bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3499: CD56 targeted chimeric antigen receptors for immunotherapy of multiple myeloma
Authors: Benjamin Reuben , Condomines Maud , Gunset Gertrude , Sadelain Michel 
Published: August 2012

Abstract
We have developed an adoptive T cell therapy strategy for treating multiple myeloma using chimeric antigen receptors targeting CD56. CD56 is strongly expressed by malignant plasma cells in 70% of patients with myeloma and represents a potential immunotherapy target. CD56 is also expressed at lower levels on normal tissue types including neuronal cells, NK cells and a subset of activated T cells. A second generation CAR was constructed containing the scFv of the murine monoclonal antibody against human CD56 (N901) as well as the CD28 transmembrane and cytoplasmic signaling domains. CD56 CAR cells were generated by retroviral transduction of human T cells and showed antigen dependent proliferation and cytokine secretion in vitro when stimulated with CD56 positive myeloma cells. In vitro cytotoxicity assays showed significant lysis (40-50% lysis at effector to target ratios &gt; 5:1) of CD56 positive myeloma cell lines compared with a control prostate specific membrane antigen (PSMA) targeted CAR. To further assess the antitumor activity of CD56 CARs in vivo we developed a systemic xenograft model of myeloma by injecting the OPM2 myeloma cell line, modified to express the firefly luciferase gene, intravenously into NOD/SCID Il2rαnull mice. Bioluminescence imaging showed tumor progression predominantly within the bone marrow recapitulating the human disease phenotype. If untreated hind limb paralysis occurred at approximately 35 days following injection of 3x106 tumor cells. Cohorts of mice were then treated by intravenous injection of either 1 or 5 x106 CD56 CAR cells or control PSMA CAR cells at 7 days following tumor injection, when disease was firmly established. At the 1x106 T cell dose tumor development was significantly delayed compared to controls (median survival of 49 days compared with 34 days respectively, p=0.02) but 7/8 mice eventually progressed and had to be euthanised. In contrast all mice receiving 5x106 cells (n=8) showed complete tumor regression and remained tumor free at 3 months. Interferon-α secreting CD56 CAR cells were detected in the peripheral blood of these mice and correlated with tumor bulk with numbers eventually declining to low levels that persisted even at 3 months. These results demonstrate for the first time the impressive anti-tumor efficacy of a CD56 targeted chimeric antigen receptor in a systemic xenograft model of myeloma. CD56 CAR therapy therefore represents an attractive immunotherapy option and its use in patients with relapsed refractory myeloma should be considered.
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 3499. doi:1538-7445.AM2012-3499
Abstract 3501: Binary control of CAR-CTL by transgenic IL-7 and IL-7R expression
Authors: Bajgain Pradip , Mucharla Roopa , Heslop Helen E. , Vera Juan F. 
Published: August 2012

Abstract
While adoptive transfer of cytotoxic T lymphocytes (CTLs) engrafted with chimeric antigen receptors (CAR) has produced objective clinical responses in vivo, the infused cells usually fail to persist long-term, limiting benefit. We have recently demonstrated that CTL persistence can be improved by engineering cells to express the IL-7 receptor alpha chain (IL-7R) which is physiologically absent on CTLs. However, this approach requires access to clinical grade cytokine and biodistribution to T lymphocytes at tumor sites may be insufficient. To circumvent these problems we have prepared two CTL products: one expressing a tumor-specific CAR in combination with IL-7R (product #1), and the second engineered to co-express the same CAR and produce IL-7 cytokine (product #2). In this way, both products have anti-tumor activity mediated through the CAR, while cytokine produced from CTL#2 should support the survival and persistence of the IL-7R-expressing CTL#1. A binary system such as this should be intrinsically safer than incorporating a positive feedback loop of both cytokine and receptor in a single cell. As a proof of this principle, we used the SFG-CAR that targets the ≤ light chain expressed on B cell malignancies: SFG-CAR/IL-7R-GFP(#1) and SFG-CAR/IL-7cyto-mOrange(#2). EBV-CTLs from 3 donors were transduced with each vector. FACS analysis of transgene expression indicated that all were expressed at approximately equivalent levels: CTL#1 (CAR, IL-7Rα, and GFP; 58%±15, 53%±18, 57.8%±12) and CTL#2 (CAR and mOrange; 54%±18 and 52%±20). The modified CTL were functional, and cells transduced with either vector were able to kill the α+ B cell tumors Daudi as evaluated by Cr51 assay (72%±13 and 69%±25, respectively) at an R:S of 40:1. Preliminary data indicates that CTLs#1 were able to proliferate in response to exogenous IL-7 administration, and IL-7 cytokine production from CTLs#2 was directly proportional to the antigenic stimulation provided to the cells. In addition, when CTLs#1 and #2 were cultured together we observed that CTLs#2 were capable of promoting the expansion of their CTL counterpart in a more efficient way than that compared to exogenous administration of IL-7 or IL-2. These results indicate that binary control of CAR modified CTLs is possible through transgenic expression of IL-7R and IL-7 cytokine in two different CTL populations.
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 3501. doi:1538-7445.AM2012-3501
Abstract 3513: The anti-tumor effect of activated natural killer cells in xenograft mouse models with epithelial ovarian cancer
Authors: Young Mo Jin , Kyoung-jin Lee , Yoo-Kyeong Whang , Shin-Wha Lee , Yong-Man Kim , Dae-Yeon Kim , Jong-Hyeok Kim , Joo-Hyun Nam , Young-Tak Kim 
Published: August 2012

Abstract
Objectives: Ovarian cancer is the most common cause of death from gynecologic cancer in women. Because of the lack of effective screening and warning sign, 60-70% of patients were diagnosed at advanced stage. At present the treatment of advanced ovarian cancer is cytoreductive surgery followed by chemotherapy, and the overall response rate is 70-80%. But 50-75% of responders will relapse within about 18 -24 months. Therefore, new strategies of treatment, for examples, immunotherapy or targeted therapy, are necessary. This study is to evaluate the anti-tumor effect of activated natural killer (NK) cells in xenograft mouse model with epithelial ovarian cancer(EOC). Methods: We have made the OVCAR3-Luc stable cell line by transient transfection of pGL3-Luciferase (G418) gene. The xenograft mouse model of EOC was constructed by the intra-peritoneal injection of OVCAR3-Luc ovarian cancer cell line to the NOD/scid mice. After we confirm the tumor formation with IVIS spectrum, activated NK cells were injected with intra-peritoneal route. There was no treatment to the negative control and paclitaxel (10mg/kg) was used to the positive control. The tumor growth was evaluated by serial IVIS spectrum and biopsy at 8 weeks after any treatment. Results: Activated NK cells were injected at concentration 1 × 107 cells per mouse with intra-peritoneal route. This procedure was repeated 5 times. The NK cells significantly inhibited the tumor growth of OVCAR3-Luc-induced NOD/scid mice, up to the 57.1% comparing the negative control. Although paclitaxel decrease 69.3% of the tumor growth, it is not different to that of NK cell treating mice. Furthermore, side effects involving hair loss, abnormal behavior and weight low were not shown in NK cell-injected mouse models. Conclusion: We confirmed that activated NK cells are able to inhibit ovarian tumor growth without side effect in xenograft models. Therefore, this research demonstrates that NK cell-based immunotherapy might be desirable to the patients with ovarian cancer as an adoptive immunotherapy.
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 3513. doi:1538-7445.AM2012-3513
Abstract 3585: Second primary tumors after breast cancer: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) study
Authors: Ricceri Fulvio , Sacerdote Carlotta , Critelli Rossana ,   EPIC investigators, Vineis Paolo , Riboli Elio 
Published: August 2012

Abstract
During the last decades, improvements in medical and surgical treatments have substantially increased the chances of surviving from a cancer. Cancer survivors now amount to more than 3.5% of population in the US, and about 3% in Western Europe. Cancer survivors face the problem of subsequent cancers possibly related to the late effects of treatments or to a common aetiology for the first and subsequent cancers. Cancer patients have a 20% higher risk of new primary cancer compared with the general population. Approximately one third of cancer survivors aged &gt;60 years were diagnosed more than once with another cancer. Women with breast cancer as first primary cancer were the first largest group of multiple cancer prevalence reported in the United States in 2002, while the second and third groups were men and women with a diagnosis of primary colorectal cancer and men with prostate cancer, respectively. Multiple cancers arise in the same individual due to several causes: host factors, such as hormonal and/or genetic factors, lifestyle and environment, and treatments due to the first cancer (for example, radiotherapy) The aim of this study is to assess the incidence of second primary tumors in a cohort of women with a first breast cancer and to investigate the role of shared risk factors. The study was performed in the cohort of women with a primary breast cancer from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. To correctly assess the incidence of second primary tumors, we applied a Markov model studying the transition intensities from first to second tumor with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In the cohort of 11045 women, we observed 492 second primary tumors (not metachronous) after a median follow-up of 4.92 years. About 30% (140) of them were second primary breast cancers, 65 were colorectal cancers and 39 were endometrial cancers. In this cohort, there was a slight, not statistically significant increase of cancer incidence in women with breast cancer, compared to the general population; this was for all tumors together, except non-melanoma skin cancers. Analysis by subgroups identified a significant increase for second breast cancers and for endometrial cancers. Our findings suggest that second primaries may be an important problem for cancer survivors. We will now investigate the role played by lifestyle factors, genetics and possibly therapies in second primary occurrence.
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 3585. doi:1538-7445.AM2012-3585
Abstract 3620: A multiplex quantitative immunofluorescence assay for DNA damage repair in response to cytotoxic treatment
Authors: Marrero Allison M. , Lawrence Scott M. , Balasubramanian Priya , Pommier Yves G. , Tomaszewski Joseph E. , Parchment Ralph E. , Doroshow James H. , Kinders Robert J. 
Published: August 2012

Abstract
The use of DNA damaging agents remains one of the most common approaches to cancer therapy. The type of damage caused by the agent will determine which of the five main DNA damage repair (DDR) processes will respond. Initially we are developing multiplex quantitative immunoflourescence assays (qIFAs) for biomarkers of active Homologous Recombination (HR) and Nucleotide Excision Repair (NER) pathway and plan to develop mutiplex assays for the other repair pathways in the near future. The first multiplex panel to quantify DDR response has been developed to include Nbs1 phosphorylated at Serine343 and γH2AX, both early markers of DNA double strand breaks as well as ERCC1, which plays a key role in NER. Quantitation of repair pathway activation after drug treatment builds upon our validated qIFA for γH2AX, which scores individual nuclei as positive or negative for the biomarker and quantifies the γH2AX response as the fraction of nuclear area that is occupied by γH2AX foci. In contrast, the multiplex qIFA was designed to quantify the global DNA repair protein response to a variety of cytotoxic, genotoxic and targeted agents administered singly and in combination. Initial evaluations were performed in vitro on a panel of cell lines, characterized for repair pathway defects: the BRCA1-null human ovarian cancer line UWB1.289 (ATCC# CRL-2945), its isogenic line with restored BRCA1 named UWB1.289+BRCA1 (ATCC# CRL-2946), and SKOV3 (BRCA1 WT). Both gemcitabine and cisplatin increased pNbs1 both in UWB1.289 and UWB1.289+BRCA1, but not in SKOV3. Co-expression of pNbs1 with γH2AX was observed but was not 100% concordant. Combination treatment with a topoisomerase 1 inhibitor and PARP1/2 inhibitor (the indenoisoquinoline NSC 724998 with ABT-888) increased nuclear ERCC1 only in UWB1.289, but not in the isogenic UWB1.289+BRCA1 line, or in the ovarian lines SKOV3 and IGROV1, or the human fibroblast line GM00637. Assessment of drug-induced DDR response in a panel of cell lines with known repair defects is planned with the expectation that this will provide a scientific foundation for interpreting qIFA results when the assay is used to analyze clinical biopsies, and will assist in the evaluation of combination therapy strategies, such as synthetic lethality, designed to take advantage of DNA repair defects. Funded by NCI Contract No. HHSN261200800001E.
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 3620. doi:1538-7445.AM2012-3620
Abstract 3664: Breast cancer companion diagnostic platform based on objectively defined tumor co-expression patterns stratifies multiple clinical and therapeutic endpoints comparison to existing molecular subtyping definitions
Authors: Rhodes Daniel R. , Tomlins Scott , Thomas Dafydd G. , Williams Paul , Wyngaard Peter , Sadis Seth , Oades Kahuku , Vo Lien , Chattopadhyay Sukla , Wang Yipeng , Lee Byung-In , Monforte Joseph 
Published: August 2012

Abstract
Gene expression profiles of human breast tumors have greatly expanded our understanding of the genes and pathways that underlie breast cancer. Profiling studies have also supported a molecular classification of breast cancer. The resulting molecular subtypes Luminal, Basal-like, ERBB2+, and Normal-like were shown to have different prognostic and predictive characteristics. Related studies have led to a proliferation of multigene prognostic and predictive diagnostic tests. Two independent multigene tests, OncoType Dx and MammaPrint, have been shown to be helpful in predicting the risk of recurrence of patients with early stage breast cancer. Current multigene tests consistently prioritize the proliferation, estrogen receptor (ER), and ERBB2 pathways. An alternative approach to identifying key molecular variables within breast cancer is based on a definition of objectively defined tumor co-expression patterns. To this end, we defined co-expression patterns within 56 independent breast cancer molecular profiling datasets representing &gt;5,000 unique patients. We then performed a meta-analysis across datasets to define the most robust, consistently occurring co-expression patterns. These patterns, termed modules, recapitulate the proliferation, ER, and ERBB2 pathways, but also monitor expression of other important variables including core cancer cell growth pathways, immune signaling and microenvironment, and hallmark genomic aberrations. An important feature of co-expression patterns is that a small number of genes serve as an effective surrogate for each module. Thus, we created a single multigene qPCR test that measures the expression of 18 distinct breast cancer modules and validated the test for use with formalin-fixed paraffin-embedded (FFPE) tumor samples. In retrospective microarray scoring analyses with key clinical datasets, and with analysis of FFPE specimens from breast cancer cohorts, we demonstrate that breast cancer modules can be used to recapitulate the molecular subtypes of breast cancer and to have prognostic and predictive properties similar to the current multigene tests. Because they recapitulate existing molecular tests, while also reading out many additional axes of molecular variability, breast cancer modules provide a universal assay with broad application to companion diagnostics development.
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 3664. doi:1538-7445.AM2012-3664
Abstract 3745: The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKcs-mediated DNA damage responses
Authors: Mukherjee Bipasha , Tomimatsu Nozomi , Amancherla Kaushik , Camacho Cristel , Burma Sandeep 
Published: August 2012

Abstract
Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy due to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent inhibitor of PI3K/Akt signaling that is currently in phase I/II clinical trials. BEZ235 is reported to specifically inhibit PI3Ks and mTOR with little effect on other kinases. However, we find that BEZ235 also potently inhibits the two major kinases responding to DNA double-strand breaks (DSBs), ATM and DNA-PKcs, both in vitro and in vivo. Consequently, BEZ235 blocks both non-homologous end joining (NHEJ) and homologous recombination (HR) DNA repair pathways, resulting in significant attenuation of DSB repair. Additionally, phosphorylation of ATM targets and implementation of the G2/M cell cycle checkpoint are also attenuated by this drug. The consequence is profound radiosensitization at very low concentrations (100 nM) of BEZ235. This radiosensitizing effect is significantly more potent than that seen with much higher concentrations (10 μm) of inhibitors of DNA-PKcs or ATM that are currently being optimized for clinical testing. Since radiotherapy is the standard of care for GBM, we investigated the potential utility of BEZ235 as a radiosensitizing agent in a panel of GBM lines. We find that BEZ235 treatment confers an extreme degree of radiosensitization and significantly attenuates DSB repair irrespective of Akt activation status in these lines. Finally, we show that BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug in vivo. Our results, showing that BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential clinical utility of BEZ235 as an effective radiosensitizer.
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 3745. doi:1538-7445.AM2012-3745
Abstract 3752: Nanoparticles delivery of a novel AKT/PDK1 inhibitor inhibits pancreatic cancer tumor growth
Authors: Meuillet Emmanuelle J. , Moses Sylvestor A. , Lucero-Acuna Armando , Guzman Roberto , Jeffrey Justin , Pagel Mary 
Published: August 2012

Abstract
AKT (protein kinase B), a pleckstrin homology (PH) lipid binding domain and a serine/threonine kinase containing protein is a key component of the phophatidylinositol-3-kinase (PtdIns3-K) cell survival signaling pathway which is activated in pancreatic cancers. In this study, we describe the effects of a novel inhibitor of AKT/PDK1 (PH-427) that binds to the PH domain of AKT (Ki = 2.67 ± 0.37 μM) and PDK1 (Ki = 5.20 ± 0.45 μM) [1] thus preventing its binding to PtIns-(3,4,5)P3 at the plasma membrane and subsequent activation of both kinases. PH-427 inhibits AKT/PDK1 activities at low micromolar concentrations in BxPC-3 (wt-KRAS) and not in MiaPaCa2 (mt-KRAS) human pancreatic cancer cell lines. Accordingly, we have shown that in vivo, PH-427 is poorly efficient in MiaPaCa2 xenografts as compared to BxPC-3 xenografts. In order to increase the potency and delivery of PH-427 to the tumor, we have encapsulated the compound (&gt;10% of the compound) into (poly-d, l-lactide-co-glycolide) (PLGA) nanoparticles (PNP). We demonstrate that PH-427 incorporates well in the nanoparticles (PH-427-PNP) (&lt;200 nm in size) and is slowly released from the polymer with a 90% released over a period of 30 days. We show that PH-427-PNP were very efficient in reducing MiaPaCa-2-Luc orthotopic pancreatic tumor growth as evaluated by luminescence using an AMI-1000 scanner. MiaPaCa2-Luc pancreas tumor volume was significantly reduced in animals treated with PH-427-PNP as compared to animal treated with PH-427 alone or the PNP alone (41.4±29.9 versus 2051±387 and 631±45 mm3). In conclusion, PH-427 alone did not alter tumor growth in MiaPaCa-2-Luc but was able to reduce tumor growth significantly when encapsulated in PNP. Finally and interestingly, metastasis to the liver and other organs was also significantly inhibited by PH-427-PNP as compared to PNP or PH-427 alone. [1]. Meuillet EJ, Ihle N, Lemos R, Moses SA, Song Z, Zhang S, Mash EA, Powis G (2010). Mol Cancer Ther 9(3):706-717.
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 3752. doi:1538-7445.AM2012-3752