bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A81: Immune-cancer interactions in tumors and tumor-draining lymph nodes: Novel prognostic indicators for breast cancer
Authors: Mansfield James , Lee Peter 
Published: October 2015

Abstract
It is becoming clear that immune cells play many important but sometimes conflicting roles in cancer., and iImmune profile changes at sites of immune–cancer interactions, such as the tumor microenvironment and tumor-draining lymph nodes (TDLNs), may represent a sensitive predictor of local and distant tumor metastasis. However, standard pathologic analysis of tumor sections has remained at the visual assessment of one marker per serial section level; it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune and other cells in-situ in solid tumors to dissect the complex interplay between immune/stromal cells and cancer cells within tumors, tumor-draining lymph nodes (TDLNs), and blood. We generate immune profiles that include complete immunophenotyping and identification of cellular spatial relationships within and between the tumor microenvironment and TDLNs from formalin-fixed paraffin-embedded lymph node and tumor specimens from cancer patients using a combination of multiplexed IHC/IF, multispectral imaging, and automated image analysis which delivers quantitative per-cell measures of each marker. These per-cell intensities are then translated into a phenotype for each cell. We have found that immune cell populations as well as their spatial distributions and clustering patterns have strong correlation with clinical outcome.
Citation Format: James Mansfield, Peter Lee. Immune-cancer interactions in tumors and tumor-draining lymph nodes: Novel prognostic indicators for breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A81.
Abstract A85: Identification and enrichment for rare naturally occurring tumor-reactive T cells in the tumor microenvironment reveals new and diverse opportunities for cancer immunotherapy
Authors: Powell Daniel J. 
Published: October 2015

Abstract
The existence of naturally-occurring, tumor-reactive T-cells in human cancer has rationalized the application of immunotherapy in oncology, however the immunobiology of spontaneous tumor-reactive T-cells in cancer is not well-defined due to difficulties in identifying and validating these responses. The ability to identify and characterize rare tumor-reactive T cells has strong prognostic value and holds the potential to enable various forms of immunotherapy, including adoptive T cell therapy, TCR gene therapy and immune checkpoint inhibition. In our attempt to explore the immunobiology of naturally-occurring immune responses in patients, we have now elucidated CD137 as a biomarker for bona fide naturally-occurring, tumor-reactive T-cells in cancer and developed a rapid, accurate system to comprehensively isolate tumor infiltrating lymphocytes (TILs) with tumor-rejecting capability directly from resected tumors. CD137+ TILs from various tumor types recognized autologous and HLA-matched tumor in an HLA-restricted manner, resulting in proflammatory cytokine production and cancer killing in vitro, and tumor growth inhibition in vivo; CD137-negative TILs did not. More so, multiparameter phenotyping of the CD137+ TIL subset revealed a vast network of expressed negative immunoregulatory molecules and opportunities for immune checkpoint inhibition. Our findings implicate a role for CD137 in the immunobiology of human cancer where it is preferentially expressed on the tumor-reactive TIL subset, and provides a new roadmap for the rational design of cancer immunotherapy trials.
Citation Format: Daniel J. Powell, Jr. Identification and enrichment for rare naturally occurring tumor-reactive T cells in the tumor microenvironment reveals new and diverse opportunities for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A85.
Abstract B05: A biologic screen to evaluate potential toxicity of chimeric antigen receptor modified T cells against primary normal human tissues
Authors: Cogdill Alexandria P. , Boesteanu Alina , Haines Kathleen , Fraietta Joseph , Scholler John , Loew Andreas , Thekkat Pramod , Brogdon Jennifer , Maus Marcela V. , June Carl , Johnson Laura A. 
Published: October 2015

Abstract
Adoptive cell therapy with chimeric antigen receptor (CAR) engineered T lymphocytes has recently shown great success for the treatment of hematologic malignancies. Similar strategies based on enhancing T cell function and redirecting these lymphocytes against solid tumors are being developed, however, early attempts have resulted in unexpected toxicity of normal cells expressing shared antigen or cross-reactive antigens. A primary challenge in translating new CARs to therapeutic platforms is the lack of robust models to predict potential adverse events pre-clinically. To address this challenge, we developed an in vitro system consisting of thirteen expanded primary human cell types. To detect potential off-tumor on-target effects on normal tissues, we co-cultured CARs directed against human epidermal growth factor receptor (EGFR) in our primary cell panel. Flow cytometric and chromium release assays were used to measure intracellular cytokine production by effectors and specific cell lysis of targets, respectively. T cells expressing a CAR against wild-type EGFR elicited strong effector cytokine production and effectively lysed both tumor and normal cells expressing EGFR. In contrast, T cells engineered to express a humanized CAR against mutant EGFR variant III (EGFRvIII), a tumor-specific antigen, reacted only with tumors and did not react to the panel of primary cell targets. This demonstrated a lack of potential cross-reactivity related to off-tumor on-target effects in the normal cell types represented here, suggesting improved safety for clinical use. The thirteen primary cell types we have generated form a panel of normal cells to test novel CAR T cells for potential toxicity and an adequate therapeutic index prior to first-in-human studies.
Citation Format: Alexandria P. Cogdill, Alina Boesteanu, Kathleen Haines, Joseph Fraietta, John Scholler, Andreas Loew, Pramod Thekkat, Jennifer Brogdon, Marcela V. Maus, Carl June, Laura A. Johnson. A biologic screen to evaluate potential toxicity of chimeric antigen receptor modified T cells against primary normal human tissues. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B05.
Abstract B06: Imaging regulatory mechanisms that limit intratumoral CTL function in a mouse melanoma model
Authors: Feferman Tali , Zabolinsky Natalia G. , Manaster Yoav , Hutzler Anat , Shakhar Guy 
Published: October 2015

Abstract
Introduction: Immunotherapies that harness CTLs to eradicate solid tumors, melanoma in particular, have re-emerged as potent clinical options in recent years. Improving the dispersion and cytotoxicity of intratumoral CTLs may further benefit patients. To gain insight into the regulatory processes that limit CTL activity in melanoma we investigated the influence of PD-1 signaling and Tregs on CTL behavior.
Methodology: To mimic adoptive cell therapy we transferred mice bearing B16.OVA melanoma tumors with OT-I CTLs. To study Treg-mediated regulation, we used FOXP3-GFP-LuciDTR-4 host mice, in which 95% of the cells expressing Foxp3 could be depleted using diphtheria toxin. To study PD-1 mediated regulation we injected anti PD-1 to WT host mice. Tumor rejection was monitored for 2-5 weeks.
Two-photon imaging of live mice was used to follow the behavior of CTLs and Tregs within tumors. Time-lapse confocal microscopy was used to follow the influence of PD-1 signaling on the behavior of CTLs and their interaction with B16-Ova cells.
Results: Tumor rejection was closely regulated by Tregs as tumors were densely infiltrated by these cells and their depletion dramatically accelerated tumor rejection. Interactions between CTLs and Tregs seemed indirect, as they did not form conjugates. Following their transfer, antigen-specific OT-I CTLs, as well as polyclonal CTLs, entered murine tumors through selected ICAM-decorated intratumoral vessels. As CTLs accumulated, Treg numbers in the tumors dropped and CTLs could be observed conjugating tumor cells and killing them. Treatment with anti PD-1 increased CTL velocities and accelerated killing of B16.OVA cells in vitro, and was mirrored in vivo by enhanced tumor rejection.
Whereas CTL migration and cytolysis was limited to oxygenated tumor areas within 50 µm of flowing blood vessels, Tregs exhibited higher velocities, were not affected by the proximity of blood vessels, and penetrated deeper into avascular areas.
Conclusions: Our findings suggest that regulatory mechanisms influence CTL efficiency partly by affecting their migration. CTLs, more than Tregs, depend on oxygen for intratumoral locomotion and cytolysis. This disparity allows tumor cells to escape CTL lysis in deep hypoxic tumor niches where high Treg to CTL ratios favor their survival. Thus, differential motility and dependence on oxygen among CTLs and Tregs can dictate the efficiency of CTL-based therapies of melanoma.
Citation Format: Tali Feferman, Natalia G. Zabolinsky, Yoav Manaster, Anat Hutzler, Guy Shakhar. Imaging regulatory mechanisms that limit intratumoral CTL function in a mouse melanoma model. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B06.
Abstract B08: Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors
Authors: Heczey Andras , Liu Daofeng , Tian Gengwen , Marinova Ekaterina , Gao Xiuhua , Guo Linjie , Hicks John , Dotti Gianpietro , Metelitsa Leonid 
Published: October 2015

Abstract
Advances in the design of chimeric antigen receptors (CARs) have improved the anti-tumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells and their restriction by polymorphic HLA molecules limit their therapeutic potential and are associated with toxicity, especially in allogeneic settings. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) can build upon the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKTs were engineered to express a CAR against the GD2 ganglioside, which is highly expressed by neuroblastoma. We compared CAR constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB co-stimulatory endodomains. CAR expression rendered NKTs highly cytotoxic against neuroblastoma cells without affecting their TCR-induced proliferation and CD1d-dependent killing of M2-polarized macrophages. We observed a striking Th1-like polarization of NKTs by 4-1BB-containing CARs in vitro and in mice. Expression of both CD28 and 4-1BB endodomains in the CAR maximized persistence of NKTs in NSG mice with neuroblastoma xenografts. These NKTs, expressing CAR with two co-stimulatory endodomains localized to the tumor site more effectively than T cells with the same CAR (p &lt; 0.001). Three weekly injections of 107 CAR NKTs prolonged survival of humanized (hu)NSG mice with metastatic neuroblastoma (75.2 ± 6 days) compared to a single injection (52.1 ± 4.3 days, p = 0.007) or untreated control (35.4 ± 1.2 days, p &lt; 0.0001). A single injection of CAR T cells was associated with tumor regression early after treatment but resulted in lethal graft-versus-host disease (GvHD) within 5 weeks that prevented evaluation of the anti-tumor activity. In contrast, CAR NKTs did not induce GvHD, even after repeated injections. These results establish the potential of NKTs to serve as a safe and effective platform for CAR-directed cancer immunotherapy.
Citation Format: Andras Heczey, Daofeng Liu, Gengwen Tian, Ekaterina Marinova, Xiuhua Gao, Linjie Guo, John Hicks, Gianpietro Dotti, Leonid Metelitsa. Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B08.
Abstract B12: Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor
Authors: O'Brien Shaun , Thomas Rajan M. , Albelda Steven M. , Wells Andrew D. , Wang Liang-Chuan S. 
Published: October 2015

Abstract
Recent success of adoptive transfer of T cells expressing chimeric antigen receptors (CARs) in patients with blood-borne malignancies has resulted in growing enthusiasm to apply the same approach to treat solid tumors. CAR-expressing T cells, however, will likely face many challenges that will limit their efficacy in solid tumors. One possible obstacle will be the intrinsic negative feedback system that prevent continuing T cell responses. The transcription factor Ikaros, which has been shown to suppress endogenous T effector functions through epigenetic remodeling of cytokine gene loci, may be one such negative regulator. Here we show that anti-mesothelin CAR (mesoCAR) T cells with reduced levels of Ikaros consistently mediate better in vitro cell killing and in vivo tumor regression than their wild-type counterparts. This increased anti-tumor activity was accompanied by increased persistence of mesoCAR T cells, as well as increased IFN-γ production. Enhanced cytolytic activity was also evidenced in mesoCAR T cells with reduced Ikaros, which could be partially explained by increased CD107a upregulation and Granzyme B production. Reduction in the Ikaros level in mesoCAR T cells did not affect T cell receptor and CAR signaling, but was able to render them more resistant to soluble inhibitory factors like TGF-β and adenosine. In summary, inhibition of the transcriptional repressor Ikaros in CAR T cells could be an attractive strategy to overcome immunosuppressive tumor microenvironment and enhance their tumoricidal capacity. Further clinical development is warranted.
Citation Format: Shaun O'Brien, Rajan M. Thomas, Steven M. Albelda, Andrew D. Wells, Liang-Chuan S. Wang. Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B12.
Abstract B14: CD4+CD25+ regulatory T lymphocytes: Prognostic indicator of Chinese breast cancer patients receiving dentitric cells-cytokine induced killer cells infusion
Authors: Song Qing-Kun , Ren Jun , Wang Xiao-Li , Zhou Xin-Na , Yang Hua-Bing , Li Yu-Chen , Wu Jiang-Ping 
Published: October 2015

Abstract
Introduction: Dentitric cell-cytokine induced killer cell infusion is a beneficial immunotherapy for breast cancer among Chinese women. This study aimed to verify the prognostic value of cellular immunity among patients receiving infusions.
Methods: 251 female breast cancer patients participated in the study. Mononuclear cells were harvested from peripheral blood and expanded in vitro. With adequate cell counts, the cultured cells were infused into body. After cell infusion, the cellular immunity was measured by flow cytometry. Progression-free and overall survival were estimated by Kaplan-Meier method with Log-rank test. Cox hazard proportion regression model was used to estimate the hazard ratio and 95% confidence interval.
Results: Proportion of CD4+CD25+ T lymphocyte had a dose-relationship with overall survival (p&lt;0.05), but not progression-free survival. The overall survival was 156 months among patients with lower proportion of CD4+CD25+ T cells compared with 76 months among patients with higher proportion (p&lt;0.05). Higher proportion was associated with a death risk increased by 69% (HR=1.69, 95%CI 1.07, 2.68). Among advanced patients (≥stage III), higher proportion of regulatory T cells were related with hazard ratio of 1.78 (95%CI 1.10, 2.91).
Conclusion: CD4+CD25+ regulatory T lymphocytes were a potential indicator for prognosis of breast cancer patients with the immunotherapy of dentitric cell-cytokine induced killer cells, especially among advanced stage. It might integrated with treatment for further management.
Citation Format: Qing-Kun Song, Jun Ren, Xiao-Li Wang, Xin-Na Zhou, Hua-Bing Yang, Yu-Chen Li, Jiang-Ping Wu. CD4+CD25+ regulatory T lymphocytes: Prognostic indicator of Chinese breast cancer patients receiving dentitric cells-cytokine induced killer cells infusion. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B14.
Abstract B44: The role of CD4 T cells in murine model of NASH-promoted HCC
Authors: Ma Chi , Han Miaojun , Terabe Masaki , Berzofsky Jay , Felsher Dean , Greten Tim 
Published: October 2015

Abstract
Non-alcoholic steatohepatitis (NASH), a common condition in obese patients, is an important risk factor for HCC. However, only little information exists about the immunological mechanisms of how NASH promotes hepatocarcinogenesis. Methionine choline deficient (MCD) diet is widely used to induce NASH. In this study we fed Lap-tTA-myc mice, which develop HCC, with MCD diet. MCD diet accelerated tumor development in MYC on mice. A robust decrease of hepatic CD4 but not CD8 T cells was observed in NASH mice, which was exacerbated by MYC transgene expression. As expected higher level of cell death was detected in these hepatic CD4 T cells. Phenotypic analysis demonstrated that these CD4 T cells had a CD44highCD62Llow effector memory phenotype and produced more IFNγ. Selective CD4 T cell depletion further accelerated HCC development suggesting an important role of these cells for tumor development. Next, we studied the cause of CD4 T cells. In co-culture experiments we demonstrated that lipid-laden hepatocytes from mice on MCD diet induced selective CD4 but not CD8 T cells death through a contact-independent mechanism. FFAs were found from hepatocyte culture medium, and linoleic acid recapitulates the selective toxicity to CD4 T cells. Blocking ROS abolished linoleic acid-induced CD4 T cell death. Our results suggest the critical role of CD4 T cell in the disease progression of NASH to HCC, and provide a new link between lipid metabolism dysfunction with impaired anti-tumor surveillance.
Citation Format: Chi Ma, Miaojun Han, Masaki Terabe, Jay Berzofsky, Dean Felsher, Tim Greten. The role of CD4 T cells in murine model of NASH-promoted HCC. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B44.
Abstract B62: Modulating innate-adaptive immune cell interactions to achieve tumor rejection
Authors: Almeida Ana S. , Kees Tim , Egeblad Mikala 
Published: October 2015

Abstract
A variety of immune cells, the most abundant being macrophages and T cells, typically infiltrate tumors. These immune cells can recognize and kill cancer cells. For example, macrophages activated with interferon-gamma and lipopolysaccharide can kill cancer cells both directly and indirectly, by enhancing the cytotoxic T cells' killing activities. Cancer cells, however, evade the attacking immune cells and even re-instruct macrophages and cytotoxic T cells to facilitate tumor growth, rather than halt it. It is now clear that in a clinical setting T cell deactivation can be overcome using anti-CTLA4 or anti-PDL1 antibodies, leading to tumor regression. Although exciting recoveries are experienced by many patients, the majority of patients do not have long-term benefits of such treatments. Therefore, ways are urgently needed to modify these immune activating approaches so they become beneficial to an expanded patient population.
One underexplored strategy, which we are undertaking, is to re-activate the macrophages so they can kill cancer cells and further enhance the anti-tumor T cell responses. To test different strategies for re-activating macrophages, we are developing co-culture models with cancer cells, T cells and macrophages. In addition, we study interactions between these three cell types in vivo, using intravital imaging of mouse models of breast and pancreatic cancer. Our findings will offer new insights into the mechanisms by immune suppressive signals can be overcome and generate new methods for studying immune responses to cancer in real-time.
Citation Format: Ana S. Almeida, Tim Kees, Mikala Egeblad. Modulating innate-adaptive immune cell interactions to achieve tumor rejection. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B62.