TY - JOUR
T1 - Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity
AU - Tully, Kathryn M.
AU - Tendler, Salomon
AU - Carter, Lukas M.
AU - Sharma, Sai Kiran
AU - Samuels, Zachary V.
AU - Mandleywala, Komal
AU - Korsen, Joshua A.
AU - Reyes, Avelyn Mae Delos
AU - Piersigilli, Alessandra
AU - Travis, William D.
AU - Sen, Triparna
AU - Pillarsetty, Nagavarakishore
AU - Poirier, John T.
AU - Rudin, Charles M.
AU - Lewis, Jason S.
N1 - Funding Information:
This work was supported in part by NIH grants U01 CA213359 and R01 CA213448 (to J.T. Poirier, C.M. Rudin, J.S. Lewis), R35 CA263816 (to C.M. Rudin), and R35 CA232130 (to J.S. Lewis). K.M. Tully was supported by the Weill Cornell Graduate School of Medical Sciences (grant no. T32 GM073546) Predoctoral Training Grant in Pharmacological Sciences. Technical services provided by the Memorial Sloan Kettering Cancer Center Small-Animal Imaging Core Facility, supported in part by NIH Cancer Center Support Grant P30 CA008748, are gratefully acknowledged. NIH Shared Instrumentation Grant S10 RR028889, which provided funding support for the purchase of the NanoSPECT/CT Plus, is gratefully acknowledged. Finally, the authors gratefully acknowledge the Memorial Sloan Kettering Cancer Center Anti-Tumor Assessment Core, the Memorial Sloan Kettering Molecular Cytology Core, and the Tri-Institutional Laboratory of Comparative Pathology.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Purpose: Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. Experimental Design: We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A”-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. Results: [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [177Lu]Lu-DTPA-CHX-A”-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 mCi and 750 mCi doses of [177Lu]Lu-DTPA-CHX-A”-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [177Lu]Lu-DTPA-CHX-A”-SC16 had pathologically confirmed complete responses (CR). In the patient-derived xenograft model Lu149, all doses of [177Lu]Lu-DTPA-CHX-A”-SC16 markedly prolonged survival. At the 250 mCi and 500 mCi doses, 5 of 10 and 7 of 9 mice demonstrated pathologically confirmed CRs, respectively. Four of 10 mice that received 750 mCi of [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining 6 mice demonstrated pathologically confirmed CRs. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. Conclusions: Together, the compelling antitumor efficacy, pathologic CRs, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A”-SC16.
AB - Purpose: Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. Experimental Design: We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A”-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. Results: [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [177Lu]Lu-DTPA-CHX-A”-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 mCi and 750 mCi doses of [177Lu]Lu-DTPA-CHX-A”-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [177Lu]Lu-DTPA-CHX-A”-SC16 had pathologically confirmed complete responses (CR). In the patient-derived xenograft model Lu149, all doses of [177Lu]Lu-DTPA-CHX-A”-SC16 markedly prolonged survival. At the 250 mCi and 500 mCi doses, 5 of 10 and 7 of 9 mice demonstrated pathologically confirmed CRs, respectively. Four of 10 mice that received 750 mCi of [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining 6 mice demonstrated pathologically confirmed CRs. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. Conclusions: Together, the compelling antitumor efficacy, pathologic CRs, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A”-SC16.
UR - http://www.scopus.com/inward/record.url?scp=85128160793&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-1533
DO - 10.1158/1078-0432.CCR-21-1533
M3 - Article
C2 - 35046060
AN - SCOPUS:85128160793
SN - 1078-0432
VL - 28
SP - 1391
EP - 1401
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -