CD27 is a member of the TNF-Receptor superfamily expressed on CD4+ and CD8+ T cells, on NK and NKT cells and on B cells. It promotes T cell co-activation, proliferation, clonal expansion and differentiation into antigen specific cytotoxic and memory T cells after stimulation with its ligand CD70. Its stimulatory signal is mediated via the NFkB pathway, but also via the phosphatidylinositol 3 kinase and the protein kinase B. Moreover, CD27 signaling influences the innate immune response via a direct activation of NK cells and a subsequent secretion of interferon-gamma (IFN-γ). CD27 plays a central role in immunological responses and by promoting T cell and NK cell activation it contributes to anti-tumor immunity. Previous studies have demonstrated tumor growth inhibition with anti-CD27 agonistic monoclonal antibodies in different mice models for solid and hematological tumors. This mechanism of action can be partly explained by the recruitment of IFN-γ producing CD8+ T cells within the tumor. CD27 is a promising target for antitumor therapy. Kineta has generated a library of 147 fully human anti-CD27 monoclonal antibodies after immunization of Trianni mice. From this library, a lead candidate with strong agonistic proprieties has been selected. This anti-CD27 antibody originates from a unique clade after alignment of the variable heavy chains. Kineta’s lead candidate demonstrates selectivity and cross-reactivity with Non-Human Primate (NHP)-CD27 but not with the mouse-CD27. It also induces strong NFkB signaling in a Jurkat T cell-reporter, either soluble or cross-linked. It also induces T cell proliferation and secretion of pro-inflammatory cytokines in vitro. This T cell activation occurs only in the presence of a TCR engagement preventing future risks of spontaneous activation of naïve T cells in vivo. Our lead antibody also induces direct activation of NK cells demonstrated by the expression of CD69 on their surface. We have evaluated the anti-tumor properties of our lead antibody as a single agent in vivo in human CD27 Knock-In (KI) mice. Our anti-CD27 candidate induces a significant anti-tumor activity in the EG7 thymoma model. We have also demonstrated the anti-tumor efficacy of this lead candidate in Raji cells implanted in Scid mice. Preliminary experiments performed in human CD27 KI mice have demonstrated a long half-life of our antibody at different concentrations. Epitope characterization, NHP pharmacokinetic analysis and additional in vivo studies of our lead anti-CD27 antibody in different tumor models use as a single agent and in combination with different check-point inhibitors are on-going. Citation Format: Shawn Iadonato, Jessica Cross, Nathan Eyde, Emily Frazier, Neda Kabi, Chen Katz, Remington Lance, Kurt Lustig, Yulia Ovechkina, David Peckham, Shaarwari Sridhar, Carla Talbaux, Isabelle Tihista, Mei Xu, Thierry Guillaudeux. CD27 an emerging immuno-oncology target at the cross-roads of innate and adaptive anti-tumor immune responses [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A60.
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA/PD-1H) is a B7 family member highly expressed on circulating and intra-tumoral myeloid cells. It is a negative checkpoint inhibitor that inhibits anti-tumor T cell response. In patients, VISTA is associated with poor overall survival in multiple tumor indications and is also a potential mediator of resistance to anti-CTLA-4 and anti-PD1 therapies. Therefore, VISTA is a unique target for cancer immunotherapy. Kineta has developed a fully human monoclonal antibody targeting VISTA, KVA12123, that is currently being evaluated in a Phase 1/2 clinical trial in cancer patients with advanced solid tumors. This trial also includes a combination arm with pembrolizumab. In order to inform which patients may be susceptible to respond to our anti-VISTA antibody, we hypothesized that the best responders should be associated with a high expression of the target in the tumor microenvironment (TME). Therefore, after assay validation of VISTA labelling by immuno-histochemistry, we analyzed a large set of tumor samples and showed that VISTA was highly expressed on tumor infiltrating immune cells. This was particularly true for patients with non-small cell lung cancers, colorectal cancers, head and neck squamous cell carcinomas, hepatocellular carcinomas, melanomas and squamous cell carcinoma of the skin, and cervical cancers as well as ovarian cancers. VISTA expression was detected mostly on CD163 positive macrophages infiltrating the tumor. These macrophages potentially promote immunosuppression present in the TME and contribute to treatment failure with current immune checkpoint inhibitors like anti-PD1/PD-L1 and CTLA-4. While previous studies reported VISTA expression on cancer cells, we were not able to confirm these results. In all tumor tissues tested, only infiltrating immune cells were labelled for VISTA. We have investigated in parallel the expression level of soluble VISTA in the serum collected from cancer patients independent of this clinical trial. Sera were screened for patients with multiple tumor types. Patients of diverse sex and age were compared to healthy donors. After validation of the ELISA assay, we showed that sera derived from cancer patients exhibit high levels of soluble VISTA, and these levels tend to correlate with age. More data are needed to confirm that high levels of soluble VISTA are associated with advanced disease. In the ongoing Phase 1/2 clinical trial, tumor tissues and serum samples will be collected from cancer patients prior to treatment with KVA12123 to inform the possible significance of these biomarkers. This work could help to better understand the response to KVA12123 in relation to the expression level of VISTA in cancer tissues as well as in the blood. Citation Format: Neda Kabi, Chen Katz, Remington Lance, Jessica Cross, Nathan Eyde, Emily Frazier, Kurt Lustig, Yulia Ovechkina, David Peckham, Shaarwari Sridhar, Carla Talbaux, Isabelle Tihista, Mei Xu, Shawn Iadonato, Thierry Guillaudeux. VISTA expression in patients with advanced solid tumors: A potential biomarker in VISTA-101 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 972.
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