bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1928: Resistance of human melanoma to MART-1/HLA A2.1 specific CTL (F5 CTL)-killing: poor recognition, low MART-1 expression and reversal of resistance
Authors: Jazirehi Ali R. , Baritaki Stavroula , Bonavida Benjamin , Economou James S. 
Published: February 2011

Abstract
Adoptive cell therapy (ACT) using ex vivo engineered autologous lymphocytes encoding high affinity TCRα/β genes specific for MART-1+/HLA-A2.1+ (F5 CTL) kill human melanoma lines in vitro in an MHC-I restricted and caspase-dependent manner and mediate modest clinical responses. Development of antigen-loss tumor variants is one mechanism of immune escape. The objective of this study is to investigate the mechanism of resistance to CTL-killing due to loss of recognition and reversal of resistance by pharmacological inhibitors. We hypothesized that the development of Ag-loss variants is due to degradation or epigenetic modifications of MART-1. Also, we hypothesized that aberrant apoptotic cell signaling contribute to immune resistance. To test the hypotheses, we generated F5 CTL-resistant clones (R) from sensitive parental (P) lines by growing the cells under F5 CTL selective pressure followed by limiting dilution. Detailed analysis revealed that compared to P cells, M244R clone exhibit significantly higher resistance to F5 CTL killing, proliferate at a higher rate, and are unable to trigger IFNγ release by F5 CTLs suggesting diminished MART-1 expression (loss of MART-1 was confirmed by gene analysis, surface HLA-A2.1 was unaltered). F5 CTLs recognized and interacted with MART-1 pulsed M244R clone (IFNγ secretion and conjugate formation), yet, the cells still remained resistant to F5 CTL killing. We observed deregulation and constitutive hyper-activation of the components of the NF-κB pathway leading to over-expression of anti-apoptotic Bcl-2, Mcl-1 and Bcl-xL in M244R clones. The proteasome inhibitor bortezomib efficiently blocked NF-κB activity, reduced the expression of resistant factors, restored recognition and sensitized the M244R clones to F5 CTL-induced killing. These novel results suggest that bortezomib, not only interferes with the deregulated signaling pathway but also restores recognition of low MART-1 expressing, poorly recognized immune resistant variants by F5 CTLs, thus, reverses the acquired resistance. These results also imply that immune resistance can not be solely explained by the development of MHC-/antigen-loss variants and is partly due to perturbed cell survival signaling pathways of the tumor cells. Targeted therapy with specific pharmacological inhibitors in conjunction with F5 CTL can override F5 CTL-resistance, which can improve clinical response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1928.
Abstract 1931: Impact of bortezomib-induced proteasome inhibition in vivo on antitumor T cell responses
Authors: Shanker Anil , Kluyver Rachel De , Sayers Thomas J. 
Published: February 2011

Abstract
Inhibition of cellular proteasome function crucial for protein turn-over is a recent approach to overcome the resistance of tumors to cell death, a major clinical problem. Bortezomib (also known as Velcade/PS-341), a specific and reversible proteasome inhibitor, has been shown to sensitize some mouse and human tumors to apoptosis induced by the TNF-related apoptosis-inducing ligand (TRAIL) or its receptor (DR5) agonist monoclonal antibody (mAb). In established mouse renal cell (Renca) and breast (4T1) tumor models, the administration of DR5 agonist mAb to tumor-bearing mice pre-treated with bortezomib reduced experimental lung metastases. The combination of bortezomib and DR5 agonist mAb also significantly increased long-term survival of mice bearing Renca tumors compared with either agent alone. The therapeutic effects of bortezomib on tumor metastases and survival of tumor-bearing mice occurred in the absence of overt toxicity. However, little is known concerning the effects of bortezomib on specific immune responses. We thus analyzed the effects of proteasome inhibition on anti-tumor T cell responses in vivo. In mice with established Renca-HA tumor expressing influenza virus hemagglutinin (HA) as a surrogate tumor antigen, we evaluated the antigen-specific proliferation of adoptively transferred monoclonal HA-specific MHC class I or II restricted T cells following various schedules of bortezomib administration. No inhibition of T cell proliferation or cytolytic function in vivo was observed following bortezomib treatments. Nor was there any evidence of defective dendritic cell maturation in bortezomib-treated mice. However, a significant decrease in total T cell yield was noted in the tumor-draining LNs of mice treated with bortezomib. Thus, bortezomib-inhibitory effects on T cell responses seem quantitative rather than qualitative. The basis for this decrease in T cell number is under further investigation. The findings imply that, with an appropriate scheduling, it may be possible to combine bortezomib-induced sensitization of tumors to apoptosis with tumor-specific T cell immunotherapy regimens for increased therapeutic benefit in cancer.
Funded in part by NCI Contract # N01-CO-12400 and HHSN261200800001E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1931.
Abstract 1933: Adoptive T cell therapy shifts the secretion ability of cytokines to Th1 and decreases the number of Tregs in patients with cancer
Authors: Ishikawa Takeshi , Kokura Satoshi , Matsumoto Tsuguhiro , Funaki Jun , Adachi Satoko , Okayama Tetsuya , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Handa Osamu , Konishi Hideyuki , Yagi Nobuaki , Wakabayashi Naoki , Naito Yuji , Yoshikawa Toshikazu , Sakamoto Naoyuki , Tanigawa Mari , Uno Kazuko 
Published: February 2011

Abstract
[Aim] We analyzed the secretion ability of cytokines from peripheral blood mononuclear cells (PBMC) and the number of peripheral blood Tregs before and after adoptive T cell therapy (CD3-LAK) in order to assess the relation of the immunological responses and the efficacy of the treatment.
[Method] Patients who received CD3-LAK treatment more than four times were done an entry of this study. We conducted this study after having obtained the informed consent of the study for these patients. We measured the secretion ability of cytokines from PBMC using the peripheral blood collected from the patients before treatment and 2 weeks later after the 4th treatment. The methods we measured the secretion ability of cytokines are shown below. IFN-alpha: We stimulated the whole blood by Sendai virus for 20 hours, and IFN-alpha of supernatant was measured by bioassay. The other cytokines (IL-2, IL-4, IL-10, TNF-alpha, IFN-gamma etc): We stimulated the whole blood by PHA for 48 hours, and the cytokines of supernatant were measured by BioPlex array. In terms of the change of the number of peripheral blood Tregs, we analyzed Foxp3 and CD4 positive T cells by flow cytometry.
[Result] The values of IFN-gamma and TNF-alpha were significantly high after the treatment. Ratio of Treg to CD4 was significantly low after the treatment. The survival time of the group of patients in whom the number of Treg decreased after the treatment was longer than that of the other group of patients.
[Discussion] We found that even in patients with refractory advanced cancer, the therapeutic intervention of CD3-LAK makes positive change - the secretion ability of cytokines from PBMC shifts to Th1, the number of Treg in peripheral blood decreases. And it suggests that adoptive T cell therapy influences immunoescape mechanism in patients with cancer. It will be necessary to clarify the mechanism of the effect and to develop an adoptive immunotherapy which has more beneficial clinical effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1933.
Abstract 1934: Hyperthermia enhances the anti-tumor activity of adoptive transfer of naïve T cells
Authors: Matsumoto Tsuguhiro , Kokura Satoshi , Ishikawa Takeshi , Funaki Jun , Adachi Satoko , Okayama Tetsuya , Sakamoto Naoyuki , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Handa Osamu , Konishi Hideyuki , Wakabayashi Naoki , Yagi Nobuaki , Naito Yuji , Kato Akiko , Tomita Keisuke , Enoki Tatsuji , Yoshikawa Toshikazu 
Published: February 2011

Abstract
Objective: Recently, in the case of the adoptive immunotherapy, less-differentiated T cell (naïve T cells) has been postulated to be more effective for tumor regression than late effector T cells. On the other hand, hyperthermia augments MHC class I antigen presentation via HSPs expression and attenuates the production of immunosuppressive cytokines such as IL-10 and TGF-beta from cancer tissue. There is increasing evidence that the use of hyperthermia is effective as an adjunct to cancer immunotherapy. Therefore, the purpose of this study was to evaluate the effects of hyperthermia on adoptive transfer of naïve T cells in a subcutaneous B16 melanoma model. Experimental design: Male C57BL/6 mice were injected s.c. with B16 murine melanoma cells. Splenocytes for adoptive transfer were isolated from tumor-bearing mice and primary stimulation was accomplished using plate-bound anti-CD3 monoclonal antibody. Cells were expanded in culture media containing IL-2, IL-7 and recombinant human fibronectin fragment (FN-CH296). Prior to adoptive transfer, CD62Lhigh and CD62Llow populations were sorted using a MACS CD62L-positive selection column. Subcutaneous B16 bearing mice were treated with hyperthermia on day 3 and day 4, and then mice were treated with two doses of CD62Lhigh or CD62Llow cells via a tail vein on day 6 and day 10. Tumor volume, body weight and the number of regulatory T cell (Treg) within spleen were examined on day 17. Results: The tumor volume significantly decreased in CD62Lhigh adoptive transfer therapy combined with hyperthermia compared to CD62Llow adoptive transfer therapy combined with hyperthermia or hyperthermia alone. The body weight and the number of Treg within spleen did not have the significant difference among these groups. Conclusion: These data suggest that hyperthermia enhances the anti-tumor effect of adoptive transfer therapy using naïve T cells, but not late effector T cells. Hyperthermia would have potential to activate and expand naïve T cell in vivo after adoptive transfer. These results may benefit further efforts on developing novel adoptive immunotherapies based on hyperthermia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1934.
Abstract 1935: Myeloid derived suppressor cells generated in the absence of Muc1 can inhibit allo expansion of T cells while preserving graft versus tumor activity
Authors: Poh Tze Wei , Gendler Sandra 
Published: February 2011

Abstract
Allogeneic hematopoietic stem cell (HSC) transplantation is a promising area of therapy for various hematological malignancies like chronic/acute myeloid leukemia, myelodysplasia and lymphomas. Its effectiveness at inducing the graft versus tumor (GVT) effect is however, compromised by the graft versus host disease (GVHD) frequently observed in recipients post transplant. One of the strategies utilized in minimizing the effect of GVHD while still preserving GVT activity has been to target immunosuppressive cell types like Treg cells or myeloid derived suppressor cells (MDSCs), in an attempt to correct the balance between GVHD and GVT. MDSCs have been shown to be able to inhibit GVHD but not much is known about the ability of MDSCs to preserve GVT. We have previously shown that myeloid progenitors lacking Muc1 from Muc1 knockout (KO) C57BL/6 (H-2b) mice generate more effective MDSCs in vitro and in vivo. In this current study, we study the potential of using MDSCs generated in the absence of Muc1 to alleviate T cell expansion while preserving CTL activity. Our preliminary data shows that MDSCs generated from Muc1 KO C57BL/6 (H-2b) bone marrow are able to inhibit C57BL/6 (H-2b) T cell proliferation in an allogeneic mixed lymphocyte reaction, using Balb/c (H-2d) stimulators, more effectively than wildtype (WT) MDSCs. Interestingly, despite the reduced T cell proliferation in the presence of KO MDSCs, the CTL activity of these C57BL/6 T cells was still preserved, as demonstrated by their ability to lyse Balb/c A-20 leukemia cells. These results inidicate that co transplant of MDSCs generated in the absence of Muc1 can alleviate GVHD across fully mismatched major histocompatibility complex (MHC) barriers while still preserving the GVT ability of the allograft. This would also validate the clinical desirability of down regulating MUC1 in HSCs for more effective generation of MDSCs in a clinical allogeneic HSC transplantation setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1935.
Abstract 1936: Anti CD30 chimeric immune receptor mRNA for therapy of CD30+ lymphomas
Authors: Karkanitsa Pavel , Weissman Sherman , Rabinovich Peter , Abken Hinrich , Hombach Andreas , Komarovskaya Marina , Foss Francine M. 
Published: February 2011

Abstract
CD30 is a transmembrane receptor which is overexpressed on Hodgkin lymphoma and large cell anaplastic lymphoma and represents an attractive target for therapy. Current methods of immunotherapy of CD30+ lymphomas include antibody based therapy (immunotoxins, bispecific molecules, radioimmunotherapy), and cellular immunotherapy. Here we describe an approach to cellular immunotherapy of CD30+ lymphomas using a synthetic mRNA of an anti CD30 chimeric immune receptor (anti CD30-CIR) introduced into activated T cells by electroporation. Anti-CD30 CIR consists of a single chain antibody directed against CD30, a transmembrane anchor to localize the protein in the cellular membrane, and the cytoplasmic domain of the TcR receptor chain. In these studies, the cDNA coding sequence was used as a template to produce anti CD30-CIR mRNA. Normal T cells expanded in vitro were electroporated with CIR mRNA and expression of anti CD30-CIR was detected by biotin-conjugated F(ab’)2 followed with Streptavidin-APC. To measure cytotoxicity of the CIR, target cells (HH, K562, Jurkat) were pulsed with carboxyfluorescein diacetate succinimidyl ester (CFSE) and then were cultured with T cells transfected with anti-CD30 CIR mRNA or mock transfected T cells. Cytotoxicity was evaluated at different target::effector (T: E) ratios and normalized by standard algorithm. Twenty-four hours after electroporation almost all viable T cell (&gt;90%) expressed anti-CD30 CIR and were able to specifically kill CD30+ targets in a 4h in vitro assay. These results demonstrate that anti-CD30-CIR mRNA modified T cells can be generated and are capable of killing CD30-expressing cells in vitro and therefore may be an effective strategy for the therapy of refractory CD30-expressing lymphomas.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1936.
Abstract 1939: Augmenting effector function and abrogating Treg function by OX40 costimulation enhances adoptive transfer tumor-specific CTL response
Authors: Murata Satoshi , Ueki Tomoyuki , Kitamura Naomi , Mekata Eiji , Shimizu Tomoharu , Shiomi Hisanori , Abe Hajime , Naka Shigeyuki , Tatsuta Takeshi , Yamaguchi Tsuyoshi , Mori Tsuyoshi , Umeda Tomoko , Kubota Yoshihiro , Cho Hirotomi , Yamamoto Hiroshi , Endo Yoshihiro , Kurumi Yoshimasa , Tani Tohru 
Published: February 2011

Abstract
We have recently shown that OX40 (CD134) costimulation provided with GM-CSF-secreting vaccine can bypass CD8+ T cell tolerance. OX40 costimulation can also abrogate Foxp3+ regulatory T cell (Treg)-mediated suppression of antitumor immunity by reducing Foxp3 expression on Tregs. In addition, OX40 costimulation can directly augment tumor-specific CTL function without CD4+ T cell help in vivo. Here we show that pre-treatment with agonistic anti-OX40 mAb augments the antitumor immune effects of adoptive CD8+ T cell therapy in the clinically relevant wild-type model, not TCR-transgenic, mouse model. CD8+ T cells stimulated with tumor antigen (HER2/neu immunodominant peptide and T2 cells), including a small number of tumor antigen-specific effector CD8+ T cells, were transferred into tumor-bearing FVB/N mice. We could detect the response of tumor antigen-specific CD8+ T cells that were adoptively transferred into the recipient mice, however, the response was not sufficient to eradicate an established tumor. In addition, we showed that pre-treatment with OX40 costimulation in tumor-bearing recipient in order to inhibit the Treg-mediated suppressive function enhanced tumor specific immune response of adoptively transferred CD8+ T cells in the recipients, thus resulting in the eradication of an established tumor. Moreover, adoptively transferred CTLs, with OX40 costimulation in vitro before transfer, significantly enhanced a tumor-specific immune response in the tumor-bearing recipient. Furthermore, when tumor antigen-specific CTLs costimulated through OX40 in vitro were adoptively transferred into the tumor-bearing recipients that had been pre-treated with OX40 costimulation to inhibit Treg function, transferred tumor-specific CTLs were effectively maintained in this recipient 7 times more than in the recipient with CTL transfer alone without OX40 treatment, and about 3 times more than in the recipient with a single treatment of OX40 costimulation. These findings therefore suggest that both direct enhancement of adoptive transfer CTL function and pre-inhibition of Treg-mediated suppressive function in recipients with OX40 costimulation are useful strategy for antitumor adoptive CTL therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1939.
Abstract 194: Loss of imprinting and abnormal expression of insulin-like growth factor II in gastric cancer
Authors: Chen Teng , Zuo Qin-Song , Zhao Ronghua , Feng Dian-Xu , Chen Chao , Jiang Yi-Min , Cruz-Correa Marcia , Casson Alan G. , Han Feng 
Published: February 2011

Abstract
Introduction: Gastric carcinoma (GC) is a leading cause of cancer mortality worldwide, and is highly prevalent in China. Loss of imprinting (LOI) of insulin-like growth factor II (IGF-2) gene is an important epigenetic phenomenon related to carcinogenesis and tumor progression in many human cancers. To date, however, few studies have evaluated the IGF-2 LOI in GC.
Aims: This study aimed: (1) to examine the prevalence of LOI of IGF-2 in tumor, matched normal gastric mucosa, and peripheral blood lymphocyte (PBL) from a well characterized series of patients with GC, and in PBL from a control group, (2) To examine the association of LOI of IGF-2 with circulating IGF-2 and tissue IGF-2 expression.
Methods: IGF-2 genomic imprinting status was analyzed by PCR and RT-PCR followed by restrictive endonuclease (Apa I) digestion. Prevalence of LOI in PBL from 33 Apa I informative GC patients (21 males, age: 59.91±13.87) was compared with that from 21 informative controls (13 males, age: 56.81±13.28). Findings were also associated with the clinicopathologic parameters in patients with GC. IGF-2 level in peripheral blood (ng/ml) and tumor were determined with ELISA and immunohistochemical staining, respectively.
Results: LOI of IGF-2 was positive in 48.48% (16/33) GC tumor, 21.21% (7/33) adjacent mucosa (AM), 12.12% (4/33) distant mucosa (DM), and 15.15% (5/33) PBL. The prevalence of LOI in PBL was not significantly different between GC patients (5/33, 15.15%) and controls (2/21, 9.52%) (p=0.693). Patients with LOI-positive tumor were more likely to be advanced stage (93.75% vs. 58.82%, p=0.039) or have positive lymph nodes (87.50% vs. 52.94%, p=0.057). Significantly increased blood IGF-2 level was seen in GC patients with LOI-positive tumor (808.07±255.25) when compared with those with LOI-negative tumor (396.21±198.94) (p&lt;0.01). The positive rate of IGF-2 staining was significantly higher in tumor (10 of 16, 62.50%), AM (7 of 7, 100.00%), and DM (3 of 4, 75.00%) with LOI than that in tissues without LOI (tumor: 2 of 17, 11.76%; AM: 2 of 26, 7.69%; DM: 2 of 29, 6.90%) (p&lt;0.01).
Conclusions: The results of this study suggest that IGF-2 is a critical factor in carcinogenesis and progression of GC, with LOI of IGF-2 modulating tissue and circulating expression of IGF-2. IGF-2 LOI may represent a potential epigenetic marker for gastric cancer risk, prognosis and treatment stratification.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 194.