Inhaled dry powder cisplatin increases antitumour response to anti-PD1 in a murine lung cancer model
Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells.
Highlights
• Inhaled cisplatin dry powder (CIS-DPI) shows activity against lung tumours in mice.
• CIS-DPI induces upregulation of PD-L1 on lung tumours.
• CIS-DPI added to anti-PD1 therapy increases treatment efficacy in vivo.
• The combination induces the intratumoral recruitment of dendritic cells and T cells.
Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy.
2.4 Cisplatin dry powder for inhalation (CIS-DPI)
CIS-DPI and blends used for mouse endotracheal administration were prepared according to the protocols described in our previous work [17]. Briefly, a previously-micronized cisplatin suspension (2% w/v, Umicore, Germany) was spray-dried in the presence of hydrogenated castor oil (1.98% w/v, Kolliwax, BASF) and tocopheryl polyethylene glycol succinate (0.02% w/v, Biomadys, France). The main characteristics of CIS-DPI obtained were in line with those previously reported and listed in Supplementary Table 1.
Blends of the cisplatin spray-dried powder were then prepared in lactose monohydrate (Lactohale 300, DFE Pharma, Goch Germany) using a Turbula 2C motion mixer (Bachofen AG, Uster Switzerland) to appropriate cisplatin concentrations. Each blend was characterized for its cisplatin content and content uniformity. The results obtained were in line with those previously reported [17], with relative standard deviations (RSD) below 5% observed for all the CIS-DPI blends prepared, except the blend for the administration of 0.1 mg/kg cisplatin in the dose-range finding study (Fig. 1) for which an RSD of 12% was observed.
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Tamara Davenne, Pauline Percier, Lionel Larbanoix, Muriel Moser, Oberdan Leo, Etienne Meylan, Stanislas Goriely, Pierre Gérard, Nathalie Wauthoz, Sophie Laurent, Karim Amighi, Rémi Rosière, Inhaled dry powder cisplatin increases antitumour response to anti-PD1 in a murine lung cancer model, Journal of Controlled Release, Volume 353, 2023, Pages 317-326, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2022.11.055.