bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P035: A promising cancer immunotherapy target: Novel fully human agonist antibodies against the human T-cell costimulatory receptor CD27
Authors: Ovechkina Yulia , Sridhar Shaarwari , Jurchen David , Peckham David , Tarcha Eric , Iadonato Shawn , Guillaudeux Thierry 
Published: January 2022

Abstract
CD27 is a member of the TNF receptor superfamily and plays a critical role in T-cell activation by providing a costimulatory signal. CD27 signaling enhances T-cell proliferation, activation and differentiation of effector and memory T cells and therefore promotes cytotoxic T cell (CTL)-based anti-tumor immunity. Agonistic stimulation of CD27 is a promising cancer immunotherapy approach to boost specific T cell driven anti-tumor responses. In this study, we generated a series of 147 fully human monoclonal anti-CD27 antibodies and tested their agonist properties to stimulate T cell activation. Using a NF-κB reporter Jurkat cell line, we evaluated in vitro the ability of anti-CD27 antibodies to induce CD27 receptor activation. With this assay, five antibodies have been selected for their agonist properties. When combined with suboptimal T cell receptor (TCR) stimulation, agonist antibodies induced CD27 receptor activation with an EC50 of 1-5 ug/mL. We also used human peripheral blood T cells to characterize the CD27-mediated costimulatory effects of agonist antibodies in combination with TCR stimulation. Our anti-CD27 monoclonal antibodies boosted T cell proliferation and induced IL-2 and TNFalpha secretion only in a presence of TCR engagement. Moreover, CD27 agonists induce strong T cell proliferation in a Mixed Lymphocyte Reaction. CD27 antibodies were shown to bind human and cynomolgus monkey CD27 with a KD value of 5-20 nM as determined by BioLayer Interferometry, but do not bind to mouse CD27. In vivo experiments are currently ongoing to demonstrate the efficient anti-tumor activity of the selected CD27 agonist antibodies in different mice tumor models. In conclusion, we have developed and successfully selected efficient fully human immunostimulatory agonist CD27 mAbs as a promising cancer immunotherapy.
Citation Format: Yulia Ovechkina, Shaarwari Sridhar, David Jurchen, David Peckham, Eric Tarcha, Shawn Iadonato, Thierry Guillaudeux. A promising cancer immunotherapy target: Novel fully human agonist antibodies against the human T-cell costimulatory receptor CD27 [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P035.
Abstract P040: Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors
Authors: Nguyen Yen , Zhao Xiaoyu , Ewald Sarah , Harris Tajie , Zong Hui 
Published: January 2022

Abstract
While checkpoint inhibitors carry great promises for T-cells-based immunotherapy for brain tumors, the presence of abundant T cells supported by the tumor microenvironment (TME) is a prerequisite for it to be effective. Our lab and others' work using mouse models and patient samples demonstrated that, Shh-subtype medulloblastoma, a well-studied pediatric brain tumor, lacks both T cell infiltration and a supportive TME, posing a critical barrier for immunotherapy. I envision that the protozoans Toxoplasma gondii (T.gondii) as a biological agent could provide a unique solution, because T.gondii can naturally disseminate to the brain and induce significant infiltration and activation of T cells asymptomatically. We hypothesize that T.gondii could attract T cells into brain tumors while at the same time convert the non-supportive TME into one that is conducive for T cells. Using a mouse model for medulloblastoma based on a genetic system called Mosaic Analysis with Double Markers (MADM) that recapitulates the tumorigenic process in human by producing few and precisely labeled mutant cells, I was able to assess the immuno-modulatory potential of T.gondii in the context of an intact immune system and endogenous TME. Our preliminary data revealed three exciting facets about T.gondii's immunotherapeutic potential. Via histological assessment and flow cytometry, we found that at 24 days post infection, abundant T cells are recruited into TME. Correspondingly, we detected significant elevation of IFNg and IFNg-driven genes in the tumors, suggesting Th-1 immunity presence in TME. Lastly, we found that T.gondii challenge is associated with reduced tumor incidence. These results indicates T.gondii holds potent immuno-modulatory capability and potentially anti-tumoral functions. My follow-up studies with dive more deeply into three aspects: 1) determine whether T. gondii can sustainably recruit functional T cells into the tumor mass; 2) determine whether T. gondii can help shape a T cell-supportive TME, especially through activating Th1-immune response in innate immune cells; and 3) identify the underlying mechanisms for T.gondii to exert tumor-suppressing activities.
Citation Format: Yen Nguyen, Xiaoyu Zhao, Sarah Ewald, Tajie Harris, Hui Zong. Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P040.
Abstract P042: Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer
Authors: Vermeer Daniel , Westrich Joseph , Colbert Paul , Welbon Craig , Lee John H. , Raben David , Spanos William C. , Pyeon Dohun 
Published: January 2022

Abstract
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a fast-growing health problem in the United States. By analyzing the transcriptomes of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC patient tissues, we previously revealed that expression of CXCL14, constitutively expressed in basal epithelial cells, is downregulated in HPV-positive HNSCC. In contrast, the expression of proinflammatory chemokines, particularly CXCL1, CXCL2, and CXCL8, are significantly upregulated in both HPV+ and HPV- HNSCCs. We further showed that restored expression of CXCL14 in HPV+ HNSCC cells leads to tumor-free survival in vivo by increasing MHC-I antigen presentation on the cancer cell surface and CD8+ T cell activation. Interestingly, high CXCL1, CXCL2, and CXCL8 expression levels significantly correlate to poor HNSCC patient survival, showing an exact opposite pattern of the clinical outcomes associated with the CXCL14 expression levels. To determine the roles of these chemokines in HPV+ HNSCC development, CXCL1 and CXCL2 genes (no murine CXCL8 ortholog) were deleted using a CRISPR-Cas9 knockout system in HPV+ murine HNSCC cells. Using these stably engineered HNSCC cells, we investigated tumor growth, immune cell infiltration, and metastasis in immunocompetent syngeneic mice. Interestingly, the deletion of CXCL1 and CXCL2 significantly delays in vivo tumor growth, decreases myeloid-derived suppressor cell (MDSC) infiltration in the tumor, and decreases lung metastasis. However, the numbers of natural killer (NK), CD4+, and CD8+ T cells in the tumor microenvironment were not affected by CXCL1 and CXCL2 knockout. Next, mice injected with the murine HNSCC cells were treated twice daily with AZD5068, a selective inhibitor of CXCR2, which is a common receptor of CXCL1, CXCL2, and CXCL8 expressed on myeloid cells. Our result showed that the treatment of CXCR2 suppresses in vivo tumor growth in a similar pattern with CXCL1 and CXCL2 knockout. These results suggest that the dysregulation of chemokine expression in HPV-infected cells plays an important role in regulating tumor growth, antitumor immune responses, and metastasis of HPV+ HNSCC. Our findings may provide promising strategies to develop novel immunotherapies for HPV+ HNSCC patients which can likely be extended to other non-viral cancers with immunosuppressive phenotypes.
Citation Format: Daniel Vermeer, Joseph Westrich, Paul Colbert, Craig Welbon, John H. Lee, David Raben, William C. Spanos, Dohun Pyeon. Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P042.
Abstract P059: An increase in eosinophils is associate with response to chemo-immunotherapy in metastatic triple negative breast cancer
Authors: Ghebeh Hazem , Elshenawy Mahmoud A. , Al-Sayed Adher , Al-Tweigeri Taher 
Published: January 2022

Abstract
Background: Several trials have reported on eosinophilia in cancer patients receiving immunotherapy therapy of cancer especially checkpoint inhibitors. There is limited reports on eosinophilia and immunotherapy in triple-negative breast cancer (TNBC).
Patients: We are reporting on eosinophilia and the increase in eosinophil count in a trial testing the combination of Durvalumab band paclitaxel in metastatic TNBC NCT02628132. In this trial 19 patients were recruited, however, only 14 received the combination therapy while the 5 drop out due to progression on paclitaxel alone priming cycle.
Results: One of the patients developed eosinophilia after having a complete response status. The developed eosinophilia lasted for a year and subsided with temporary holding treatment. Among all patients enrolled who received the combination therapy, there was a statistically significant correlation between an increase in eosinophil count (&gt;300/mm3) during treatment and a having partial or complete response to the combination therapy (p 0.028). In agreement, survival analysis showed a significant association between disease-free survival (DFS) and higher PCE count (p 0.005). A similar trend existed with overall survival (OS), although it did not reach significance (p 0.167). The increase in eosinophil count correlated significantly with skin rash/pruritus (p 0.028). On the other hand, the association between baseline PEC before treatment and response to treatment was not statistically significant despite the positive trend.
Conclusions: An increase in circulating eosinophil count correlates with response to therapy with chemo-immunotherapy combination in metastatic TNBC. This study supports the role eosinophils are playing in the treatment of cancer.
Citation Format: Hazem Ghebeh, Mahmoud A. Elshenawy, Adher Al-Sayed, Taher Al-Tweigeri. An increase in eosinophils is associate with response to chemo-immunotherapy in metastatic triple negative breast cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P059.
Abstract P060: Identification of host-intrinsic resistance mechanisms to immune checkpoint inhibitors (ICI) in Diversity Outbred mice
Authors: Hackett Justin , Glassbrook James , Muniz Maria , Gibson Heather M. 
Published: January 2022

Abstract
The advent of immune checkpoint inhibitors (ICI) for cancer therapy has improved outcomes for a variety of malignancies, however many a significant proportion of patients fail to benefit. While tumor-intrinsic mechanisms are likely involved in therapy resistance, it is unclear to what extent genetic heterogeneity of the host plays in response. To investigate this in a pre-clinical setting, we utilize the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. DO mice are genetically distinct animals generated by cross-breeding 8 inbred founder strains, and CC mice are recombinant inbred mice generated from the same 8 founders as DO. We find a wide variation in response to anti-PD-1/anti-CTLA-4 ICI in B16F0-bearing (C57BL/6xDO)F1 mice (n=142) with ~30% showing partial response with delayed tumor onset and ~13% showing complete tumor elimination with protection against subsequent contralateral rechallenge. Genetic linkage analysis using the R/qtl2 package identifies genomic loci associated with therapeutic outcomes. Importantly, the MHC locus was not significantly associated with response. Of the strongly associated loci, the region within chromosome 13 was further validated in CC mice bearing the positive (NZO) versus negative (C57BL/6) driver genotypes at this locus. ICI response was detected in 2/3 (C57BL/6xCC)F1 predicted responder models, with no response in predicted non-responders. This locus solely contains the murine prolactin family. Prolactin is a known immunomodulating cytokine with association to various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice, which notoriously fail to respond to ICI alone against B16F0 tumors, with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Combined ICI with prolactin shows an interaction effect against B16F0, with 5/8 mice exhibiting slowed tumor growth relative to controls. To test whether this host-derived phenomenon applies to additional tumor models, we tested ICI response to Lewis Lung Carcinoma (LLC) in a (C57BL/6xCC)F1 model where response to B16F0 was observed. Relative to inbred C57BL/6 mice, where no response to ICI is observed, this (C57BL/6xCC)F1 model shows a similar response to ICI against LLC as was detected for B16F0. Collectively, this study shows that host genetics play a role in ICI response and that prolactin may be a positive regulator of ICI efficacy.
Citation Format: Justin Hackett, James Glassbrook, Maria Muniz, Heather M. Gibson. Identification of host-intrinsic resistance mechanisms to immune checkpoint inhibitors (ICI) in Diversity Outbred mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P060.
Abstract P061: Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits the efficacy of immune checkpoint blockade
Authors: Ho William W. , Gomes-Santos Igor L. , Aoki Shuichi , Datta Meenal , Kawaguchi Kosuke , Talele Nilesh P , Roberge Sylvie , Ren Jun , Liu Hao , Chen Ivy X , Andersson Patrik , Chatterjee Sampurna , Kumar Ashwin S. , Amoozgar Zohreh , Zhang Qixian , Huang Peigen , Ng Mei Rosa , Chauhan Vikash P , Xu Lei , Duda Dan G. , Clark Jeffrey W. , Pittet Mikael J. , Fukumura Dai , Jain Rakesh K 
Published: January 2022

Abstract
Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared to their subcutaneous tumor counterparts. Furthermore, treatment with FMS-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.
Citation Format: William W. Ho, Igor L. Gomes-Santos, Shuichi Aoki, Meenal Datta, Kosuke Kawaguchi, Nilesh P Talele, Sylvie Roberge, Jun Ren, Hao Liu, Ivy X Chen, Patrik Andersson, Sampurna Chatterjee, Ashwin S. Kumar, Zohreh Amoozgar, Qixian Zhang, Peigen Huang, Mei Rosa Ng, Vikash P Chauhan, Lei Xu, Dan G. Duda, Jeffrey W. Clark, Mikael J. Pittet, Dai Fukumura, Rakesh K Jain. Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits the efficacy of immune checkpoint blockade [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P061.
Abstract P064: Dual effect of epigenetic inhibitor and CAR-NK cell therapy in bladder cancer
Authors: Morales Lucia , Nunes Sandra Pinto , Munera-Maravilla Ester , Casado Jose Antonio , Río Paula , Valeri Antonio , José-Enériz Edurne San , Agirre Xavier , Prosper Felipe , Paramio Jesús María 
Published: January 2022

Abstract
Bladder cancer (BC) causes 220,000 deaths per year worldwide since current therapies cannot be used in a large proportion of patients due to comorbidities. Recently, new treatments have been developed, including immunotherapies aimed to induce an antitumor response by activating the patients' immune system. However, since those treatments are only effective in a small subset of patients, new therapies are needed. Epigenetic modifications are drivers of BC and their modulation by inhibitors is considered a promising approach for BC management. Moreover, these compounds also show immunomodulatory properties, including NK cells antitumor activities. We observed that novel inhibitor of epigenetic machinery CM-1758, against histone deacetylases, display growth inhibition in a variety of human BC cell lines (5637, RT112, 253J, J82 and TCCSUP) in the low micromolar range. In addition, the compound induced the surface expression of NK cell ligands (NKG2DLs) in four of these tumor cells as measured by flow cytometry. Furthermore, we developed chimeric antigen receptor (CAR)-NK cells that express high levels of CAR composed by a fusion of NKG2D receptor ectodomain with 4-1BB and CD3z. Cytotoxic effects of NKG2D CAR-NK cells in co-culture with BC tumor cells were significantly potentiated as compared with parental NK-92 cells. In particular, 253J cells treated with CM-1758, that augmented its NKG2DLs levels, increased their sensitivity to NKG2D CAR-NK cells in co-culture and this effect was dependent on NKG2D receptor. Our results support that treatment with epigenetic inhibitors may facilitate the use of CAR-NK-based cell therapies as a promising strategy for BC management.
Citation Format: Lucia Morales, Sandra Pinto Nunes, Ester Munera-Maravilla, Jose Antonio Casado, Paula Río, Antonio Valeri, Edurne San José-Enériz, Xavier Agirre, Felipe Prosper, Jesús María Paramio. Dual effect of epigenetic inhibitor and CAR-NK cell therapy in bladder cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P064.
Abstract P065: Effects of targeted radiotherapy on tumor immune landscape in diverse murine tumor models
Authors: Wirtz Tristan , Lee Catherine , Xie Tao , Manzuk Lisa , Kraus Manfred , Dillon Christopher , Affolter Timothy , Giddabasappa Anand 
Published: January 2022

Abstract
Radiotherapy (RT) has traditionally been seen as a means to induce targeted tumor cell death, and more than 50% of all cancer patients receive RT. RT is also known to induce immune cell activation, and the advent of immunotherapeutic treatments such as checkpoint inhibition has sparked increased interest in using RT to enhance an anti-tumor immune response. However, to take advantage of the immunological effects of RT, a deeper understanding of the effects of RT on tumor-infiltrating leukocytes (TILs) is essential. Therefore, we systematically analyzed the effects of RT on tumor growth and the tumor-infiltrating immune cells in five syngeneic tumor models with diverse immune cell-infiltration profiles. These tumor types show strong differences in the overall immune cell infiltration, as well as in the composition of the infiltrating immune cell populations. After RT, tumors that were characterized as hot (e.g. CT26) showed increased sensitivity and dose-dependent tumor growth inhibition compared to cold tumor models (e.g. B16F10). Immune cell profiling indicated that RT led to strong changes in TILs of some tumor types, such as MC38 and CT26. These changes included reduced fractions of macrophages and increases in NK cells and also CD8 T cells. Single cell RNA sequencing also revealed an increase in CD8 T cells expressing proliferation-related genes. Furthermore, macrophage clusters expressing markers of proliferation were specifically eradicated by RT, while monocytes and neutrophils were less affected. The monocytes and neutrophils in the models that showed little changes in TILs after RT expressed marker genes of type-I interferon response. These findings predict that tumors that are highly infiltrated by neutrophils and monocytes, with little intra-tumoral proliferation and type-I interferon response signature, are likely resistant to an RT-mediated anti-tumor immune response. The present work has laid a strong foundation to develop next-generation combinatorial treatments using RT and immunotherapy.
Citation Format: Tristan Wirtz, Catherine Lee, Tao Xie, Lisa Manzuk, Manfred Kraus, Christopher Dillon, Timothy Affolter, Anand Giddabasappa. Effects of targeted radiotherapy on tumor immune landscape in diverse murine tumor models [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P065.