Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
J Immunother Cancer. 2020 Dec;8(2). doi: 10.1136/jitc-2020-001673.
The therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment responses and duration of responses are still less than expected. Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has potential to treat bladder cancer, as previously demonstrated by successful expansion of tumor reactive T cells from human bladder tumors.
A model system using OT-I T cells and an ovalbumin expressing MB49 tumor cell line (MB49OVA) was developed to study ACT in bladder cancer. Systemic ACT-treated mice were given T cells intravenously after lymphodepleting chemotherapy and followed by interleukin (IL)-2 administration. Intravesical ACT treated mice were given T cells directly into the bladder, without chemotherapy or IL-2. TILs were isolated from MB49 orthotopic tumors and expanded ex vivo in IL-2. Immune cell infiltrates were analyzed by flow cytometry. T cell infiltration was studied using a CXCR3 blocking antibody.
Systemic ACT-treated mice had a decrease in tumor growth, increase in T cell infiltration and long-term immune protection compared with control-treated mice. OT-I T cells delivered intravesically were able to control tumor growth without lymphodepleting chemotherapy or IL-2 in MB49OVA orthotopic tumors. Intravesical delivery of TIL expanded from MB49 tumors was also able to decrease tumor growth in mice with MB49 orthotopic tumors. Blocking CXCR3 on OT-I T cells prior to intravesical delivery decreased T cell infiltration into the tumor and prevented the control of tumor growth.
This study demonstrates how TIL therapy can be used in treating different stages of bladder cancer.
膀胱癌的治疗手段最近已经通过引入新的疗法而得到丰富，包括免疫检查点抑制剂、受体酪氨酸激酶抑制剂和抗体药物偶联物，然而治疗反应和反应持续时间仍低于预期。使用肿瘤浸润淋巴细胞（TILs）的过继细胞疗法（ACT）有可能治疗膀胱癌，因为先前已经从人膀胱癌中成功地扩增了肿瘤反应性 T 细胞。
建立了一个使用 OT-I T 细胞和表达卵清蛋白的 MB49 肿瘤细胞系（MB49OVA）的模型系统，以研究膀胱癌中的 ACT。全身 ACT 治疗的小鼠在接受淋巴细胞耗竭化疗后静脉内给予 T 细胞，随后给予白细胞介素（IL）-2。膀胱内 ACT 治疗的小鼠直接将 T 细胞注入膀胱，不进行化疗或 IL-2。TIL 从 MB49 原位肿瘤中分离出来，并在 IL-2 中进行体外扩增。通过流式细胞术分析免疫细胞浸润。使用 CXCR3 阻断抗体研究 T 细胞浸润。
与对照组相比，全身 ACT 治疗的小鼠肿瘤生长减少，T 细胞浸润增加，具有长期免疫保护作用。OT-I T 细胞经膀胱内给予，无需淋巴细胞耗竭化疗或 MB49OVA 原位肿瘤中的 IL-2，即可控制肿瘤生长。从 MB49 肿瘤中扩增的 TIL 经膀胱内给予也能够降低 MB49 原位肿瘤小鼠的肿瘤生长。在膀胱内给予 OT-I T 细胞之前阻断 CXCR3，可减少 T 细胞浸润到肿瘤中，并阻止肿瘤生长的控制。
本研究表明 TIL 疗法如何用于治疗膀胱癌的不同阶段。
