Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics
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2023-12-01
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Abstract
We studied the antitumor efficacy of a combination of ¹⁷⁷Lu-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 ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-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 ¹⁷⁷Lu-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: ¹⁷⁷Lu-BiOncoFAP led to a significantly higher self-absorbed dose in FAP-positive tumors (0.293 ± 0.123 Gy/MBq) than did ¹⁷⁷Lu-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 ¹⁷⁷Lu-BiOncoFAP as single agents led to cancer cures in only a limited number of treated animals. In ¹⁷⁷Lu-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.
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64 (12)
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1934 - 1940
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Society of Nuclear Medicine
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Subject
combination therapies; fibroblast activation protein; immunocytokines; radioligand therapeutics; tumor targeting