177Lu-labeled αPD-L1 antibody synergizes with an immune checkpoint inhibitor for colorectal tumors

Introduction: Modern cancer immunotherapy using immune checkpoint inhibitors has shown impressive response rates and prolonged survival. However, a considerable number of patients did not respond to the treatment of immune checkpoint inhibitors. Radionuclide labeled immune checkpoint inhibitor assisted treatment strategy will help to maximize its therapeutic effect on solid tumors. A highly tumor-specific αPD-L1 antibody, Y003, was screened by PET imaging and its potential on radioimmunotherapy was also evaluated. Moreover, the adjuvant immunotherapy with ¹⁷⁷Lu-DOTA-Y003 were investigated on tumor-bearing mice.

Methods: 6-8 weeks old male C57BL/6 mice were subcutaneously injected with 1 × 10⁶cells suspended in 100 µL PBS. When the tumors reached ~500 mm³, mice were intravenously (i.v.) injected with ⁸⁹Zr-DFO-Y003 (3.7±0.1MBq) and imaged at 2, 12, 24, 48, 72, 96 and 120h. On the fifth day after tumor inoculation, Y003 treatment group mice were intraperitoneally (i.p.) injected with PBS, 5 mg/kg Y003, or 10 mg/kg Y003 every 2 days for 12 days or 6 injections. ¹⁷⁷Lu-DOTA-Y003 treatment group mice were developed intravenously (i.v.) with PBS, 3.7MBq ¹⁷⁷Lu-DOTA-Y003, or 11.1MBq ¹⁷⁷Lu-DOTA-Y003, repeat once a week later. For the Radioimmunotherapy synergized with immunotherapy (Combination therapy) group, mice with 5 days tumor inoculation were injected with 3.7MBq 177Lu-DOTA-Y003 i.v. on the first day and 5mg/kg of Y003 i.p. on the 3rd, 5th, 7th day. A same treatment course was repeated on 13th day. When the tumor volume reaches 1000mm3, the mouse is regarded as death, and the survival curve is drawn. The activity level and body weights of the micewere monitored for toxicity. Tumors and spleens were harvested on 2 days after injection of 177Lu-DOTA-Y003for the flow cytometry assay for immune response.

Results: Y003 alone and ¹⁷⁷Lu-DOTA-Y003 alone have modest therapeutic effect, while ¹⁷⁷Lu-DOTA-Y003 adjuvant radioimmunotherapy group showed remarkable results: tumor growth significantly slowed down, the survival of ¹⁷⁷Lu-DOTA-Y003 adjuvant radioimmunotherapy group was prolonged significantly, and the survival rate was 100% at 36 days post-treatment, while all of the other groups died, indicating that the treatment effect of ¹⁷⁷Lu-DOTA-Y003 adjuvant radioimmunotherapy was significant. The average survival time of ¹⁷⁷Lu-DOTA-Y003 adjuvant radioimmunotherapy group was also significantly prolonged.

Conclusions: ¹⁷⁷Lu-DOTA-Y003 adjuvant immunotherapy could achieve double effects, especially at low radiation and antibody doses.

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