Radionuclide-Labeled Antisilencing Function 1a Inhibitory Peptides for Tumor Identification and Individualized...

Area of Science:

• Oncology
• Nuclear Medicine
• Immunotherapy

Background:

• Immune checkpoint blockade (ICB) therapy shows promise in cancer treatment but suffers from low response rates and poor patient stratification.
• Noninvasive positron emission tomography (PET) imaging, combined with specific immune biomarkers, can offer spatiotemporal insights for guiding cancer therapy.

Purpose of the Study:

• To identify antisilencing function 1a (ASF1a) as a novel biomarker for delineating tumor immune microenvironments using immune PET (iPET).
• To develop an iPET radiotracer targeting ASF1a for predicting anti-PD-1 (αPD-1) therapy response.
• To explore therapeutic strategies for ICB-resistant tumors based on ASF1a iPET imaging.

Main Methods:

• Development of an iPET radiotracer (⁶⁸Ga-AP1) targeting ASF1a.
• Correlation of iPET signal intensity with anti-PD-1 therapy response.
• Evaluation of combination therapy (¹⁷⁷Lu-AP1 and αPD-1) and alpha-particle therapy (²²⁵Ac-AP1) in ICB-resistant tumors.

Main Results:

• The ⁶⁸Ga-AP1 iPET tracer successfully targeted ASF1a in tumors.
• iPET signal intensity showed a negative correlation with anti-PD-1 therapy response, identifying ICB-resistant tumors (ASF1a^High-iPET).
• Both combination therapy and standalone ²²⁵Ac-AP1 therapy significantly enhanced efficacy and prolonged survival in ICB-resistant models.

Conclusions:

• ASF1a is a viable biomarker for iPET imaging to assess tumor immune microenvironments and predict ICB response.
• The developed radiotracer provides a tool for evaluating immune response and stratifying patients for immunotherapy.
• Versatile radionuclide-labeled AP1 peptides offer potential therapeutic strategies for ICB-resistant cancers, enabling simultaneous diagnosis and personalized treatment planning.