Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity

Kathryn M. Tully, Salomon Tendler, Lukas M. Carter, Sai Kiran Sharma, Zachary V. Samuels, Komal Mandleywala, Joshua A. Korsen, Avelyn Mae Delos Reyes, Alessandra Piersigilli, William D. Travis, Triparna Sen, Nagavarakishore Pillarsetty, John T. Poirier, Charles M. Rudin, Jason S. Lewis

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1391-1401
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number7
DOIs
StatePublished - 1 Apr 2022
Externally publishedYes

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