Rova-T enhances the anti-tumor activity of anti-PD1 in a murine model of small cell lung cancer with endogenous Dll3 expression

Rovalpituzumab tesirine (Rove T) offers a targeted therapy for similar to 85% of SCLC patients whose tumors express DLL3, but clinical dosing is limited due to off-target toxicities. We hypothesized that a sub-efficacious dose of Rova-T combined with anti-PD1, which alone shows a clinical benefit to similar to 15% of SCLC patients, might elicit a novel mechanism of action and extend clinical utility. Using a pre-clinical murine SCLC tumor model that expresses Dll3 and has an intact murine immune system, we found that sub-efficacious doses of Royal' with anti-PD1 resulted in enhanced anti-tumor activity, compared to either monotherapy. Multiplex immunohistochemistry (IHC) showed CD4 and CD8 T-cells primarily in normal tissue immediately adjacent to the tumor. Combination treatment, but not anti-P D1 alone, increased Ki67+ /CD8 T-cells and Granzyme B+/CD8 in tumors by flow cytometry and IHC. Antibody depletion of T-cell populations showed CD8 + T-cells are required for in vivo anti-tumor efficacy. Whole transcriptome analysis as well as flow cytometry and IIIC showed that Rova-T activates dendrific cells and increases Ccl5, Il-12, and Icam more than anti-PD1 alone. Increased tumor expression of PDL1 and MHC1 following Rova-T treatment also supports combination with anti-PD1. Mice previously treated with Rova-T + anti-PD1 withstood tumor re-challenge, demonstrating sustained anti-tumor immunity. Collectively our pre-clinical data support clinical combination of sub-efficacious Rova-T with anti-PD1 to extend the benefit of immune checkpoint inhibitors to more SCLC patients.

Automated summary

Combining sub-efficacious doses of Rova-T with anti-PD1 enhances anti-tumor activity and sustains anti-tumor immunity in SCLC patients. The combination treatment activates immune response, increases CD8 T cells, and results in prolonged anti-tumor effects.