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Aromatase inhibitors (AIs) are a class of drugs commonly given to patients with estrogen receptor (ER)-dependent breast cancers to reduce estrogenic stimulation. However, AIs like Letrozole are associated with negative side effects such as cognitive deficits, sleep disturbances and hot flashes. We have previously shown that these negative effects can be recapitulated in common marmosets (Callithrix jacchus) treated with Letrozole (20 μg daily) for 4 weeks and that marmosets treated with Letrozole show increased levels of estradiol in the hippocampus (Gervais et al., 2019). In order to better understand the mechanisms through which AIs affect cognitive function and increase steroid levels in the hippocampus, we used bulk, paired-end RNA-sequencing to examine differentially expressed genes among Letrozole-treated (LET; n = 8) and vehicle-treated (VEH; n = 8) male and female animals. Gene ontology results show significant reduction across hundreds of categories, some of the most significant being inflammatory response, stress response, MHC Class II protein complex binding, T-cell activation, carbohydrate binding and signaling receptor binding in LET animals. GSEA results indicate that LET females, but not LET males, show enrichment for hormonal gene sets. Based on the transcriptional changes observed, we conclude that AIs may differentially affect the sexes in part due to processes mediated by the CYP-450 superfamily. Ongoing studies will further investigate the longitudinal effects of AIs on behavior and whether AIs increase the risk of stress-induced neurodegeneration.

BackgroundOR2805 antibody was discovered using B cells derived from an elite responder to checkpoint inhibitor (CPI) therapy. It is a fully human IgG1 antibody that binds to CD163, an immune-suppressive receptor highly expressed on tumor associated macrophages (TAMs). High numbers of CD163-expressing TAMs generally predict an unfavorable prognosis in solid tumors. These CD163-expressing TAMs contribute to an immune-suppressive tumor microenvironment and inhibit an anti-tumor T-cell response by engaging immune checkpoints and secreting immune-suppressive cytokines. Relieving the immune suppression of CD163-expressing TAMs to improve anti-tumor T-cell responses is a rational therapeutic strategy as monotherapy and in combination with CPI therapy.MethodsCocultures of immunosuppressive primary human polarized M2c macrophages with autologous CD8+ T cells or phytohemagglutinin (PHA)-T cell blasts (exhausted T cells) were used to interrogate OR2805-dependent immunomodulatory responses as single agent and in combination with pembrolizumab, an anti-PD1 antibody. The anti-tumor activity of OR2805 was evaluated in humanized mouse models. Safety and pharmacokinetics (PK) profile of OR2805 was evaluated in cynomolgus monkeys and human whole blood for cytokine release assessment.ResultsIn coculture assays, OR2805-treatment relieved the suppressive effect of M2c macrophages as demonstrated by increased T-cell proliferation and the release of IFN-γ and perforin. OR2805 restored the IFN-γ production of exhausted T cells and showed a synergistic effect on cocultures treated in combination with pembrolizumab. OR2805-treatment demonstrated significant anti-tumor activity in lung cancer xenograft models in humanized NSG-SGM3 mice. In cynomolgus monkeys, OR2805 demonstrated a typical IgG1 PK profile and good serum exposure. Furthermore, OR2805 did not trigger the release of IL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, or TNF-α cytokines in whole blood from either healthy donors or NSCLC patients.ConclusionsOR2805 reduced M2c-mediated immunosuppression and enhanced T cell effector functions. OR2805-treatment resulted in significant anti-tumor activity in lung cancer xenograft models in humanized mice. The pharmacology, PK, and toxicokinetic data support further development of OR2805 as an anti-cancer therapy, both as a monotherapy and in combination with CPI therapy.

BackgroundSiglec-15 is an immunosuppressive sialic acid-binding Ig-like lectin expressed by myeloid cells, tumor associated macrophages (TAMs), and some human tumors. Interactions between Siglec-15 on TAMs and sialoglycans found on cancer cells contribute to the immunosuppressive tumor microenvironment. Furthermore, Siglec-15 expressed by TAMs inhibits anti-tumor immune responses by engaging unknown immune checkpoint(s) on T cells. Notably, the mutually exclusive expression of Siglec-15 and the checkpoint ligand PD-L1 in the tumor tissue emphasizes Siglec-15 as an attractive target for combination immunotherapy. Anti-Siglec-15 antibody is currently being evaluated in clinical trials for the treatment of cancer.MethodsAnti-Siglec-15 antibodies were cloned from B cells derived from rabbits immunized with human Siglec-15 protein. The antibodies were evaluated for binding to human and cynomolgus Siglec-15 by enzyme-linked immunosorbent assay (ELISA). Top clones were selected based on activity in a panel of functional and phenotypic assays using primary human macrophages and T cells and were subsequently fully humanized. The humanized anti-Siglec-15 IgG1 antibodies were screened for binding to human and cynomolgus Siglec-15 by ELISA, binding to cells expressing Siglec-15, and ability to rescue T cell functional activity (proliferation and IFN-γ) from M2c-mediated immune suppression in vitro. The pharmacokinetics of lead humanized Siglec-15 IgG1 antibodies and their anti-tumor activity were evaluated in humanized mouse models.ResultsWe have identified a panel of fully humanized anti-Siglec-15 antibodies that bind to recombinant human and cynomolgus Siglec-15 proteins, to Siglec-15-expressing cell lines and immunosuppressive M2c macrophages without appreciable binding to other Siglec family members. Lead antibodies were identified using functional screens modeling Siglec-15-mediated immune suppression by M2c macrophages. These antibodies restored T cell immune responses in two different M2c/CD8 T cell coculture assays. In the first model, lead antibodies rescued the proliferative and IFN-γ responses of anti-CD3-activated human T cells from the inhibitory activity of M2c macrophages. In the second model, these antibodies restored the ability of exhausted CD8 T cells to secrete IFN-γ in the presence of M2c macrophages. Lead antibodies demonstrated a half-life of 6–11 days in humanized FcRn mice, and tumor growth inhibition in humanized NSG-SGM3 mice.ConclusionsWe have identified novel humanized anti-Siglec-15 antibodies that restore effector function of activated and exhausted T cells from M2c-mediated immune suppression, with excellent half-life and anti-tumor activity in humanized mouse models. These data provide a strong rationale for further development of these antibodies for anti-cancer immunotherapy.

Background: OR2805 is a fully human IgG1 antibody that binds to CD163, an immune-suppressive receptor highly expressed on tumor associated macrophages (TAMs). High numbers of CD163-expressing TAMs generally predict an unfavorable prognosis in solid tumors. CD163-expressing TAMs contribute to an immune-suppressive tumor microenvironment (TME) and inhibit an anti-tumor T-cell response by engaging immune checkpoints, producing immune-suppressive cytokines, and promoting T-cell skewing towards a pro-cancer Th2 phenotype. Relieving the immune suppression of CD163-expressing TAMs in the TME to improve T-cell-mediated responses is a rational adjunct to immune checkpoint inhibitor (CPI) therapy. Methods: OR2805 was discovered using OncoResponse's discovery platform by cell-based functional and phenotypic assays. B cells derived from CPI elite responders were cultured at clonal density, and IgG antibodies in supernatants were evaluated for binding to myeloid-derived suppressor cells. Variable-regions from positive hits were sequenced, cloned, and expressed as recombinant IgG1. OR2805 was identified as one of the top hits that relieved myeloid cell-mediated immune suppression. Co-cultures of immunosuppressive primary human M2 macrophages and autologous T cells were used to interrogate OR2805-dependent immunomodulatory responses in vitro. The anti-tumor activity of OR2805 in vivo was evaluated in a humanized mouse model. Results: OR2805 binds to CD163 expressed on TAMs and M2-like macrophages. OR2805 does not bind to other hematopoietic cells nor to a panel of human primary non-immune cells. OR2805 treatment reduces expression of cell-surface markers associated with tumor-promoting M2c-like macrophages. In co-culture assays, OR2805 relieves the suppressive effect of M2 macrophages and results in increased T-cell activation and proliferation, upregulation of T-cell activation markers, and enhanced T-cell-mediated tumor cell killing. Administration of OR2805 in humanized NSG-SGM3 mouse tumor models resulted in approximately 55% and 75% reduction in A549 tumor growth and NCI-H1975 tumor growth, respectively. In this model, OR2805 treatment significantly increased the proportions of human CD8+ T cells and human CD11b+ myeloid cells, as well as significantly enhanced expression of activation markers by human CD8+ T cells. Conclusions: OR2805 reduces M2 macrophage-mediated immunosuppression and enhances anti-tumor immune responses. OR2805 treatment induces anti-tumor activity in lung cancer xenograft models in humanized mice. These data support further development of OR2805 as an anti-cancer therapy, both as a monotherapy and an addition to current CPI therapy. Citation Format: Peter Probst, Randi Simmons, Valerie Wall, Meghan Zuck, Myriam Bouchlaka, Sam Lam, Raymond Fox, Darbie Whitman, Tom Graddis, Kamal D. Puri. OR2805, an anti-CD163 antibody derived from an elite responder to checkpoint inhibitor therapy relieves immunosuppression caused by tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1719.

Background The EHF and ELF5 genes, located on chromosome 11p and linked to asthma phenotypes, are high-potential candidate genes conferring asthma susceptibility. The purpose of this study was to investigate the genetic association among single nucleotide polymorphisms (SNPs) of EHF and ELF5 , and their relationship with asthma in the Taiwanese population. Methods We selected and performed genotyping on 16 SNPs that encompass the genomic region of EHF and ELF5 in Taiwanese children with or without asthma. A total of 1983 children, 523 in the test group and 619 and 842 in two validation groups, were recruited for this study. Results The SNP rs3910901, located in the 5′ upstream region of ELF5 , was found to have a weak association ( p = 0.043) with asthma in the odds ratio analysis. The genotype distribution was similar in all comparison groups, but the CC genotype was more frequent in asthma patients. Logistic regression adjusted allergy comorbidity showed obviously diluted association. Conclusion The results indicated that SNP rs3910901 may have a minor impact on pediatric asthma in the Taiwanese population.

Over the years, there is an increasing trend of using quality tools and techniques in service sectors to address customer feedback. Deployment of such quality tools in the education sector is relatively new. Coleman College in Singapore faced feedback from the student community that the Advanced Diploma in Accounting course is too focused on academic learning. This issue was brought up to the Academic Board for further discussion. There were a couple of suggestions and the team embarked on a root cause analysis to analyse the feedback. One root cause identified is the lack of skill-based learning in the current course. The team then brainstorm to incorporate MYOB, the accounting software, into the course programme as a new module. In addition to adding more practical aspects to the course, this implementation also benefits the students by improving their employability. A post-implementation feedback was gathered again to ascertain the effectiveness of the learning outcome. The feedback was positive and the implementation is successful.