assays and in vivo in a murine xenograft model of metastatic cancer. XC-agarose chromatography using mAb-Tropin 277 and FITC-IgGs, followed by stringent washing and analysis of column eluates and retentates (A,B), demonstrates aptamer-dependent binding of IgGs to XC-proteins (retentates), as well as depletion of the fluorescent IgGs from solution (column pass-through). The mAb-Tropin 277 dependent targeting of fluorescent IgGs (via the systemic circulation) to tumors is demonstrated in a murine metastatic cancer model (C). Taken together with the in vitro binding data—which showed that the bifunctional mAb-targeting onco-aptamers efficiently sequester IgGs (A) and concentrate the bound IgGs on collagen matrices (B)—this in vivo data indicates that mAb-Tropins concentrate and compartmentalize IgGs/mAbs within the TME (C).
Citation Format: Frederick L. Hall, Sant P. Chawla, Neal S. Chawla, Erlinda M. Gordon. Targeting monoclonal antibodies to the tumor microenvironment for cancer immunotherapy. [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 2203.
Abstract 2205: Exosomal encapsulation of doxorubicin reduces the cardiac toxicity of mice
Authors: Rizzolio Flavio , Hadla Mohamad , Corona Giuseppe , Caligiuri Isabella , Palazzolo Stefano , Semeraro Sabrina , Gamini Amelia , Canzonieri Vincenzo , Toffoli Giuseppe 
Published: July 2016

Abstract
Exosomes are nanovesicles produced by cells embedded of cellular information and represent a formidable natural cargo for communication. The name “FedExosomes” denotes the general idea that exosomes could deliver cargo that conveniently manipulated could be of help for patient therapy. Up to now, a few papers demonstrated that modified exosomes could deliver drugs specifically to cancer cells and many laboratories are now studying their properties and compositions. Differently from previously published papers that focused on the efficacy of the doxorubicin encapsulated in exosomes (exoDOX), for the first time, we demonstrated that unmodified exosomes loaded with DOX are less toxic than free DOX by altering the biodistribution of the drug. The heart tissue of mice treated with a toxic dosage of DOX exhibited scattered cytoplasmic paranuclear vacuoles and focal intense eosinophilic cytoplasm, devoid of their transversal striations with moderate disarrangement of cardiomyocytes. The heart tissue of exoDOX treated mice at the same dosage appeared normal. Mass spectrometry studies confirmed that although the quantity of exoDOX in the blood was the same compared to DOX, accumulation in the heart was reduced of about forty percent. Maximum tolerated dose of exoDOX treated mice is double than free DOX. Mice treated at double concentration of exoDOX vs DOX have reduced tumor burden compared to free DOX without observable toxicity.
We demonstrated that exoDOX increased the therapeutic index of DOX by reducing toxic side effects and envisage a similar mechanism for others chemotherapeutic drugs. Since the exosomes could be prepared directly from the patients, our preclinical approach could have a possible immediately application in the clinic.
Citation Format: Flavio Rizzolio, Mohamad Hadla, Giuseppe Corona, Isabella Caligiuri, Stefano Palazzolo, Sabrina Semeraro, Amelia Gamini, Vincenzo Canzonieri, Giuseppe Toffoli. Exosomal encapsulation of doxorubicin reduces the cardiac toxicity of mice. [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 2205.
Abstract 2206: Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer
Authors: Wehbe Moe , Anantha Malathi , Backstrom Ian , Malhotra Armaan , Edwards Katarina , Bally Marcel 
Published: July 2016

Abstract
Clioquinol is an FDA approved antifungal and antiprotozoal drug that has recently garnered attention for its anti-cancer activities. In vitro studies with CQ activity suggest that its mechanism of activity may be dependent its ability to bind and transport copper. CQ binds copper to form a stable dimeric complex (2 mol CQ:1 mol Cu ((CuCQ2)). Although therapeutically interesting, CuCQ2 is virtually insoluble in aqueous solutions and therefore it has been difficult to develop formulations suitable for administration. To address this, a liposomal CuCQ2 formulation was developed and characterized for maximum tolerated dose, pharmacokinetics and efficacy in xenograft models. Liposomes (∼100nm) composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio) were prepared to contain 300 mM CuSO4. CQ is added to the outside of these pre-formed liposomes; at the appropriate incubation temperature CQ crosses the liposomal membrane where it can interact with the encapsulated Cu to form the insoluble CuCQ2 complex which becomes trapped. The maximum tolerated dose of the resultant formulation was determined in CD-1 mice. The pharmacokinetics of the formulation (liposomal lipid, CQ and Cu) were measured following intravenous administration at a well tolerated dose. Efficacy was measured in two cancer models (sc U251 glioblastoma and i.p A2780 ovarian). The maximum tolerated dose of liposomal CuCQ2 was 30 mg/kg when administered i.v (q2d for two weeks) and 15 mg/kg when administered i.p (QD for two weeks). Pharmacokinetics studies with liposomalCuCQ2 administered iv at 30 mg/kg indicated an terminal elimination half-life (t1/2) of 5.4 hr and an AUC of 994 ug•hr/mL. Results demonstrate that the CuCQ2 complex remains intact upon injection. When used to treat animals bearing established sc U251 glioblastoma tumors showed 30% smaller tumours than those treated with vehicle alone. The activity of liposomal CuCQ2 in the A2780 intraperitoneal cancer model will be presented. This work describes, for the first time, a novel injectable formulation of CuCQ2; this formulation is active against established xenograft models. The activity of this formulation will now be assessed in the context of copper-dependent inhibition of NFκB signalling.
Citation Format: Moe Wehbe, Malathi Anantha, Ian Backstrom, Armaan Malhotra, Katarina Edwards, Marcel Bally. Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer. [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 2206.
Abstract 2210: Multiple antigens stimulating cellular therapy increases immune responses in patients with hepatocellular carcinoma
Authors: Han Yanyan , Huang Jing , Tao Ran , Guo Yabing , Liu Li , Wu Dongyun , Li Jin , Zhou Xiangjun , Hou Jinlin 
Published: July 2016

Abstract
Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common tumors in China, and frequently occurs in the patients with chronic hepatitis B virus (HBV) infection. To investigate whether adoptive cell therapy induces tumor specific immune responses in HCC patients and further brings clinical benefits, Multiple Antigens Stimulating Cellular Therapy (MASCT) was applied in addition to conventional therapies.
Methods: Activated T cells that were prepared from the autologous peripheral blood mononuclear cells (PBMCs). Cells were stimulated and amplified with dendritic cells (DCs) pulsed by multiple tumor antigen peptides, including tumor associated antigen peptides and HBV antigen peptides. All patients received infusions of 5-10×107cells/kg of body weight of the resulting T cells every 1-3 months. The immune responses in the patients' PBMCs were examined before and after the treatment.
Results: The resulting amplified cells were almost exclusively CD3+ (95% ± 1%), with a major percentage being CD3+CD8+ cells (70% ± 5%) and a minor proportion being CD3+CD4+(19% ± 3%) and CD3+CD56+ (14% ± 1%) cells, while there were insignificant amounts of CD4+CD25+Foxp3+ regulatory T cells (0.4% ± 0.1%). These T cells have restored immune functions and HLA-restricted specific cytotoxicity against HCC cells. After repeating treatment of MASCT, the frequency of regulatory T cells in the patients’ PBMCs was significantly decreased, and the proliferation and function of tumor antigen specific T cells were enhanced. The specific immune responses against each kind of tumor antigens were also detected in patients. And these immune responses were gradually increased during the treatment of MASCT. Moreover, in retrospective study, the disease control rate (DCR) in one year was found to be raised to 80% in stage B HCC patients receiving MASCT combined with conventional therapies.
Conclusions: Our study has demonstrated that MASCT is a well tolerate immunotherapy in patients with HCC. Specific T cell responses against tumor antigens can be strongly induced in vivo. Our study also indicated that repeated MASCT treatment improves both the immunologic function and disease control of patients with HCC.
Citation Format: Yanyan Han, Jing Huang, Ran Tao, Yabing Guo, Li Liu, Dongyun Wu, Jin Li, Xiangjun Zhou, Jinlin Hou. Multiple antigens stimulating cellular therapy increases immune responses in patients with hepatocellular carcinoma. [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 2210.
Abstract 2223: Membranous expression of programmed cell death-ligand 1 (PDL1) on cancer cells is induced by cisplatin in an ATR dependent manner
Authors: Schaaf Lea , Dong Meng , Heine Simon , van der Kuip Heiko , Aulitzky Walter E. 
Published: July 2016

Abstract
Cancer cells frequently develop strategies allowing to escape potential immune attacks by the host. One central component of this defense mechanism is the PDL1-PD1 axis with PDL1 expression on the surface of antigen presenting cells. DNA damaging chemotherapeutic are known to have suppressive effect on the immune system. Possible effects on immune checkpoints, however, are poorly understood. We investigated if Cisplatin, a widely used chemotherapeutic for treatment of ovarian and lung carcinomas, might influence expression of PDL1 on cancer cells of these pathologies. Treatment of cell lines as well as precision-cut tissue slices from patient tumors with clinically relevant dosages of cisplatin led to a significant induction of PDL1 protein in cancer cells as revealed by Western Blot and IHC analyses. This effect was independent on ATR or ATM activity since pre-treatment with ATR or ATM inhibitors had no significant effect on cisplatin induced total PDL1 protein levels. Interestingly, however, we observed an almost complete inhibition of cisplatin-induced membranous PDL1 upon ATR but not ATM inhibition as revealed by FACS analysis in unfixed cells. The role of the ATR axis was further corroborated by the finding that presentation of PDL1 at the cell surface was paralleled by phosphorylation of CHK1.
Together our data indicate an important role of DNA damage induced ATR/CHK1 activity on the localization of PDL1 at the surface of cancer cells. These data implicate that combination of cisplatin with either anti-PD1 or anti-PDL1 antibodies or ATR/CHK1 inhibitors should reduce immunosuppressive mechanisms and enhance chemotherapy efficacy.
Citation Format: Lea Schaaf, Meng Dong, Simon Heine, Heiko van der Kuip, Walter E. Aulitzky. Membranous expression of programmed cell death-ligand 1 (PDL1) on cancer cells is induced by cisplatin in an ATR dependent manner. [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 2223.
Abstract 2224: Discovery, development and characterization of a new class of therapeutic anti-PD-1 antibody
Authors: Wang Lei , Amirina Najmia , Scheuplein Fellix , Spaulding Vikki , Wang Yanyan , Vadde Sri , Chiu M. Isabel , Doty Daniel , McQuade Thomas , Feng Bin , Ranganath Sheila , Nguyen. Anhco “Cokey” 
Published: July 2016

Abstract
Blockade of immune checkpoint (IC), such as PD-1, confers durable clinical benefit to a minority of melanoma and lung cancer patients. Challengingly, the 5-year survival rate is still below 30% in those patients, and most other solid tumors are not particularly responsive to immunotherapy. Therefore, more IC blocking mAbs are under development to meet clinical needs. Using Enumeral's unique single cell immunoprofiling platform, we developed a novel class of anti-PD-1 antibodies, named 244C8, with distinct epitope binding site than currently marketed anti-PD-1 antibodies. To evaluate the function of 244C8 on anti-tumor immunity, we employed ex vivo methods to determine responsiveness of tumor infiltrating lymphocytes (TILs), isolated from human lung cancer biopsies, to various anti-PD-1 antibodies, including our lead anti-PD1 therapeutic candidate 244C8. The results show that all anti-PD-1 antibodies tested reversed T cell exhaustion in tumor microenvironment. Further, 244C8-treated cells produced increased IFN-y compared to nivolumab, indicating a stronger anti-tumor immunity. In the settings of mixed lymphocyte reaction (MLR) and CMV antigen-recall assays, 244C8 treatment also led to higher levels of T cell activation compared to conventional anti-PD-1 antibodies. Interestingly, in both ex vivo and in vitro models, we observed a pattern of cytokine production in 244C8-treated cells that is consistently distinct from that produced by conventional/marketed anti-PD-1 antibodies, suggesting a differentiated mechanism of action.
Citation Format: Lei Wang, Najmia Amirina, Fellix Scheuplein, Vikki Spaulding, Yanyan Wang, Sri Vadde, M. Isabel Chiu, Daniel Doty, Thomas McQuade, Bin Feng, Sheila Ranganath, Anhco “Cokey” Nguyen. Discovery, development and characterization of a new class of therapeutic anti-PD-1 antibody. [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 2224.
Abstract 2229: PD-L1 is expressed on CD11bhighCD14highHLA-DR+ myeloid cells in the tumor microenvironment of non-small cell lung cancer (NSCLC)
Authors: Sonn Chung-Hee , Oh Yunji , Kim Tae Eun , Ha Jung Sun , Kim Hong Kwan , Cho Jong Ho , Shin Sumin , Kim Jhingook 
Published: July 2016

Abstract
Understanding the immune system of cancer patients is essential for the development of optimal treatment. We analyzed tumor cells and infiltrating immune cells in tumor tissues of NSCLC to determine the type of cells which expressed immune checkpoint molecules and/or their ligands, and compared them to clinicopathological characteristics. To obtain a single cell suspension from the tumor tissues of lung cancer patients, each fresh tumor sample was chopped and treated with collagenase and DNase. The dissociated tumor tissue cells (DTCs) were stained with fluorochrome-labeled mAbs and the distribution of immune cell components and expression of surface markers in DTCs were determined by FACSuite analysis. The yield of DTCs was 5.87±4.73×10⁁7/gram. PD-L1, which is a ligand for immune checkpoint molecule PD-1, is expressed on CD11bhigh myeloid cells in the blood, regardless of HLA-DR expression. On the other hand, PD-L1 is expressed on CD11highCD14highSSClow myeloid cells in the tumor site. All PD-L1 expressing cells were positive for HLA-DR, a ligand for a T cell receptor of CD4 T cells. Furthermore, these cells also expressed both CD86 and CD124. Interestingly, most tumor cells expressed very low levels of the PD-L1 molecule. And we found that CD11highCD14+HLA-DR- myeloid cells did not express PD-L1. The proportion of CD11highCD14+HLA-DR-PD-L1- myeloid cells was higher in advanced stage patients than early stage patients. In conclusion, PD-L1 is expressed on CD11bhighCD14highHLA-DR+SSClow myeloid cells, but not CD11bhighCD14+HLA-DR- myeloid cells. We propose that the PD-L1+ myeloid cells are likely to play an important role in tumor immunity. Further functional studies will be necessary to determine how the interaction between the cells will affect immunity. code noagegendersmokingstagecell typePD-L1+HLA-DR+CD14highCD11bhigh cells (%)PD-L1-HLA-DR-CD14+CD11bhi cells (%)L-03257maleyesIAmucinous adenocarcinoma39.81.2L-05281maleyesIAadenocarcinoma19.44.1L-04849maleyesIIIAsquamous cell carcinoma4.09.0L-02471maleyesIIIAadenocarcinoma11.20.4L-03665maleyesIVadenocarcinoma11.45.3L-04273maleyesIVadenocarcinoma21.65.5L-04674malenoIAadenocarcinoma6.11.6L-02167femalenoIBlarge cell, adenocarcinoma14.72.3L-01976femalenoIBadenocarcinoma15.816.7L-27145femalenoIVadenocarcinoma11.217.2L-27245femalenoIVadenocarcinoma9.924.8
Citation Format: Chung-Hee Sonn, Yunji Oh, Tae Eun Kim, Jung Sun Ha, Hong Kwan Kim, Jong Ho Cho, Sumin Shin, Jhingook Kim. PD-L1 is expressed on CD11bhighCD14highHLA-DR+ myeloid cells in the tumor microenvironment of non-small cell lung cancer (NSCLC). [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 2229.
Abstract 2234: Exploring the oncolytic potential of Newcastle Disease Virus
Authors: Harper James A. , Travers Jon , Franks Ruth , Burke Shannon , Navarro Christel , Xing Cheng , Wang Weijia , Xu Qi , Wilkinson Robert W. , Jin Hong , Carroll Danielle 
Published: July 2016

Abstract
Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell death occurs as a natural consequence of the viral life cycle and newly produced virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of potentially producing novel tumour antigens that can induce an immune-mediated therapeutic response.
Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of mammalian cancers in PhI clinical studies. Using reverse genetics, we generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. We have additionally inserted the GM-CSF gene in order to maximize anti-tumour immune response and provide an in situ, patient/tumour- specific vaccine, combined with potent oncolysis. We have evaluated the biological characteristics of recNDVGM-CSF in vivo and in vitro. In vitro recNDVGM-CSF selectively replicates in and kills a wide variety of tumour cell types. In vivo, using a fibrosarcoma model that supports viral replication, a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. Additionally, following IV administration recNDVGM-CSF localises to and replicates within the tumour leading to a localised GM-CSF production within the tumour. The inherent properties of NDV (self-propagation, tumour-selective replication, immune activation) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients.
Citation Format: James A. Harper, Jon Travers, Ruth Franks, Shannon Burke, Christel Navarro, Cheng Xing, Weijia Wang, Qi Xu, Robert W. Wilkinson, Hong Jin, Danielle Carroll. Exploring the oncolytic potential of Newcastle Disease Virus. [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 2234.
Abstract 2236: Long lasting CR status of stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine (AFTV)
Authors: Kuranishi Fumito , Sumi Yusuke , Uemae yoij , Ohno Tadao 
Published: July 2016

Abstract
(INTRODUCTION) The prognosis of advanced (stage IV) cancer is very poor. However, we have already reported two cases of eradication of advanced breast cancer with bone metastasis (AACR 2013 and AACR 2015) after combined treatments including AFTV. We here additionally report successful cases of gall bladder cancer (stage IV, liver metastasis) and colon cancer (stage IV, lung metastasis).
(CASE 1) A 61-year-old female with stage IV gall bladder cancer (T3N1M1: liver metastasis) was operated in May 2011 including partial resection of liver. She was treated with, as the first-line adjuvant therapy, AFTV followed with conventional chemotherapy. This patient is still alive without any recurrence confirmed by CT etc.
(CASE 2) A 60 year-old male with stage IV (N3, H0, P1, M1: lung, lt. adrenal gland, abdominal wall) was operated in August 2009. Then conventional chemotherapy, 2 courses of AFTV and radiation were applied sequentially. No recurrence was observed for more than 5 years.
(DISCUSSION) We diagnosed both patients staying at long lasting complete remission. The prognoses of stage IV gall bladder cancer and abdominal wall-metastasized colon cancer are very poor despite of conventional treatments. Adverse effects of AFTV were less than grade 2, therefore combination therapies including AFTV are worth to consider, although larger scale clinical trial is essential.
Citation Format: Fumito Kuranishi, Yusuke Sumi, yoij Uemae, Tadao Ohno. Long lasting CR status of stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine (AFTV). [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 2236.