Combining a nanoparticle-mediated radioimmunotherapy with dual blockade of LAG3 and TIGIT improves the treatment efficacy in anti-PD1 resistant lung cancer

Abstract Background: While improvements in radioimmunotherapy have made significant headway in improving outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to radioimmunotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of radioimmunotherapy.Methods: We combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT and tested the treatment efficacy in an anti-PD1 resistant lung cancer model in mice. 129Sv/Ev mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected to the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 mg), αLAG3 (200 mg), and αTIGIT (200 mg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. Results: This nanoparticle-mediated combination therapy is effective at controlling growth of treated and distant untreated tumors, enhancing animal survival and is the only one that led to complete destruction of both tumors in approximately 30% of treated mice. Corresponding with this improved response is a robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment.Conclusions: Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune check point receptors and provide pre-clinical rationale for investigation into its translation into human patients.