Abstract 1856: Pemetrexed-cisplatin-bevacizumab combo in lung cancer models: impact on tumor immunity
Authors: Sicard Guillaume , Giacometti Sarah , Barlesi Fabrice , Fanciullino Raphaelle , Ciccolini Joseph 
Published: June 2023

Abstract
Dual chemotherapy (i.e., Pemetrexed and Cisplatin, CT) plus anti-VEGF Bevacizumab could be associated with anti-PD1 such as Pembrolizumab in NSCLC patients with low PDL1 levels. To support this new combination, to what extent those drugs could reshape tumor immunity remains to be evaluated, prior to establishing optimal scheduling or sequencing with Pembrolizumab. Both Pemetrexed and Cisplatin are expected to trigger immunogenic cell death, whereas Bevacizumab could help T lymphocytes to extravasate and better infiltrate tumor micro-environment. Here, we studied the impact of Cisplatin and Pemetrexed at two dose levels (i.e., low dose and Maximal Tolerated Dose, MTD) and fixed flat-dose Bevacizumab, alone or in combination (i.e., Cisplatin, Pemetrexed, Cisplatin + Pemetrexed, with our without Beva), on the immune repertoire of BalbC mice ectopically grafted with KLN-205 murine lung tumors. CD45, CD4, CD8, FoxP3-CD4 (Tregs), and MDSCs were monitored by FACS analysis in blood, spleen, and tumors on D2, D7, D14, and D21 after treatment. Results were normalized by CD45 counts. All treatments led to an increase in CD4+ T cells in blood as compared with control (i.e., untreated) animals. Little increase was observed in tumors, regardless of the treatments but mice treated with the Beva+CT combo (both low dose and MTD CT) showed an increase in CD4+ in the spleen on D14. Regarding CD8+ T cells, all treatments led to an increase from D2 to D7. Beva + CT low dose led to a continuous increase in CD8+ cells, whereas in Beva+CT MTD mice, after an initial increase, a reduction in CD8+ was observed after D7 eventually. In the spleen, CD8+ proved to be stable apart from the Beva + CT low dose group which showed an increase up to D14. In tumors, an increase in CD8+ cells was observed in all the groups. No change in MDSCs levels was observed, regardless of the drugs, the dosing and the organ. Conversely, Tregs decreased in the blood in the Beva + CT low-dose group on D14, and decreased in spleen and tumors as compared with Control mice, regardless of the drugs and the dosing. Overall, our data suggest that the triple combination between Beva, Pemetrexed, and Cisplatin has a stronger impact on immune cells than each drug used as a single agent. MDSCs were the only cells to be unaffected by the treatments. Dosing could be relevant as well since the reduction in CD8+ T cells observed with MTD CT could come from drug-related lymphopenia. The Beva followed by low dose Pemetrexed + Cisplatin group is thus the more likely to harness tumor immunity, with peaks in CD4+ and CD8+ T cells and drop in Tregs observed on D14. This pilot study suggests therefore that sequencing Beva + CT low dose followed by a two-week lag time prior to administrating anti-PD1 could lead to synergism in lung cancer models.
Citation Format: Guillaume Sicard, Sarah Giacometti, Fabrice Barlesi, Raphaelle Fanciullino, Joseph Ciccolini. Pemetrexed-cisplatin-bevacizumab combo in lung cancer models: impact on tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1856.