Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL, 60612, USA.
Oncogene. 2022 Apr;41(14):2054-2068. doi: 10.1038/s41388-022-02209-w. Epub 2022 Feb 17.
Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer. SIGNIFICANCE: Enhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for "cold" microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.
肿瘤浸润淋巴细胞 (TIL) 增加与患者对免疫疗法的反应改善有关。因此，人们对增强淋巴细胞的迁移特别感兴趣，尤其是针对结直肠癌，因为大多数结直肠癌对检查点抑制剂有抵抗力且微卫星稳定。在这里，我们证明了用抗 CD3 x 抗 EGFR 双特异性抗体武装的激活 T 细胞 (ATC) 可以增加 TIL 并介导抗肿瘤细胞毒性，同时降低肿瘤细胞活力。此外，该治疗方法会诱导内源性抗肿瘤免疫，从而抵抗肿瘤再挑战并增加肿瘤中的记忆 T 细胞亚群。当与靶向肿瘤表达肿瘤坏死因子超家族成员 LIGHT 联合使用时，激活的 T 细胞增殖和浸润进一步增强，并观察到人类结直肠肿瘤消退。我们的数据表明，靶向肿瘤的武装双特异性抗体可增加 TIL 的迁移，是一种潜在的有效策略，可与联合免疫疗法联合用于治疗微卫星稳定的结直肠癌。意义：增强肿瘤浸润淋巴细胞 (TIL) 向实体瘤的迁移已被证明可以改善预后。不幸的是，在临床环境中，很少有策略对实体瘤，特别是对“冷”微卫星稳定的结直肠癌有效。为了解决这一知识空白，本研究将 TNFSF14/LIGHT 免疫调节与靶向肿瘤的激活 T 细胞武装的双特异性抗体相结合。这种独特的 T 细胞迁移策略成功地在微卫星稳定的结直肠癌模型中产生了抗肿瘤免疫，刺激了 T 细胞浸润，并有望成为治疗晚期和转移性结直肠癌的联合免疫疗法。
