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A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer.

ABSTRACT: Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKE^TM) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.

SUBMITTER: Vallera DA

PROVIDER: S-EPMC8394622 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5-2%. METHODS:Whole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4+ and CD8+ T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored. RESULTS:Using a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4+ and/or CD8+ T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, NUP214 and JAK1, recognized autologous tumors. Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells. CONCLUSIONS:Our study demonstrated the feasibility of efficiently identifying both CD4+ and CD8+ neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy.

Project description:Epidermal growth factor receptor (EGFR)-targeted cancer therapy such as anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors have demonstrated clinical efficacy. However, there remains a medical need addressing limitations of these therapies, which include a narrow therapeutic window mainly due to skin and organ toxicity, and primary and secondary resistance mechanisms of the EGFR-signaling cascade (e.g., RAS-mutated colorectal cancer). Using the redirected optimized cell killing (ROCK®) antibody platform, we have developed AFM24, a novel bispecific, IgG1-scFv fusion antibody targeting CD16A on innate immune cells, and EGFR on tumor cells. We herein demonstrate binding of AFM24 to CD16A on natural killer (NK) cells and macrophages with KD values in the low nanomolar range and to various EGFR-expressing tumor cells. AFM24 was highly potent and effective for antibody-dependent cell-mediated cytotoxicity via NK cells, and also mediated antibody-dependent cellular phagocytosis via macrophages in vitro. Importantly, AFM24 was effective toward a variety of EGFR-expressing tumor cells, regardless of EGFR expression level and KRAS/BRAF mutational status. In vivo, AFM24 was well tolerated up to the highest dose (75 mg/kg) when administered to cynomolgus monkeys once weekly for 28 days. Notably, skin and other toxicities were not observed. A transient elevation of interleukin-6 levels was detected at all dose levels, 2-4 hours post-dose, which returned to baseline levels after 24 hours. These results emphasize the promise of bispecific innate cell engagers as an alternative cancer therapy and demonstrate the potential for AFM24 to effectively target tumors expressing varying levels of EGFR, regardless of their mutational status.Abbreviations: ADA: antidrug antibody; ADCC: antibody-dependent cell-mediated cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; AUC: area under the curve; CAR: chimeric-antigen receptor; CD: Cluster of differentiation; CRC :colorectal cancer; ECD: extracellular domain; EGF: epidermal growth factorEGFR epidermal growth factor receptor; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; Fc: fragment, crystallizableFv variable fragment; HNSCC: head and neck squamous carcinomaIL interleukinm; Ab monoclonal antibody; MOA: mechanism of action; NK :natural killer; NSCLC: non-small cell lung cancer; PBMC: peripheral blood mononuclear cell; PBS: phosphate-buffered saline; PD: pharmacodynamic; ROCK: redirected optimized cell killing; RSV: respiratory syncytial virus; SABC: specific antibody binding capacity; SD: standard deviation; TAM: tumor-associated macrophage; TKI: tyrosine kinase inhibitor; WT: wildtype.

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A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer.

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