PT  - JOURNAL ARTICLE
AU  - Galbiati, Andrea
AU  - Dorten, Paulina
AU  - Gilardoni, Ettore
AU  - Gierse, Florian
AU  - Bocci, Matilde
AU  - Zana, Aureliano
AU  - Mock, Jacqueline
AU  - Claesener, Michael
AU  - Cufe, Juela
AU  - Büther, Florian
AU  - Schäfers, Klaus
AU  - Hermann, Sven
AU  - Schäfers, Michael
AU  - Neri, Dario
AU  - Cazzamalli, Samuele
AU  - Backhaus, Philipp
TI  - Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics
AID  - 10.2967/jnumed.123.266007
DP  - 2023 Dec 01
TA  - Journal of Nuclear Medicine
PG  - 1934--1940
VI  - 64
IP  - 12
4099  - http://jnm.snmjournals.org/content/64/12/1934.short
4100  - http://jnm.snmjournals.org/content/64/12/1934.full
SO  - J Nucl Med2023 Dec 01; 64
AB  - 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.