167P - Lurbinectedin, a DNA minor groove inhibitor launches a multimodal immune response through activation of the cytosolic DNA-Sensing cGAS-STING pathway.

Background

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and is accompanied by frequent primary or acquired resistance to first-line treatment of chemo-immunotherapy resulting in very modest clinical benefit. Lurbinectedin is FDA-approved as a second-line treatment for SCLC.

Methods

In this study, we evaluated the effect of lurbinectedin on the immune microenvironment in SCLC in multiple immunocompetent mouse models and performed multi-color flow cytometry and bulk RNA sequencing.

Results

In multiple immunocompetent SCLC mouse models, lurbinectedin treatment remarkably enhanced the anti-tumor effect of PD-L1 blockade in tumors that show primary resistance to immunotherapy. Moreover, lurbinectedin caused significant tumor regression in mice that had developed acquired resistance to chemoimmunotherapy treatment demonstrating its efficacy as a superior second-line treatment. Lurbinectedin treatment caused micronuclei formation and activated the cGAS/STING pathway, induced the expression of Type I and II interferon pathways, and caused significant tumor infiltration of cytotoxic and memory/effector T-cells. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased, while immunosuppressive M2 type macrophages and MDSC cells were dramatically decreased. Interestingly, lurbinectedin also led to significant induction of MHC class I in SCLC in vitro and in vivo models. Analysis of pre-and post-treatment clinical samples in patients with relapsed SCLCs validated the induction of MHC class I and interferon pathway genes. Finally, pre-and post-lurbinectedin treatment demonstrated a STING-mediated increase in damage-associated molecular patterns (DAMPs) associated with immunogenic cell death.

Conclusions

We provide the first mechanistic insight into the lurbinectedin-induced cGAS-STING activation and multimodal immune modulation in SCLC. Lurbinectedin is already approved as a second-line agent in SCLC. Hence, our findings highlight lurbinectedin as a potentially transformative therapy for SCLCs that have relapsed from chemoimmunotherapy treatment, paving the way for combination clinical trials with anti-PD-L1.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.