Overcoming immuno-resistance by rescheduling anti-VEGF/cytotoxics/anti-PD-1 combination in lung cancer model.

Background: Many tumors are refractory to immune checkpoint inhibitors, but their combination with cytotoxics is expected to improve sensitivity. Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors. Methods: In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model. A longitudinal immunomonitoring study on tumor, spleen, and blood after multiple treatments including Cisplatin, Pemetrexed, and anti-VEGF, either alone or in combination, was performed, spanning a period of up to 21 days, to determine the optimal time window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence), as well as single agent anti-PD1. Results: Immunomonitoring showed marked differences between treatments, organs, and time points. However, harnessing tumor immunity (i.e., promoting CD8 T cells or increasing the T CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a 14-day delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities (i.e., -71% in tumor volume compared to control). Conclusions: Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1.

Elderly patients whose hospitalization was medication-related were more likely to receive medication recommendations by clinical pharmacist than patients whose hospitalization was unlikely medication-related in non-geriatric units.

BACKGROUND: Elderly patients are often polymedicated, and drug-related hospitalizations are common in this population. In our hospital, pharmacists from the mobile geriatric team (MGT) coordinate medication reviews (MR) for elderly patients hospitalized in non-geriatric wards, to prevent iatrogenic. OBJECTIVE: The aim of this work is to determine whether the drug-related origin of hospitalizations can be considered as a targeting criterion for performing MRs. MATERIAL AND METHOD: We conducted a retrospective study of data from patients who received a MGT's MR between March 2021 and December 2022, from a single center of more than 1000 beds. The drug-related origin of the hospitalization was estimated as probable or unlikely by the AT-HARM10 tool. Between the two groups, we compared the number of potentially inappropriate prescriptions detected by the PIM-check and START/STOPP tools, drug-drug interactions (DI), unintended discrepancies (UDI) at entry reconciliation, the drug burden index (DBI), and the number of drug-related problems (DRP) i.e., START/STOPP score + DI + UDI. Linear regression of the number of DRP by AT-HARM10 score was computed. RESULTS: 110 patients were included. 56 hospitalizations were estimated MRH and 54 non-MRH. Mean age (85.1 ± 7.0), ADL (3.8 ± 1.9), IADL (2.0 ± 1.6), and number of medications at entry (8.9 ± 3.8) were comparable in the 2 groups. Compared with non-MRH group, MRH group had a higher number of START/STOPP criteria (5.7 ± 3.5 vs 3.0 ± 2.6; p < 0.05), PIM-check overuses (2.1 ± 1.7 vs 1.4 ± 1.4; p < 0.05), DI (8.4 ± 9.0 vs 4.7 ± 4.7; p < 0.05), UDI at entry (4.0 ± 3.34 vs 2.2 ± 2.1; p < 0.05), and higher DBI score (0.9 ± 0.7 vs 0.3 ± 0.4; p < 0.05). The number of DRP was higher in group P (17.6 ± 10.8 vs 9.8 ± 6.3; p < 0.00.5). Linear regression showed a positive correlation between AT-HARM10 score and the number of DRP (r = 0.5, p < 0.05) with a coefficient of 7.7 (CI95% = [4.3; 11.1]) and an intercept of 9.8. DISCUSSION: These results allow us to consider AT-HARM10 score as a targeting criterion for performing MR for elderly patients, as part of a curative approach to drug iatrogenic for these patients.