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

Abstract

Introduction: Small cell lung cancer (SCLC) has a 7% 5-year overall survival. C-X-C chemokine receptor 4 (CXCR4), an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212 Pb/ 203 Pb. The hypothesis that [ 212 Pb/ 203 Pb]-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. Results: SPECT/CT imaging and biodistribution studies of tumor bearing mice injected with [ 203 Pb]-pentixather demonstrated CXCR4-dependent uptake in tumors and accumulation of radioligand in kidneys and livers. Dosimetry calculations estimated [ 212 Pb]-pentixather uptake in tumor and normal tissue. [ 212 Pb]-pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. When NSG mice grafted with human hCD34+ bone marrow were treated with [ 212 Pb]-pentixather (37-111 kBq/g), significant cytopenias were observed in peripheral blood complete blood counts (CBCs) at 13-18 days post treatment which resolved by day 28-31. Flow cytometry of bone marrow hematopeotic stem cells in these animals at day 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 (hCD45+) and reconstitution of the bone marrow with murine CD45+ (mCD45+) lineages. Conclusions: [ 203 Pb]-pentixather can be used to image CXCR4 expressing SCLC xenografts and treatment with alpha emitter [ 212 Pb]-pentixather significantly prolongs SCLC xenograft median overall survival. Significantly greater mCD45+ bone marrow repopulation was detected in NSG mice engrafted with human bone marrow 28-31 days following [ 212 Pb]-pentixather treatment, relative to hCD45+ bone marrow.