論文 - 詳細
| RRC ID | 77104 |
|---|---|
| 著者 | Zhang W, Auguste A, Liao X, Walterskirchen C, Bauer K, Lin YH, Yang L, Sayedian F, Fabits M, Bergmann M, Binder C, Corrales L, Vogt AB, Hudson LJ, Barnes MP, Bisht A, Giragossian C, Voynov V, Adam PJ, Hipp S. |
| タイトル | A Novel B7-H6-Targeted IgG-Like T Cell-Engaging Antibody for the Treatment of Gastrointestinal Tumors. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Advanced-stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the antitumor activity of a novel T cell-engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors. EXPERIMENTAL DESIGN:Membrane proteomics and IHC analysis identified B7-H6 as a tumor-associated antigen in gastrointestinal tumor tissues with no to very little expression in normal tissues. The antitumor activity and mode of action of B7-H6/CD3 ITE was evaluated in in vitro coculture assays, in humanized mouse tumor models, and in colorectal cancer precision cut tumor slice cultures. RESULTS:B7-H6 expression was detected in 98% of colorectal cancer, 77% of gastric cancer, and 63% of pancreatic cancer tissue samples. B7-H6/CD3 ITE-mediated redirection of T cells toward B7-H6-positive tumor cells resulted in B7-H6-dependent lysis of tumor cells, activation and proliferation of T cells, and cytokine secretion in in vitro coculture assays, and infiltration of T cells into tumor tissues associated with tumor regression in in vivo colorectal cancer models. In primary patient-derived colorectal cancer precision-cut tumor slice cultures, treatment with B7-H6/CD3 ITE elicited cytokine secretion by endogenous tumor-infiltrating immune cells. Combination with anti-PD-1 further enhanced the activity of the B7-H6/CD3 ITE. CONCLUSION:These data highlight the potential of the B7-H6/CD3 ITE to induce T cell-redirected lysis of tumor cells and recruitment of T cells into noninflamed tumor tissues, leading to antitumor activity in in vitro, in vivo, and human tumor slice cultures, which supports further evaluation in a clinical study. |
| 巻・号 | 28(23) |
| ページ | 5190-5201 |
| 公開日 | 2022-12-1 |
| DOI | 10.1158/1078-0432.CCR-22-2108 |
| PII | 709489 |
| PMID | 36166004 |
| PMC | PMC9713360 |
| MeSH | Animals B7 Antigens / metabolism Colorectal Neoplasms* / drug therapy Cytokines Gastrointestinal Neoplasms* / drug therapy Humans Immunoglobulin G Mice T-Lymphocytes |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | MKN74(RCB1002) |