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 - 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 -