Early Clinical Development Oncology, Roche Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
ImaginAb Inc., Inglewood, California.
Cancer Res. 2020 Jul 1;80(13):2903-2913. doi: 10.1158/0008-5472.CAN-19-3269. Epub 2020 May 14.
CD8-expressing T cells are the main effector cells in cancer immunotherapy. Treatment-induced changes in intratumoral CD8 T cells may represent a biomarker to identify patients responding to cancer immunotherapy. Here, we have used a Zr-radiolabeled human CD8-specific minibody (Zr-Df-IAB22M2C) to monitor CD8 T-cell tumor infiltrates by PET. The ability of this tracer to quantify CD8 T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL. cytotoxicity assays with peripheral blood mononuclear cells and CEA-expressing MKN-45 gastric or FOLR1-expressing HeLa cervical cancer cells confirmed noninterference of the anti-CD8-PET-tracer with the mode of action of CEA-TCB/CEA-4-1BBL and FOLR1-TCB at relevant doses. , the extent of tumor regression induced by combination treatment with CEA-TCB/CEA-4-1BBL in MKN-45 tumor-bearing humanized mice correlated with intratumoral CD8 T-cell infiltration. This was detectable by Zr-IAB22M2C-PET and γ-counting. Similarly, single-agent treatment with FOLR1-TCB induced strong CD8 T-cell infiltration in HeLa tumors, where Zr-Df-IAB22M2C again was able to detect CD8 tumor infiltrates. CD8-IHC confirmed the PET imaging results. Taken together, the anti-CD8-minibody Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8 T-cell infiltrates upon either single or combination treatment with TCB antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in clinical phase II, is a promising monitoring tool for intratumoral CD8 T cells in patients treated with cancer immunotherapy. SIGNIFICANCE: Monitoring the pharmacodynamic activity of cancer immunotherapy with novel molecular imaging tools such as Zr-Df-IAB22M2C for PET imaging is of prime importance to identify patients responding early to cancer immunotherapy.
CD8 表达的 T 细胞是癌症免疫治疗中的主要效应细胞。治疗诱导的肿瘤内 CD8 T 细胞的变化可能代表一种生物标志物，用于识别对癌症免疫治疗有反应的患者。在这里，我们使用 Zr 放射性标记的人 CD8 特异性单抗（Zr-Df-IAB22M2C）通过 PET 监测 CD8 T 细胞肿瘤浸润。在 FOLR1-T 细胞双特异性（TCB）抗体单药治疗和 CEA-TCB（RG7802）和 CEA 靶向 4-1BB 激动剂 CEA-4-1BBL 的联合治疗后，通过临床前研究评估了这种示踪剂定量 CD8 T 细胞肿瘤浸润的能力。用外周血单核细胞和表达 CEA 的 MKN-45 胃癌或表达 FOLR1 的 HeLa 宫颈癌细胞进行细胞毒性测定证实，在相关剂量下，抗 CD8-PET 示踪剂不会干扰 CEA-TCB/CEA-4-1BBL 和 FOLR1-TCB 的作用模式。在 MKN-45 荷瘤人源化小鼠中，CEA-TCB/CEA-4-1BBL 联合治疗诱导的肿瘤消退程度与肿瘤内 CD8 T 细胞浸润相关。这可以通过 Zr-IAB22M2C-PET 和 γ 计数检测到。同样，FOLR1-TCB 单药治疗也能在 HeLa 肿瘤中诱导强烈的 CD8 T 细胞浸润，Zr-Df-IAB22M2C 也能再次检测到 CD8 肿瘤浸润。CD8-免疫组化证实了 PET 成像结果。综上所述，抗 CD8 单抗 Zr-Df-IAB22M2C 对 TCB 抗体融合蛋白单药或联合治疗后肿瘤内 CD8 T 细胞浸润的检测具有很高的灵敏度。这些结果进一步证明，目前处于临床 II 期的抗 CD8 示踪剂是一种很有前途的监测工具，可用于监测接受癌症免疫治疗的患者肿瘤内 CD8 T 细胞。意义：使用新型分子成像工具（如用于 PET 成像的 Zr-Df-IAB22M2C）监测癌症免疫治疗的药效学活性对于识别对癌症免疫治疗早期有反应的患者至关重要。
