Molecular Imaging Program, Center for Cancer Research , National Cancer Institute, National Institutes of Health , Building 10, Room B3B69, MSC1088 , Bethesda , Maryland 20892-1088 , United States.
Acc Chem Res. 2019 Aug 20;52(8):2332-2339. doi: 10.1021/acs.accounts.9b00273. Epub 2019 Jul 23.
This Account is the first comprehensive review article on the newly developed, photochemistry-based cancer therapy near-infrared (NIR) photoimmunotherapy (PIT). NIR-PIT is a molecularly targeted phototherapy for cancer that is based on injecting a conjugate of a near-infrared, water-soluble, silicon-phthalocyanine derivative, IRdye700DX (IR700), and a monoclonal antibody (mAb) that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light turns on this photochemical "death" switch, resulting in the rapid and highly selective immunogenic cell death (ICD) of targeted cancer cells. ICD occurs as early as 1 min after exposure to NIR light and results in irreversible morphologic changes only in target-expressing cells based on the newly discovered photoinduced ligand release reaction that induces physical changes on conjugated antibody/antigen complex resulting in functional damage on cell membrane. Meanwhile, immediately adjacent receptor-negative cells are totally unharmed. Because of its highly targeted nature, NIR-PIT carries few side effects and healing is rapid. Evaluation of the tumor microenvironment reveals that ICD induced by NIR-PIT results in rapid maturation of immature dendritic cells adjacent to dying cancer cells initiating a host anticancer immune response, resulting in repriming of polyclonal CD8T cells against various released cancer antigens, which amplifies the therapeutic effect of NIR-PIT. NIR-PIT can target and treat virtually any cell surface antigens including cancer stem cell markers, that is, CD44 and CD133. A first-in-human phase 1/2 clinical trial of NIR-PIT using cetuximab-IR700 (RM1929) targeting EGFR in inoperable recurrent head and neck cancer patients successfully concluded in 2017 and led to "fast tracking" by the FDA and a phase 3 trial ( https://clinicaltrials.gov/ct2/show/NCT03769506 ) that is currently underway in 3 countries in Asia, US/Canada, and 4 countries in EU. The next step for NIR-PIT is to further exploit the immune response. Preclinical research in animals with intact immune systems has shown that NIT-PIT targeting of immunosuppressor cells within the tumor, such as regulatory T-cells, can further enhance tumor-cell-selective systemic host-immunity leading to significant responses in distant metastatic tumors, which are not treated with light. By combining cancer-targeting NIR-PIT and immune-activating NIR-PIT or other cancer immunotherapies, NIR-PIT of a local tumor, could lead to responses in distant metastases and may also inhibit recurrences due to activation of systemic anticancer immunity and long-term immune memory without the systemic autoimmune adverse effects often associated with immune checkpoint inhibitors. Furthermore, NIR-PIT also enhances nanodrug delivery into tumors up to 24-fold superior to untreated tumors with conventional EPR effects by intensively damaging cancer cells behind tumor vessels. We conclude by describing future advances in this novel photochemical cancer therapy that are likely to further enhance the efficacy of NIR-PIT.
这是一篇关于新开发的基于光化学的癌症治疗近红外（NIR）光免疫疗法（PIT）的综合综述文章。NIR-PIT 是一种针对癌症的分子靶向光疗，它基于注射近红外、水溶性、硅酞菁衍生物 IRdye700DX（IR700）和针对癌细胞表面表达抗原的单克隆抗体（mAb）的缀合物。随后，局部暴露于近红外光会打开这种光化学“死亡”开关，导致靶向癌细胞的快速和高度选择性免疫原性细胞死亡（ICD）。在暴露于近红外光后 1 分钟内即可发生 ICD，并仅导致表达靶标的细胞发生不可逆的形态变化，这是基于新发现的光诱导配体释放反应，该反应导致共轭抗体/抗原复合物发生物理变化，从而导致细胞膜功能损伤。同时，紧邻的受体阴性细胞完全未受影响。由于其高度靶向性质，NIR-PIT 副作用较少，且恢复迅速。对肿瘤微环境的评估表明，NIR-PIT 诱导的 ICD 导致邻近死亡癌细胞的未成熟树突状细胞迅速成熟，从而启动宿主抗肿瘤免疫反应，导致针对各种释放的癌症抗原的多克隆 CD8T 细胞重新致敏，从而增强了 NIR-PIT 的治疗效果。NIR-PIT 可以靶向和治疗几乎任何细胞表面抗原，包括癌症干细胞标记物，即 CD44 和 CD133。一项使用针对表皮生长因子受体（EGFR）的 cetuximab-IR700（RM1929）的 NIR-PIT 的首次人体 1/2 期临床试验于 2017 年成功完成，该试验针对无法手术的复发性头颈部癌症患者，并导致 FDA 的“快速通道”和正在亚洲 3 个国家、美国/加拿大和欧盟 4 个国家进行的 3 期试验（临床试验.gov/ct2/show/NCT03769506）。NIR-PIT 的下一步是进一步利用免疫反应。在具有完整免疫系统的动物的临床前研究表明，NIT-PIT 靶向肿瘤内的免疫抑制细胞，如调节性 T 细胞，可进一步增强肿瘤细胞选择性的全身宿主免疫，从而导致远处转移性肿瘤的显著反应，而这些肿瘤未用光治疗。通过结合癌症靶向的 NIR-PIT 和免疫激活的 NIR-PIT 或其他癌症免疫疗法，局部肿瘤的 NIR-PIT 可能会导致远处转移的反应，并由于激活全身抗癌免疫和长期免疫记忆而抑制复发，而不会产生通常与免疫检查点抑制剂相关的全身性自身免疫不良反应。此外，NIR-PIT 还通过强烈破坏肿瘤血管后面的癌细胞，将纳米药物递送至肿瘤的效率提高了 24 倍，优于未经治疗的肿瘤的常规 EPR 效应。最后，我们描述了这种新型光化学癌症疗法的未来进展，这些进展可能会进一步提高 NIR-PIT 的疗效。
