Exploration of optimal timing of combining carboplatin with PD-1 immune checkpoint inhibitors

Background  Currently, chemotherapy combined with immunotherapy is being widely used in treating various types of tumors, but the optimal combination timing of the two is inconclusive.

Objective  To optimize the sequence and interval between carboplatin and PD-1 immune checkpoint inhibitors (ICIs), so as to minimize the toxic effect of this combination regimen on immune cells.

Methods  Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro and activated by anti-CD3 antibody, and the time when the proliferation of PBMCs reached the most active state was determined. Carboplatin was added at this time point, and the PBMCs survival rate - carboplatin concentration curve was plotted. The "safe concentration" of carboplatin that makes the survival rate of PBMCs not less than 90% was calculated, and the time corresponding to the "safe concentration" of carboplatin according to the in vivo drug time curve of carboplatin in the literature was speculated. Under the condition of immunosuppression, the time required for PD-1 antibody to bring the PBMCs’ proliferation of to the most active state was determined, and the optimal sequence and interval of PD-1 ICIs in combination with carboplatin was calculated.

Results  PBMCs reached maximum proliferation rate on day4 after activation by CD3 antibody. Carboplatin concentrations less than 3.981 µmol/L had a low toxic effect on PBMCs in vitro. In the presence of PD-L1 protein, it took 96 h for the anti-PD-1 antibody to bring PBMCs to a maximal proliferation rate.

Conclusion The order of administration of carboplatin first, followed by PD-1 immune checkpoint inhibitors is less toxic to autologous lymphocytes. If PD-1 monoclonal antibody is used first, followed by carboplatin, the interval between the two administrations shouldn't exceed 86 h, otherwise, carboplatin will be more toxic to lymphocytes.