bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A42: Combination immunotherapy of an autochthonous murine lung cancer model expressing human CEA as a tumor-associated self-antigen
Authors: Rakhra Kavya , Zhu Eric F. , Abraham Wuhbet , Moynihan Kelly D. , Mehta Naveen , Wittrup Karl D. , Irvine Darrell J. 
Published: March 2017

Abstract
While cancer immunotherapies like checkpoint inhibitors have resulted in unprecedented clinical success, they only benefit a subset of patients. To improve therapeutic outcomes for greater numbers of patients, one strategy is to rationally combine different immunotherapy modalities. We recently demonstrated that attaching albumin-binding lipophilic tails to peptide antigens or molecular adjuvants (creating amphiphile vaccines) results in enhanced T-cell responses. Additionally, we observed significant tumor regression upon combining tumor-antigen targeting antibodies with extended half-life IL-2 (exPK-IL-2) in mouse models of melanoma and prostate cancer. In the present work, we combined both approaches to treat a spontaneous model of lung adenocarcinoma expressing carcinoembryonic antigen (CEA), an oncofetal protein expressed in some human lung cancers. KrasLSL-G12D/+;;p53fl/fl mice were crossed with transgenic mice expressing human-CEA to generate a CEA-tolerant background. Lung tumors were induced by infection with a lentivirus expressing Cre recombinase and human CEA. Due to the extended latency of tumor initiation in this model, we also generated a CEA-expressing cell line from these mice to test the efficacy of different combination immunotherapy regimens. We discovered that weekly treatments combining a CEA-targeting amphiphile-vaccine, exPK-IL-2, and an anti-CEA antibody with checkpoint inhibitors (anti-PD-1 and -CTLA4) resulted in sustained tumor regression in 50% of mice bearing established tumors. We are currently testing this combination immunotherapy on autochthonous lung tumors. Our results suggest that breaking tolerance to a tumor-associated self-antigen (CEA) and combining immunotherapies to recruit both innate and adaptive immune effectors can have a potent therapeutic effect in intractable tumors like lung cancer.
Citation Format: Kavya Rakhra, Eric F. Zhu, Wuhbet Abraham, Kelly D. Moynihan, Naveen Mehta, Karl D. Wittrup, Darrell J. Irvine. Combination immunotherapy of an autochthonous murine lung cancer model expressing human CEA as a tumor-associated self-antigen. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A42.
Abstract A50: Direct oncogene cancer killing and selective tumor Treg killing through the TNFR2 receptor via dominant antibody antagonists
Authors: Torrey Heather , Butterworth John , Mera Toshi , Okubo Yoshiaki , Wang Limei , Baum Danielle , Warden Sarah , Plager Sara , Huang Daniel , Vanamee Eva , Foster Rosemary , Faustman Denise 
Published: March 2017

Abstract
A major barrier to cancer immunotherapy is lack of selective inhibitors of the regulatory T cells (Tregs) of the cancer microenvironment and methods to directly kill tumors through novel surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is a target protein with restricted expression on the most potent Tregs of the tumor infiltrate and on human tumors as a newly discovered human oncogene. We characterized the effect of TNFR2 antibody antagonists via TNFR2 in human samples from ovarian ascites compared to healthy controls. TNFR2 antagonists potently inhibited Treg proliferation with exponential potency and selectivity for the tumor microenvironment Tregs. Furthermore, common ovarian cancer cell lines such as OVCAR3 expressed the TNFR2 oncogene and were rapidly and completely killed by TNFR2 antagonistic antibodies. Dominant TNFR2 antagonists demonstrate tumor-specific Treg depletion. Blocking TNFR2 signaling with antagonist antibodies also creates a novel tool to possibly eliminate tumors expressing the TNFR2 oncogene and to more potently suppress Tregs of the tumor environment.
Citation Format: Heather Torrey, John Butterworth, Toshi Mera, Yoshiaki Okubo, Limei Wang, Danielle Baum, Sarah Warden, Sara Plager, Daniel Huang, Eva Vanamee, Rosemary Foster, Denise Faustman. Direct oncogene cancer killing and selective tumor Treg killing through the TNFR2 receptor via dominant antibody antagonists. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A50.
Abstract A53: Establishment of a brain tumor model with dysfunctional tumor immunity in mice as a platform for immunotherapeutic evaluation and PD-1 immunotherapy
Authors: Nakashima Hiroshi , Alayo Quazim , Penaloza Pablo , Barouch Dan , Chiocca Ennio Antonio 
Published: March 2017

Abstract
Several clinical trials are currently underway for patients with newly diagnosed and recurrent glioblastoma to reinvigorate tumor immunity using immune-checkpoint blockade. However, the CNS is immunologically unique in its maintenance of an immunosuppressive environment, to protect brain cells from autoimmunity and inflammation. Thus, immunotherapy of brain tumors requires novel regimens to overcome tumor immuno-suppression. Suitable preclinical animal models with exhausted tumor-specific immunity are currently not available. We thus hypothesized that a chronic LCMV (cLCMV) strain that induces T cell exhaustion in mice may be co-opted to model the impaired immunity that characterizes brain tumors. In this model, naïve and cLCMV-infected mice failed to reject a challenge with glioma in brain when murine glioma cells express one of LCMV antigens (VA-glioma) that are presented via MHC-I. In contrast, mice preimmunized with the acutely-controlled LCMV (aLCMV) strain did reject VA-glioma. In fact, in vitro co-culture of lymphocytes and glioma cells, and in vivo TIL analyses suggested that VA-glioma failed to induce CD8+ T cell responses in cLCMV-mice, in contrast to the robust CD8+ T cell response in aLCMV-mice. Furthermore, cLCMV-specific CD8 T cells lacked a central memory T cell phenotype (CD44+, CD62L-, CD127-) and expressed significantly high levels of PD-1. Thus, treatment with anti-PD1, but not isotype control antibody, successfully reinvigorated and restored antitumor immunity in cLCMV-mice that received VA-glioma cells. PD-1 blockade led to significantly improved survival. However, this treatment did not show a therapeutic effect in cLCMV-mice that received parental glioma cells that don't express the viral antigen. These data strongly suggest that PD-1 blockade is effective in brain tumors that induce impaired tumor-specific T cell immunity. In conclusion, this novel mouse model may be useful to screen for novel immune checkpoint inhibitors and combination regimes in the setting of a single dysfunctional CD8 T cell response.
Citation Format: Hiroshi Nakashima, Quazim Alayo, Pablo Penaloza, Dan Barouch, Ennio Antonio Chiocca. Establishment of a brain tumor model with dysfunctional tumor immunity in mice as a platform for immunotherapeutic evaluation and PD-1 immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A53.
Abstract A63: Macrophages expressing fibroblast activation protein-alpha are a tumor-educated polarization phenotype which facilitates metastasis
Authors: Koning Tamara de , Burchell Joy M. , Diebold Sandra S. , Arnold James N. 
Published: March 2017

Abstract
Tumor associated macrophages (TAMs) are one of the most abundant stromal cell types in cancer, and promote tumor progression by supporting angiogenesis, immunosuppression, and tumor cell migration. However, there is increasing evidence to suggest that the functions of these cells could be refined to specific subsets. A subset of TAMs identified by the cell surface marker fibroblast activation protein-alpha (FAP) has previously been demonstrated to facilitate immune suppression in an ectopic Lewis lung carcinoma model through its expression of the heme degrading enzyme heme oxygenase-1 (HO-1) (Arnold et al, 2014). Little is known about the origin of these cells, and whether they represent an autonomous population or a polarization phenotype. Here we show in orthotopic mammary 4T1 adenocarcinomas that FAP+ TAMs are a tumor-educated polarization phenotype which is functionally distinct from IL-4/-13 polarized alternatively activated macrophages. In contrast, IL-6 and integrin β1 signaling contribute to FAP+ TAM polarization. In addition to the previously described role of these cells in immune suppression we show that FAP+ TAMs facilitate pulmonary metastasis. FAP+ TAMs are the primary tumoral source of HO-1 and pharmacological inhibition of HO activity reduces pulmonary metastasis in both orthotopic 4T1 adenocarcinomas and aggressive autochthonous murine mammary adenocarcinomas (MMTV-PyMT). Using an in vitro transwell assay, we demonstrate that HO-1 activity by macrophages enhances the transendothelial migration of tumor cells. In vivo HO inhibition does not affect seeding of tumor cells in the lung once these cells have entered the circulation, suggesting that FAP+ TAMs facilitate the intravasation event. Together, these results demonstrate FAP+ TAMs to be a tumor-educated polarization phenotype which facilitates tumor cell metastasis by its expression of HO-1.
Arnold, J.N., et al., Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol Res, 2014. 2(2): p. 121-6
Citation Format: Tamara de Koning, Joy M. Burchell, Sandra S. Diebold, James N. Arnold. Macrophages expressing fibroblast activation protein-alpha are a tumor-educated polarization phenotype which facilitates metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A63.
Abstract A65: Mechanisms of melanoma cell resistance to phagocytosis
Authors: Anderson Katie L. , Snyder Kristin M. , Lins Debra , Weiskopf Kipp , Shimizu Yoji , Weissman Irving , Mescher Matthew , Modiano Jaime 
Published: March 2017

Abstract
Melanoma is notoriously resistant to apoptosis and to other cytolytic mechanisms used by immune cells; however, the mechanisms by which melanoma cells evade phagocytosis by the innate immune system are incompletely understood. Previous studies in our lab revealed that melanoma cells from human, mouse, and dog tumors display an evolutionarily conserved resistance to phagocytosis that was not observed in lymphoma cells or in other solid tumors from these three species. Blockade of CD47 to disable “don't eat me” signals and doxorubicin treatment to enhance the “eat me” signals calreticulin and phosphatidylserine lead to small increases in melanoma cell phagocytosis in vitro. However, this increase did not appear to be biologically relevant, as combination chemo-immunotherapy did not consistently promote enhanced activation of antigen-specific T cells in the tumor draining lymph node or reduce tumor burden in the B16 melanoma model. From these studies, we concluded that melanoma cells display an evolutionarily conserved resistance to phagocytosis, which cannot be fully mitigated by modulation of known pro- and anti-phagocytic pathways. Therefore, we hypothesize that melanoma cells possess an uncharacterized mechanism of resistance to phagocytosis, such as expression of a soluble or membrane bound “don't eat me” signal. To test for the presence of a soluble anti-phagocytic factor, we performed a series of assays in which human lymphoma (Raji) cells, shown to be readily phagocytosed by mouse macrophages, were placed in supernatant harvested from cultured human melanoma (M21) cells. Blockade of the known “don't eat me” signal CD47 was achieved using a SIRPα; mimotope, CV1-G4, or an isotype control. Lymphoma cell phagocytosis by mouse macrophages and response to CD47 blockade were unaffected by the presence of melanoma cell supernatant, suggesting that a secreted factor is not responsible for resistance. To test for the presence of an uncharacterized, membrane-bound “don't eat me” signal, we designed a siRNA panel containing 48 genes whose protein products are expressed on the cell surface of melanoma cells. In ongoing experiments, we are testing how knockdown of these proteins through RNA interference affects macrophage-mediated phagocytosis of melanoma cells and response to CD47 blockade.
Citation Format: Katie L. Anderson, Kristin M. Snyder, Debra Lins, Kipp Weiskopf, Yoji Shimizu, Irving Weissman, Matthew Mescher, Jaime Modiano. Mechanisms of melanoma cell resistance to phagocytosis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A65.
Abstract A68: Phosphodiesterase-5 inhibition modulates surgery-induced myeloid-derived suppressor cells to reduce postoperative metastatic disease
Authors: Tai Lee-Hwa , Alkayyal Almohanad A. , Baxter Katherine E. , Angka Leonard , Kennedy Mike , Souza Christiano Tanese de , Auer Rebecca C. 
Published: March 2017

Abstract
Purpose: Cancer surgery while necessary for primary tumor removal, has been shown to induce immune suppression and promote metastases in preclinical models and human cancer surgery patients. Activating the immune system and reversing immunosuppression have emerged as promising ways to treat cancer and they can be safely employed in the perioperative period. In this study, we evaluated the immunotherapeutic potential of phosphodiesterase-5 (PDE-5) inhibitors to target surgery-induced myeloid-derived suppressor cells (MDSC) and restore natural killer (NK) cell function in the clinically relevant perioperative period.
Experimental Design: Immunocompetent mice tumor models of major surgery were used to characterize the functional suppression of surgery-induced MDSC and to assess the in vivo efficacy of perioperative PDE5 inhibition. In cancer surgery patients with abdominal malignancies, we assessed NK cell function following co-culture with MDSC and PDE5 inhibition.
Results: Perioperative PDE5 inhibition reverses surgery-induced immunosuppression. In particular, sildenafil reduces surgery-derived granulocytic-MDSC (gMDSC) function through downregulation of arginase 1 (ARG1), IL4Rα; and reactive oxygen species (ROS) expression, enabling NK cell antitumor cytotoxicity and reducing postoperative disease recurrence. By removing surgery-derived immunosuppressive mechanisms on MDSC, sildenafil synergizes with the administration of perioperative influenza vaccination to reduce postoperative metastasis. Importantly, sildenafil reverses MDSC suppression in cancer surgery patients.
Conclusions: These findings demonstrate that PDE5 inhibitors reduce postoperative metastasis by their ability to inhibit surgery-induced MDSC. Further clinical studies are warranted to investigate the immunotherapeutic role of PDE5 inhibitors in combination with cancer surgery.
Note: This abstract was not presented at the conference.
Citation Format: Lee-Hwa Tai, Almohanad A. Alkayyal, Katherine E. Baxter, Leonard Angka, Mike Kennedy, Christiano Tanese de Souza, Rebecca C. Auer. Phosphodiesterase-5 inhibition modulates surgery-induced myeloid-derived suppressor cells to reduce postoperative metastatic disease. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A68.
Abstract A74: CAR-T cells harboring camelid single domain antibody as targeting agent to CEACAM6 antigen in pancreatic cancer
Authors: Wong Wah Yau , Tanha Jamshid , Krishnan Lakshmi , Tian Baomin , Kumar Praveen , Gaspar Kim , Demas Steve , Rohmann Sven , Chao Heman 
Published: March 2017

Abstract
Carcinoembryonic Antigen Related Cell Adhesion Molecule 6 (CEACAM6) is overexpressed in many types of human cancers such as breast, pancreatic, colorectal, and non-small-cell lung adenocarcinoma, and is an independent predictor of overall survival and disease free survival. Targeting this molecule by antibodies has slowed tumor progression in certain animal models. 2A3 is a camelid single domain antibody isolated from a whole cancer cell immunized llama library. The antibody binds specifically to the CEACAM6 antigen with high affinity (5nM as measured by SPR) and inhibits the proliferation of CEACAM6-expressing cancer cells in vitro. In this study, Chimeric-Antigen Receptor (CAR) T cells were engineered to target human CEACAM6 antigen by transducing the 2A3 antibody sequence to generate a modified chimeric CD28 signaling domain fused to chimeric CD3-zeta. Transduction efficiency and expression of 2A3 antibody were verified by flow cytometry. Co-incubation of CEACAM6-specific CAR-T (CEACAM6-CAR-T) cells with the CEACAM6-expressing pancreatic cell line BxPC-3 resulted in augmented cytotoxicity and cytokines (IL-2 and IFN-γ) release, suggesting potential anti-cancer activity of the CAR-T cells. Data from real-time cell analysis showed a significant increase in BxPC-3 cell cytotoxicity by CEACAM6-CAR-T cells, as compared to native T cells. However, CEACAM6-CAR-T cells showed much lower cytotoxic activity on negative control cell lines. The efficacy of CEACAM6-CAR-T cells in xenograft model was examined in vivo. BxPC-3 cells were inoculated subcutaneously into the hind flank of CIEA NOG mice. Three groups of mice then received intravenous injection of either PBS, native T cells, or CEACAM6-CAR-T cells, respectively, at day 1, 8, and 15. The data demonstrated very high efficacy of CEACAM6-CAR-T cells against the pancreatic cancer xenograft. CEACAM6-CAR-T cells significantly decreased the growth of the BxPC-3 xenograft as compared to that of native T cells (p-value=0.00025) and PBS (p-value=7.91x106). No toxic effect was observed based on body weight measurement. The results strongly support that CEACAM6-CAR-T cells can be used as an effective immunotherapy agent against CEACAM6-expressing cancers, and that camelid single domain antibodies can be easily adopted for CAR-T type therapies.
Citation Format: Wah Yau Wong, Jamshid Tanha, Lakshmi Krishnan, Baomin Tian, Praveen Kumar, Kim Gaspar, Steve Demas, Sven Rohmann, Heman Chao. CAR-T cells harboring camelid single domain antibody as targeting agent to CEACAM6 antigen in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A74.
Abstract A85: Investigating endogenous anti-tumor T cell responses in native tumor microenvironments
Authors: Joshi Nikhil , Jacks Tyler 
Published: March 2017

Abstract
Genetically-engineered mouse models (GEMMs) exist for most types of cancer in which autochthonous tumors develop into advanced disease in the presence of a fully functional immune system. These GEMMs would be ideal for investigating questions in cancer immunology, including those concerning the commonalities and differences between immune responses that target different cancers, and how the tumor microenvironments (TMEs) associated with different cancer types impact the functions of tumor-infiltrating immune cells. However, unlike human tumors, tumors in GEMMs have few somatic mutations and thus require exogenous neoantigens (neoAgs) to drive interactions with anti-tumor T cells. There are only a handful of mechanisms to program tumors to express neoAgs, and thus, GEMMs for most tumor types remain inaccessible for cancer immunology studies. Here, we describe the “iNversion INducible Joined neoAg” (NINJA) mouse, which can be used to program GEMM tumors with a common neoAg, and thus stimulate a common set of tumor-specific CD8 T cells. NINJA will be useful for addressing many key unanswered questions cancer immunology, including comparisons of immune responses across several cancer types and comparisons of anti-tumor T cell responses targeting de novo expressed neoAgs at different stages in tumor development. NINJA mice will also be invaluable as a preclinical platform for testing immunotherapeutics, and for investigating why certain immunotherapeutic regimens are more effective when treating some cancers and not others. NINJA is unique, because neoAgs are encoded within the genome, yet NINJA avoids central and peripheral tolerance, a common problem with other systems. This is achieved because the DNA sequences encoding the full-length neoAgs are discontinuous in the OFF state and, thus, neoAgs are silent. Induction of neoAgs is highly regulated, requiring a permanent inversion of a DNA element in NINJA, which allows production of the full-length NINJA neoAgs and GFP (a marker of neoAg expression). This inversion is regulated by Flippase (FlpO), which itself is highly regulated, requiring cells are exposed to Cre recombinase, and then doxycycline and tamoxifen. Therefore, NINJA is compatible with most Cre-inducible GEMMs of cancer. Activating NINJA with adenoviral infection results in a strong, NINJA-specific CD8 T cell response while, in contrast, activation in the setting of lung tumors leads to T cell dysfunction. Thus, NINJA is a powerful, highly versatile system for investigating T cell function in many settings, including cancer, immune tolerance, and autoimmunity.
Citation Format: Nikhil Joshi, Tyler Jacks. Investigating endogenous anti-tumor T cell responses in native tumor microenvironments. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A85.