Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.

Signal Transduct Target Ther

Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Published: June 2024

AI Article Synopsis

  • Radiotherapy paired with immune checkpoint blockade shows potential for improved cancer treatment results, targeting specific tumor sites with therapies like LNC1004, which is designed to enhance tumor uptake.
  • Studies revealed that Ga/Lu-labeled LNC1004 improves retention in specific tumor models, and its combination with anti-PD-L1 immunotherapy resulted in complete tumor eradication in mice, showcasing substantial immune response reprogramming.
  • Preliminary clinical findings indicate that Lu-LNC1004 is safe and effective for patients with hard-to-treat cancers, highlighting the importance of combining immune therapies to combat immune evasion in FAP-positive tumors.

Article Abstract

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that Ga/Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8 T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with Lu-LNC1004 for cancer patients with FAP-positive tumors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144707PMC
http://dx.doi.org/10.1038/s41392-024-01853-wDOI Listing

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