1775P - A novel 89Zr-anti-PD-1 immuno-PET-CT improves response assessment to immunotherapy in lung cancer

Background

Immune checkpoint inhibitors (ICIs) significantly improve non-small cell lung cancer (NSCLC) patient survival. Response assessment of patients on ICIs represents a challenge since an increase in tumor size or the appearance of new lesions might reflect pseudoprogression (PP). PP has been reported in a range of 3-6% in NSCLC. Conventional ¹⁸F-FDG-PET scans do not accurately discriminate PP. We have recently reported the efficacy of a combined blockade of PD-1 and Id1 in a lung cancer mouse model (Baraibar et al. Cancers 2020). We aimed to evaluate a novel ⁸⁹Zr-labelled radiotracer for micro(m)-PET-CT to detect PP in a NSCLC murine model treated with a combined blockade of PD-1 and Id1.

Methods

Syngeneic subcutaneous tumors were generated using Lewis Lung Carcinoma cells (with constitutive expression of Id1 or Id1 silenced) in C57BL6J and in Id1-deficient mice treated with PBS or a commercially available antibody against PD-1 (a-PD-1) (RPM1-14®, 300 mg, IP, on days 7, 10 and 14). To measure tumor growth and response to Id1-PD-1 blockade, SUVmax, TLG and MTV were measured by ¹⁸F-FDG-mPET. Additionally, PP was studied using a novel mPET radiotracer labelling the a-PD-1 with ⁸⁹Zr (⁸⁹Zr-a-PD-1). Mice were treated with ⁸⁹Zr-a-PD-1 or PBS on day 14 and ⁸⁹Zr uptake was measured on days 14, 17 and 20 with mPET-CT following ¹⁸F-FDG-mPET-CT.

Results

¹⁸F-FDG-PET-CT SUVmax was reduced in mice under Id1 and PD-1 blockade metabolic uptake, but no significant differences were observed, underestimating the real metabolic response induced by the treatment. However, ⁸⁹Zr-mPET-CT showed a significantly higher ⁸⁹Zr uptake when Id1 was inhibited in both, tumor cells and tumor microenvironment and mice were treated with a-PD-1 (p=0.0002). The analysis of the tumor tissues confirmed a significant infiltration of CD8⁺ T cells being responsible for the antitumor response and the enhanced ⁸⁹Zr uptake observed (p=0.0001).

Conclusions

Id1 inhibition in tumor cells and in tumor microenvironment combined with PD-1 blockade induced tumor response through enhanced CD8⁺ T cells infiltration. ⁸⁹Zr-a-PD-1 immuno-PET-CT improved response assessment in a lung cancer murine model receiving immunotherapy and warrants further preclinical and clinical evaluation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Gobierno Foral de Navarra. Ministerio de Ciencia, Innovación y Universidades.

Disclosure

All authors have declared no conflicts of interest.