肿瘤靶向白细胞介素 2 增强 FAP 导向放射性配体疗法的抗癌活性

We studied the antitumor efficacy of a combination of 177 Lu-labeled radioligand therapeutics targeting the fibroblast activation protein (FAP) (OncoFAP and BiOncoFAP) with the antibody-cytokine fusion protein L19-interleukin 2 (L19-IL2) providing targeted delivery of interleukin 2 to tumors. Methods: The biodistribution of 177 Lu-OncoFAP and 177 Lu-BiOncoFAP at different molar amounts (3 vs. 250 nmol/kg) of injected ligand was studied via SPECT/CT in mice bearing subcutaneous HT-1080. hFAP tumors, and self-absorbed tumor and organ doses were calculated. The in vivo anticancer effect of 5 MBq of the radiolabeled preparations was evaluated as monotherapy or in combination with L19-IL2 in subcutaneously implanted HT-1080. hFAP and SK-RC-52. hFAP tumors. Tumor samples from animals treated with 177 Lu-BiOncoFAP, L19-IL2, or both were analyzed by mass spectrometry-based proteomics to identify therapeutic signatures on cellular and stromal markers of cancer and on immunomodulatory targets. Results: 177 Lu-BiOncoFAP led to a significantly higher self-absorbed dose in FAP-positive tumors (0.

293 ± 0. 123 Gy/MBq) than did 177 Lu-OncoFAP (0. 157 ± 0. 047 Gy/MBq, P = 0. 01) and demonstrated favorable tumor-to-organ ratios at high molar amounts of injected ligand. Administration of L19-IL2 or 177 Lu-BiOncoFAP as single agents led to cancer cures in only a limited number of treated animals. In 177 Lu-BiOncoFAP-plus-L19-IL2 combination therapy, complete remissions were observed in all injected mice (7/7 complete remissions for the HT-1080. hFAP model, and 4/4 complete remissions for the SK-RC-52.

hFAP model), suggesting therapeutic synergy. Proteomic studies revealed a mechanism of action based on the activation of natural killer cells, with a significant enhancement of the expression of granzymes and perforin 1 in the tumor microenvironment after combination treatment. Conclusion: The combination of OncoFAP-based radioligand therapeutics with concurrent targeting of interleukin 2 shows synergistic anticancer effects in the treatment of FAP-positive tumors. This experimental finding should be corroborated by future clinical studies.