Targeting CXCR4 with 212Pb/203Pb-Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer.

Abstract

Small cell lung cancer (SCLC) has a 6% 5-year overall survival rate. C-X-C chemokine receptor 4 (CXCR4) is an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212Pb/203Pb. The hypothesis that 212Pb/203Pb-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. SPECT-CT imaging and biodistribution studies of tumor-bearing mice injected with 203Pb-pentixather demonstrated CXCR4 expression-dependent uptake and accumulation of radioligand in the kidneys and livers. Dosimetry calculations were performed to estimate 212Pb-pentixather uptake in tumor and normal tissue. 212Pb-Pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. CBCs of mice at 30 days after treatment demonstrated adequate retention of bone marrow function. NSG mice allografted with human hCD34+ bone marrow were treated with 212Pb-pentixather (37-111 kBq/g) to assess damage to human hematopoietic stem cells, demonstrating cytopenias in peripheral blood CBCs at 13-18 days after treatment, resolving by days 28-31. Flow cytometry of bone marrow in these animals at days 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 and reconstitution of the bone marrow with murine CD45+ lineages. 203Pb-Pentixather can be used to image CXCR4-expressing SCLC xenografts. Treatment with high-LET alpha emitter 212Pb-pentixather significantly prolonged overall survival, and recovery of mouse bone marrow from 212Pb-pentixather was significantly greater than that of human bone marrow.