Targeting CXCR4 with -Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer

Christensen, K. A.; Fath, M. A.; Ewald, J. T.; Robles-Planells, C.; Graves, S. A.; Johnson, S. S.; Zacharias, Z. R.; Houtman, J. C. D.; O'Dorisio, M. S.; Schultz, M. K.; Allen, B. G.; Furqan, M.; Menda, Y.; Liu, D.; Spitz, D. R.

doi:10.1101/2024.09.06.611663

bioRxiv · 10.1101/2024.09.06.611663

Targeting CXCR4 with -Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer

Christensen, K. A.·Fath, M. A.·Ewald, J. T.·Robles-Planells, C.·Graves, S. A.·Johnson, S. S.·Zacharias, Z. R.·Houtman, J. C. D.·O'Dorisio, M. S.·Schultz, M. K.·Allen, B. G.·Furqan, M.·Menda, Y.·Liu, D.·Spitz, D. R.

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Abstract

IntroductionSmall 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 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. ResultsSPECT/CT imaging and biodistribution studies of tumor bearing mice injected with [203Pb]-pentixather demonstrated CXCR4-dependent uptake in tumors and accumulation of radioligand in kidneys and livers. Dosimetry calculations estimated [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. When NSG mice grafted with human hCD34+ bone marrow were treated with [212Pb]-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[203Pb]-pentixather can be used to image CXCR4 expressing SCLC xenografts and treatment with alpha emitter [212Pb]-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 [212Pb]-pentixather treatment, relative to hCD45+ bone marrow.

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Christensen, K. A., Fath, M. A., Ewald, J. T., Robles-Planells, C., Graves, S. A., Johnson, S. S., Zacharias, Z. R., Houtman, J. C. D., O'Dorisio, M. S., Schultz, M. K., Allen, B. G., Furqan, M., Menda, Y., Liu, D., Spitz, D. R.. 2024-09-11. Targeting CXCR4 with -Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer. https://doi.org/10.1101/2024.09.06.611663

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