bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2301: Intraperitoneal CAR-T infusion results in durable protection against peritoneal metastases and control of systemic tumor growth
Authors: Cunetta Marissa , Point Gary , Liu Zhi , Guha Prajna , Darpolor Josephine , Lima Matthew , Espat N J. , Hanna Nader , Boutros Cherif , Junghans Richard P. , Katz Steven 
Published: July 2016

Abstract
Colorectal carcinomatosis due to peritoneal metastases (PM) is a significant cause of morbidity and mortality. Present treatments fail to cure the majority of patients with PM. We are developing a chimeric antigen receptor T cell (CAR-T) regional infusion immunotherapy platform for PM. We treated mice with established CEA+ MC38 PMs with anti-CEA CAR-Ts either via regional intraperitoneal (IP) or systemic tail vein (TV) infusion. When compared to TV infusion, IP delivery resulted in significantly improved responses (37-fold reduction in tumor growth, p&lt;0.01). To measure the durability of protection from IP tumor growth, we re-challenged mice with IP tumor following successful treatment with IP CAR-Ts. Mice who had received initial IP CAR-T treatment were protected from tumor growth following re-challenge for 20 days compared to control animals (1390-fold reduction in tumor growth, p = 0.016). Assessment of IP tumor 10 and 28 days following tumor re-challenge revealed a high proportion of intratumoral CAR-Ts (Day 10- 70.0%, Day 28- 46.6%; p = 0.10) and the proportion of CAR-Ts with an effector memory phenotype (CD44+CD62L-CCR7-, Day 10- 19.3%, Day 28- 60.0%; p&lt;0.01). In separate experiments, we studied the effect of IP CAR-T infusions on tumor growth at distant sites. We established both IP and subcutaneous (SQ) flank tumors in mice prior to CAR-T infusions. Following treatment, IP CAR-T infusion resulted in a significant decrease in SQ tumor growth on day 8 compared to control (5.7-fold, p = 0.03), and a trend toward improvement compared to TV (4.9-fold, p = 0.224). While CAR-Ts were not detected in whole blood, SQ tumor, or draining lymph nodes following IP CAR-T infusion, serum IFNγ levels were significantly elevated on day 4 compared to control mice (p = 0.04), and returned to baseline by day 7. Our findings demonstrate that regional IP CAR-T delivery provides durable protection against IP tumor growth in association with CAR-T effector memory programming, in addition to a systemic anti-tumor effect.
Citation Format: Marissa Cunetta, Gary Point, Zhi Liu, Prajna Guha, Josephine Darpolor, Matthew Lima, N J. Espat, Nader Hanna, Cherif Boutros, Richard P. Junghans, Steven Katz. Intraperitoneal CAR-T infusion results in durable protection against peritoneal metastases and control of systemic tumor growth. [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 2301.
Abstract 2304: Attenuated oncolytic virus HSV1716 increases in vivo expansion of GD2- targeting CAR T cells in murine solid tumor models
Authors: Haile Samuel T. , Conner Joe , Mackall Crystal 
Published: July 2016

Abstract
Neuroblastoma, osteosarcoma, and rhabdomyosarcoma are among the most prevalent childhood solid tumors. Each of these tumor types as well as melanomas exhibit increased levels of the tumor associated carbohydrate, GD2 on their cell surface making them ideal targets for chimeric antigen receptor (CAR) T cell-directed therapies. Despite the ability of GD2 CAR T cells to target tumor cells in vitro, there is great interest in improving tumor clearance in vivo, especially for solid tumors where current outcomes remain poor. We hypothesize that the immunosuppressive milieu present within the solid tumor microenvironment serves as a major factor limiting the effectiveness of GD2 CAR T cells. Additionally, we propose that administration of oncolytic viruses could induce inflammation within the tumor microenvironment that may enhance, rather than inhibit, the effectiveness of immune based therapies. GD2 CAR T cells composed of the 14G2a single chain variable fragment linked to the cytoplasmic signaling domains of CD28 and CD3 zeta (GD2-28z) were expressed in murine lymphocytes and evaluated for the ability to target and lyse GD2-expressing tumor cells. Additionally GD2-28z T cells were evaluated for their ability to secrete the proinflammatory cytokines IFNγ and IL-2. In order to determine the oncolytic ability of attenuated HSV1716, tumor cells were cultured in the presence or absence of HSV1716 and relative cell survival was measured. We observed specific lysis of GD2-expressing tumor cells when co-cultured with GD2-28z, but not mock T cells. Furthermore, GD2-28z T cells secrete IFNγ and IL-2 following co-culture with GD2-expressing tumor cells. Interestingly, melanoma cell lines were not susceptible to oncolytic lysis while rhabdomycosarcoma (RMS) cell lines were susceptible. The combination of GD2-28z and HSV1716 enhanced CAR expansion in both melanoma and RMS models. Given that the melanoma cells in our model are not susceptible to oncolytic lysis yet we observe an increased T cell expansion when used in combination with HSV1716, this supports our hypothesis that HSV1716 is inducing inflammation, which may then triggering T cell expansion.
Citation Format: Samuel T. Haile, Joe Conner, Crystal Mackall. Attenuated oncolytic virus HSV1716 increases in vivo expansion of GD2- targeting CAR T cells in murine solid tumor models. [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 2304.
Abstract 2310: With a little help from CD4 T cells in adoptive T-cell transfer
Authors: Inderberg Else M. , Wälchli Sébastien , Myhre Marit R. , Lislerud Kari , Kvalheim Gunnar , Gaudernack Gustav 
Published: July 2016

Abstract
Adoptive transfer of genetically engineered T cells offers great opportunities in cancer immunotherapy, however until recently, HLA-Class II-restricted TCRs have been largely ignored.
We have identified and cloned HLA class II-restricted CD4+ T cells isolated from patients vaccinated with long peptides derived from antigens such as hTERT, survivin and frameshift mutated TGFβRII. Several of these cancer patients demonstrated outstanding clinical responses to peptide- or dendritic cell based cancer vaccines with &gt;10-year survival. In these patients strong T-cell responses against peptides other than those used for vaccination were detected, suggesting epitope spreading.
Responses against certain peptides associated with clinical benefit were identified and CD4+ T-cell clones recognizing such peptides were isolated. In depth studies of their specificities lead to the selection of HLA-DR and -DQ restricted T-cells having high functional avidity for the HLA-peptide complexes. We studied tumor cell and/or protein recognition and found one telomerase-specific CD4+ T-cell clone recognizing a melanoma cell line with the corresponding HLA allele.
The TCR sequences of the interesting clones were identified. The ribosome skipping 2A sequence technique was used to express these TCRs in an mRNA expression vector or retrovirus. When expanded T cells were electroporated with these TCRs, both redirected CD8+ and CD4+ T cells produced TNF-α, IFN-γ and the degranulation marker (CD107a) following co-incubation with specific peptide-loaded targets.
We have demonstrated that choosing highly functional CD4+ T-cell clones specific for tumor-associated or -specific antigens from patients with clinical responses after immunotherapy treatment is a successful method for identifying highly functional HLA class II restricted TCRs for adoptive T-cell transfer.
The use of HLA class II-restricted TCRs may be of therapeutic value both in haematopoietic malignancies and in melanoma where tumor cells often express HLA class II. In addition, combining the redirection of T cells with both HLA class I- and class II-restricted TCRs may provide a more powerful therapeutic effect in adoptive T cell therapy.
Citation Format: Else M. Inderberg, Sébastien Wälchli, Marit R. Myhre, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack. With a little help from CD4 T cells in adoptive T-cell transfer. [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 2310.
Abstract 2312: TEM8/ANTXR1 specific T cells co-target tumor stem cells and tumor vasculature in triple-negative breast cancer
Authors: Byrd Tiara , Fousek Kristen , Pignata Antonella , Szot Christopher , Bielamowicz Kevin , Seaman Steven , Landi Daniel , Rainusso Nino , Sorensen Poul , Koch Joachim , Wels Winfried , Fletcher Bradley , Hegde Meenakshi , St Croix Brad , Ahmed Nabil 
Published: July 2016

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no approved targeted therapies. Tumor endothelial marker 8 (TEM8), initially identified as a marker of tumor endothelial cells in colorectal cancer and other solid tumors has recently been shown to be upregulated in TNBC and breast cancer stem cells (BCSCs). We investigated whether TEM8 specific chimeric antigen receptor (CAR) T cells recognize and kill both tumor endothelial cells as well as TNBC tumor cells. TEM8 specific CAR molecules were generated using single chain variable fragment derived from the monoclonal antibody, L2. L2 CAR T cells selectively recognized TEM8, secreted immunostimulatory cytokines and effectively killed both TEM8 positive TNBC and tumor endothelial cell lines. Moreover, L2 CAR T cells targeted breast cancer stem cells significantly reducing the number of mammospheres relative to non-transduced T cells. In vivo, adoptive transfer of L2 CAR T cells induced regression of established vascularized TNBC xenografts. Hence, TEM8 may serve as an attractive target for immunotherapy of TNBC.
Citation Format: Tiara Byrd, Kristen Fousek, Antonella Pignata, Christopher Szot, Kevin Bielamowicz, Steven Seaman, Daniel Landi, Nino Rainusso, Poul Sorensen, Joachim Koch, Winfried Wels, Bradley Fletcher, Meenakshi Hegde, Brad St Croix, Nabil Ahmed. TEM8/ANTXR1 specific T cells co-target tumor stem cells and tumor vasculature in triple-negative breast 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 2312.
Abstract 2316: GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for hepatocellular carcinoma
Authors: Trinh Thu Le , Wu Qunfeng , Chang Lung-Ji , Ho Mitchell , Liu Chen 
Published: July 2016

Abstract
FDA-approved targeted therapy for advanced hepatocellular carcinoma (HCC) is limited with the only option of Sorafenib treatment with severe side effects. Immunotherapy based on adoptive transfer of tumor-specific T cells have demonstrated a promising clinical outcome for solid tumors. In our study, we developed T cells expressing the fourth generation of GPC3-specific chimeric antigen receptor (α-GPC3 CAR) that efficiently eliminated GPC3-positive HCC cells (Huh7 and HepG2) without killing GPC3-negative primary hepatocytes. This CAR was constructed using a lentiviral vector containing CD28, CD27 and 41BB costimulatory domains, a CD3ζ signaling domain fused to a FKBP-iCasp9 apoptosis inducing gene, and a GPC3-specific sequence derived from HN3, a single-domain VH human monoclonal antibody (gift from Mitchell Ho, NCI). After 16h of incubation at the E (α-GPC3 CAR T cells) : T (Huh7 or HepG2 cells) ratio of 1:1, α-GPC3 CAR T cells effectively lysed Huh7 (39%) and HepG2 (77%) but not primary hepatocytes (9%), while the control CAR T cells (α-CD30 CAR) could not initiate a specific lysis on those cells. At the E:T ration of 3:1, the specific killing increased to 78% (Huh7) and 99% (HepG2) while remaining low with primary hepatocytes (11%). Especially at the very low E:T ratio of 1:10, combination with Sorafenib priming (24h, IC10 concentration) prior to CAR T incubation boosted the specific lysis up to 25% (p = 0.0416). These results indicate that combination of GPC3-specificCAR T cells transfer and Sorafenib regimen could be a promising therapeutic option for the treatment of HCC, with the doses of both CAR T and Sorafenib reduced up to 10 times, hence lower side effects while preserving the efficacy of tumor-specific cytotoxicity.
Citation Format: Thu Le Trinh, Qunfeng Wu, Lung-Ji Chang, Mitchell Ho, Chen Liu. GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for 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 2316.
Abstract 2331: HDAC6, new role as master regulator of PD-L1 and immune-related pathways
Authors: Knox Tessa , Lienlaf Maritza , Perez Patricio , Pabon Mibel , Lee Calvin , Cheng Fengdong , Sahakian Eva , Powers John , Deng Susan , Keiran Smalley , Kozikowski Alan , Pinilla Javier , Sarnaik Amod , Seto Ed , Weber Jeffrey , Sotomayor Eduardo , Villagra Alejandro 
Published: July 2016

Abstract
Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to modify a variety of other proteins involved in diverse cellular processes unrelated to the chromatin environment, including the modulation of proteins related to cell cycle/apoptosis and immune regulation. In contrast to the well-documented effects of HDAC inhibitors (HDACi) in the control of cell cycle and apoptosis, their role in immunobiology is still not completely understood, and the reported immunological outcomes when using HDACi are heterogeneous. Our group recently reported that the pharmacological or genetic abrogation of a single HDAC, HDAC6, modulates the expression of immuno-regulatory proteins, including PD-L1, PD-L2, MHC class I, B7-H4 and TRAIL-R1. We primarily focused in PD-L1, which is an important negative regulator of T-cell function and often over-expressed in cancer cells. In a mechanistic point of view, we have found that the pharmacological inhibition and genetic abrogation of HDAC6 inactivates the STAT3 pathway, impairs the nuclear translocation and the recruitment of STAT3 to the PD-L1 promoter and subsequently down-regulates the expression of PD-L1. Moreover, the in vivo abrogation of HDAC6 reduces tumor growth in melanoma models, effect that is enhanced in the presence of the immune check-point blocking antibodies anti-PD-1 and anti-CTLA4. These results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immunomodulatory agents in cancer.
Citation Format: Tessa Knox, Maritza Lienlaf, Patricio Perez, Mibel Pabon, Calvin Lee, Fengdong Cheng, Eva Sahakian, John Powers, Susan Deng, Smalley Keiran, Alan Kozikowski, Javier Pinilla, Amod Sarnaik, Ed Seto, Jeffrey Weber, Eduardo Sotomayor, Alejandro Villagra. HDAC6, new role as master regulator of PD-L1 and immune-related pathways. [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 2331.
Abstract 2332: Patient-derived tumor xenografts in humanized NSG-SGM3 mice: a new immuno-oncology platform
Authors: Yao Li-Chin , Cheng Mingshan , Wang Minan , Banchereau Jacques , Palucka Karolina , Shultz Leonard , Bult Carol , Keck James G. 
Published: July 2016

Abstract
Humanized mice engrafted with tumors enable in vivo investigation of the interactions between the human immune system and human cancer. We have recently found that humanized NOD-scid IL2Rγnull (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of check-point inhibitors. Next generation NSG strains include triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSG-SGM3). Here we provide a direct comparison of check-point inhibitors evaluation in NSG and NSG-SGM3 mice engrafted with CD34+ human hematopoietic progenitor cells (HPCs) from the same donor and implanted with PDX tumors. Corroborating earlier studies, reconstitution of human immune system in the blood was faster and more robust in NSG-SGM3 compared to NSG recipients throughout the course of the study (18 weeks). Human CD45+ cells reached 25% of total blood cells at week 4 in hu-NSG-SGM3 mice and at week 9 in hu-NSG mice. A majority of blood hCD45+ cells in hu-NSG-SGM3 at week 4 were CD33+ myeloid cells. Circulating hCD3+ T cells reached 10% at week 9 and included regulatory T cells (Tregs), consistent with earlier studies. Hu-NSG mice displayed comparable hCD3+ T cells in the blood only at 12-15 weeks and did not contain Tregs. PDX tumors were then engrafted into partially HLA-matched hu-NSG-SGM3 mice at 9 weeks post engraftment. Two PDX models previously shown to respond to anti-PD1 therapy in hu-NSG mice, BR1126 and LG1306, were used. Treatment with the anti-PD-1 receptor antibody pembrolizumab (Keytruda) significantly reduced tumor growth in both models. Thus, PDX-bearing hu-NSG-SGM3 mice might serve as a new and improved platform for preclinical immuno-oncology efficacy studies.
Citation Format: Li-Chin Yao, Mingshan Cheng, Minan Wang, Jacques Banchereau, Karolina Palucka, Leonard Shultz, Carol Bult, James G. Keck. Patient-derived tumor xenografts in humanized NSG-SGM3 mice: a new immuno-oncology platform. [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 2332.
Abstract 2333: Possible prediction of tumor specific checkpoint inhibitor response based on TCGA somatic mutation load
Authors: Colli Leandro Machado , Machiela Mitchell J. , Myers Timothy , Jessop Lea , Yu Kai , Chanock Stephen J. 
Published: July 2016

Abstract
Immune checkpoint inhibitor therapy has been shown to be effective in a subset of patients with melanoma, non-small cell lung cancer (NSCLC) and kidney cancer. Recent studies have suggested that the number of non-synonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from immune checkpoint inhibitor treatment. It is hypothesized that NsMs generate novel epitopes and gene products which can be detected by the immune system. The aim of this study is to apply prior information on NsM count and immune checkpoint inhibitor treatment to a range of tumor subtypes in the TCGA database to evaluate the proportion cases that could be possible responders. In our analysis of published studies of melanoma and NSCLC, the receiver operator characteristic (ROC) curve suggests a cutoff of 192 NsM would have a maximum combination of sensitivity (74%) and specificity (59.3%) for potential clinical benefit for patients. We conducted an analysis of 7,757 samples from 26 different TCGA tumor types and observed that approximately 16.2% of TCGA samples harbor more than 192 NsM, and thus could be in the category associated with a higher likelihood of response to immune checkpoint inhibitors. Based on NsM count, bladder, colon, gastric, and endometrial cancers each contained more than 30% of tumors with a high NsM and thus, could be possible candidates for checkpoint immune therapy. Although our model estimates clinical response to immune checkpoint treatment from NsM count is preliminary and needs future validation, information on NsM count can be useful for selecting tumor types most likely to benefit in clinical trials of immune checkpoint inhibitor treatment.
Citation Format: Leandro Machado Colli, Mitchell J. Machiela, Timothy Myers, Lea Jessop, Kai Yu, Stephen J. Chanock. Possible prediction of tumor specific checkpoint inhibitor response based on TCGA somatic mutation load. [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 2333.
Abstract 2343: The immune modulatory roles of IAP inhibitor, LCL161, and its connection to immune-checkpoint molecules
Authors: Pinzon-Ortiz Maria , Hastings William , Longmire Tyler , Shaw Pamela , Rong Xianhui , Murakami Masato , Lee Benjamin H. , Dranoff Glenn , MacIsaac Kenzie , Cao Z. Alexander 
Published: July 2016

Abstract
Tumor immunotherapy is a unique therapeutic modality in our fight against human cancers. The recent success of immune-checkpoint therapies highlights the value and potential of this approach. Previous studies have demonstrated positive immune-modulatory activities of the IAP inhibitor, NVP-LCL161. In this study, we sought to further explore the immune-modulatory activities of NVP-LCL161 in connection with immune-checkpoint molecules.
In PBMC stimulation assays, NVP-LCL161 potently induced IFN and enhanced proliferation, while down-modulating IL-10 production. Additionally, the role of NVP-LCL161 on immune-checkpoint modulation was revealed in CyTOF analysis of in vitro stimulated PBMCs. NVP-LCL161 treatment led to increases in TIM-3 expression on multiple T cell subsets, and on cells of the myeloid lineage. These observations illustrate potential modulation of specific immune-checkpoint molecule by NVP-LCL161, thus suggesting possible synergy between TIM-3 immunecheckpoint blockade and NVP-LCL161. NVP-LCL161 was further combined in vivo with anti-PD1 antibody in the murine syngeneic tumor model, MC38. At multiple dosing schedules, synergy was observed with this combination, which appeared to be independent of single agent efficacy. Expression profiling of MC38 tumor tissues by a customized Nanostring panel revealed elevation of gene signatures in T cells, dendritic cells, cytokines and chemokines, amongst others.
In summary, the preclinical data support the hypothesis that NVP-LCL161 is an active immune modulator. Its combination activity with immune_checkpoint inhibitors would warrant further exploration in both preclinical and clinical setting.
Citation Format: Maria Pinzon-Ortiz, William Hastings, Tyler Longmire, Pamela Shaw, Xianhui Rong, Masato Murakami, Benjamin H. Lee, Glenn Dranoff, Kenzie MacIsaac, Z. Alexander Cao. The immune modulatory roles of IAP inhibitor, LCL161, and its connection to immune-checkpoint molecules. [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 2343.