Suppressive myeloid cells in the tumor microenvironment (TME) are associated with poor survival of cancer patients and resistance to T cell checkpoint inhibitors. These myeloid cells shield cancer cells from the sentinel immune response and create a niche for tumor growth. Repolarizing immuno-suppressive myeloid populations in the TME attracted considerable interest from scientific community and several companies, and has produced early positive clinical data. One of the targets that potently sustains macrophage suppressive phenotypes and is highly expressed on tumor associated macrophages is PSGL-1. Blocking a previously unknown epitope on PSGL-1 triggers macrophage repolarization to a pro inflammatory state. We have determined that our therapeutic candidate VTX-0811, anti-PSGL-1 monoclonal antibody (mAb), repolarizes M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed by primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that VTX-0811 upregulated TNF-α/NF-κB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism, and Myc signaling pathways, consistent with a broad M2-to-M1 shift. Furthermore, repolarized macrophages enhanced inflammatory responses in complex primary multi-cellular assays.VTX-0811 also showed efficacy in a humanized mouse PDX model of melanoma. VTX-0811 suppressed tumor growth to a significantly greater degree compared with an anti-PD-1 mAb. At the cellular and molecular levels, the treatment led to an inflammatory microenvironment, including a reduced MDSC population, and increased systemic pro-inflammatory mediators. Compared with anti-PD-1 monotherapy, VTX-0811 alone and in combination with anti-PD-1 increased the fraction of CD8+ T cells among the infiltrating T cells. Significant combination effects of VTX-0811 plus anti-PD-1 were seen within the tumor tissue, spleen, and peripheral blood.Additionally, pre-clinical efficacy of VTX-0811 was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve cellular and molecular composition of the TME. VTX-0811 increased secretion of inflammatory cytokines and chemokines known to be involved in immune activation of the TME and fresh leukocyte recruitment, as well as linked to clinical response to T cell checkpoint inhibitors.VTX-0811 is a humanized high affinity IgG4/κ mAb that demonstrated safety in NHP primates up to 200mg/kg dosed weekly for 5 total doses. VTX-0811 does not induce activation of unstimulated PBMC or unstimulated blood-derived neutrophil or T cell cultures. These data provide biological and mechanistic support for advancing this program into the clinic with a first in human trial planned for early 2022. Citation Format: Igor Feldman, Tatiana Novobrantseva, Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Susan Low, Steve Sazinsky, Michael Brehm, Boris Klebanov. VTX-0811, a first-in-class PSGL-1 blocking monoclonal antibody, repolarizes tumor associated macrophages and induces inflammation in the tumor microenvironment, leading to suppression of tumor growth in pre-clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5602.
PF 214, RoBlau 4530, DDR 2 Kombinat fur Veteriniirimpfstoffe Dessau Vortrag anlaBlich des 4. Leipziger Biotechnologie-Symposiunis 12.-16. Dezember 1988 Summary Pathogenic strains of Bordetella bronchiseptica undergo phase changing under in vitro conditions. This is the irreversible loss of virulence factors. Adhesins are involved in these structures. They permit adhesion and colonization of bacteria to respiratory epitheliums. Phase 111-bacteria adhere as well as Phase I-bacteria under in vitro conditions (cells of respiratory epithelium from guinea Four phase 111-strains of seven isogenic pairs adhere in a significant higher number per cell than phase I-agents. These results are confirmed by results of investigations with phase 111-strains constructed throughout cultivation on several culture media. Phase 111-bacteria colonize in significant lower numbers under in vivo conditions in rabbits and guinea pigs. Purin auxotrophic mutant strains colonize less in guinea pigs than in rabbits. I n vitro adhesion does not reflect the real bacteria-host interaction between adhesin and receptor. pigs). Einleitung
VSIG4 (V-set immunoglobulin-domain-containing 4) is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance, via interactions with C3 fragments, as well as a negative regulator of T cell activation by an undetermined mechanism. VSIG4 is expressed in tumor associated macrophages with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, stomach cancer and glioma, suggesting an important role in tumor immune evasion. Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing tumor associated macrophages (TAMs) to an inflammatory phenotype capable of coordinating an anti-tumor immune response. Through a series of in vitro and ex vivo assays we demonstrate that anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Anti-VSIG4 antibodies upregulate pro-inflammatory cytokines in M-CSF plus IL-10 driven monocyte-derived M2c macrophages, as well as in TAM-like macrophages in vitro derived from monocytes cultured in the presence of ascites fluid from ovarian cancer patients. To determine whether anti-VSIG4-induced macrophage repolarization can activate T cells, monocyte-derived M2c macrophages were co-cultured with autologous T cells in the presence of staphylococcal enterotoxin B (SEB) activation and anti-VSIG4 antibodies. Here, anti-VSIG4 antibodies upregulate both pro-inflammatory myeloid-derived cytokines (GM-CSF) and T cell-derived cytokines (IFNγ). To extend these observations to a relevant translational model, we treated fresh, patient-derived tumor samples with anti-VSIG4 antibodies and relevant controls ex vivo. Across numerous patient-derived samples, which included multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels greater than observed by treatment with anti-PD-1 or a clinical macrophage repolarizing agent (anti-ILT-4). Taken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms. Citation Format: Steve Sazinsky, Ani Nguyen, Mohammad Zafari, Ryan Phennicie, Joe Wahle, Veronica Komoroski, Kathryn Rooney, Craig Mizzoni, Boris Klebanov, Jessica Ritter, Denise Manfra, Igor Feldman, Tatiana Novobrantseva. Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P105.
VSIG4 is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance as well as a negative regulator of T cell activation by an undetermined mechanism. VSIG4 is expressed in tumor associated macrophages (TAMs) with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, and glioma, suggesting an important role in tumor immune evasion. Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing TAMs to an inflammatory phenotype capable of coordinating an anti-tumor immune response. The ability of anti-VSIG4 antibodies to repolarize M2-like macrophages and induce broad immune activation was studied in in vitro, ex vivo, and in vivo models. In in vitro primary cell assays, anti-VSIG4 upregulated pro-inflammatory cytokines and chemokines in M-CSF plus IL-10 driven monocyte-derived M2c macrophages, inducing a shift toward an M1-like phenotype. In a multicellular assay system, blockade of VSIG4 on M2c macrophages co-cultured with autologous T cells in the presence of SEB activation upregulated the expression of both pro-inflammatory myeloid-derived cytokines and T cell-derived cytokines, suggesting that macrophage repolarization in vitro can induce T cell activation. To assess these observations in a relevant translational model, fresh, patient-derived tumor samples were treated ex vivo with anti-VSIG4. Across multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels generally greater than observed by treatment with anti-PD-1. To determine whether targeting VSIG4 can lead to an anti-tumor effect in vivo, syngeneic mouse models were dosed with anti-mouse VSIG4 antibodies. Tumor growth inhibition was observed in syngeneic mouse models dosed with anti-VSIG4 alone and in combination with anti-PD-1. Tumor growth inhibition was partially reversed in studies where CD8+ T cells were depleted, demonstrating that targeting VSIG4 on macrophages can elicit a coordinated attack on tumors in vivo through both innate and adaptive immune responses. Taken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms. Citation Format: Stephen Sazinsky, Ani Nguyen, Mohammad Zafari, Boris Klebanov, Jessica Ritter, Veronica Komoroski, Denise Manfra, Igor Feldman, Tatiana Novobrantseva. Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures, and inhibits tumor growth in in vivo murine tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5613.
Macrophages are multifunctional cells that are employed by the tumor to further its growth and adaptation. While tumor‐associated macrophages (TAMs) have widely diverse phenotypes, tumors coevolve with the ones that can promote tumorigenesis. Functionally, TAMs/myeloid cells constitute the largest negative influence on the tumor microenvironment and need to be reprogrammed in order to enable successful anti‐tumor response in most tumors. It is predicted that successful TAM repolarization has the potential to become a staple of immuno‐oncology across most indications.
Suppressive myeloid populations in the tumor microenvironment are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical studies have produced positive data for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. One new macrophage repolarizing target, PSGL-1, is expressed at high levels on immuno-suppressive TAMs and differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining a suppressive functional macrophage state. To assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model. We have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-a/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays. The PSGL-1 antibody also showed efficacy in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood. Lastly, pre-clinical efficacy of our lead anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment. The data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer. Citation Format: Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Veronica Komoroski, Brian O'Nuallain, Ryan Phennicie, Kevin Kauffman, Dominika Nowakowska, Joe Wahle, Steve Sazinsky, Michael Brehm, Igor Feldman, Tatiana Novobrantseva. PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P107.
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