Synapse - Radioimmunotherapy targeting Delta-like ligand 3 in small cell lung cancer exhibits antitumor efficacy with low toxicity

Radioimmunotherapy targeting Delta-like ligand 3 in small cell lung cancer exhibits antitumor efficacy with low toxicity Journal Article

Authors:	Tully, K. M.; Tendler, S.; Carter, L. M.; Sharma, S. K.; Samuels, Z. V.; Mandleywala, K.; Korsen, J. A.; Reyes, A. M. D.; Piersigilli, A.; Travis, W. D.; Sen, T.; Pillarsetty, N.; Poirier, J. T.; Rudin, C. M.; Lewis, J. S.
Article Title:	Radioimmunotherapy targeting Delta-like ligand 3 in small cell lung cancer exhibits antitumor efficacy with low toxicity
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. © 2022 American Association for Cancer Research.
Keywords:	genetics; mouse; animal; animals; mice; lung neoplasms; membrane proteins; cell line, tumor; lung tumor; tissue distribution; signal peptide; intracellular signaling peptides and proteins; membrane protein; tumor cell line; ligand; ligands; radioimmunotherapy; small cell lung cancer; small cell lung carcinoma; humans; human; dll3 protein, human
Journal Title:	Clinical Cancer Research
Volume:	28
Issue:	7
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2022-04-01
Start Page:	1391
End Page:	1401
Language:	English
DOI:	10.1158/1078-0432.Ccr-21-1533
PUBMED:	35046060
PROVIDER:	scopus
PMCID:	PMC8976830
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85128160793&doi=10.1158%2f1078-0432.CCR-21-1533&partnerID=40&md5=17d74c64428743c24ff7d320acdb25cc
Notes:	Article -- Export Date: 2 May 2022 -- Source: Scopus