Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients

Abstract

Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a preclinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Furthermore, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two patients with mesothelioma, who were resistant to gemcitabine or anti-PD-1 as monotherapy. Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared with single treatment in the absence of steroids.

Immune checkpoint inhibition for the treatment of mesothelioma

“…PD-L1 expression on tumor cells is a logical biomarker for the prediction of treatment response to immune checkpoint therapies targeting the PD pathway. PD-L1 expression occurs in 15-40% of mesothelioma tumors, in particular the non-epithelial subtypes and has been associated with poor patient outcome [49][50][51][52][53][54][55][56] . In studies of PD-L1 expression in mesothelioma, a variety of antibodies, scoring metrics and cut-offs have been used.…”

Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model

“…8 This may be due to the large number of peripheral MDSCs or other immunosuppressive factors induced in the course of cancer progression, which render the vaccine unable to trigger effective anti-tumor immune responses in vivo. Several studies including our work have demonstrated that chemotherapeutic agents (such as carboplatin/ paclitaxel, 50,51 gemcitabine, 52,53 and cyclophosphamide [54][55][56] ) have the effect of further enhancing the anti-tumor effects of DNA vaccine and other immunotherapies. Therefore, in order to achieve better therapeutic effect, vaccines need to be used in combination with appropriate immunomodulators, such as Dox in clinical application in breast cancer.…”

Development of a Novel Prognostic Risk Classification System for Malignant Pleural Mesothelioma

“…Further, lymphocytes have recently attracted increasing attention as a target of immune checkpoint inhibitors (ICIs). [43][44][45][46] Thus, in patients with a low NLR, there is a suspicion that they have a richness of lymphocytes having the potential of producing immunity-promoting effects and that these patients can be good candidates for receiving ICIs. 47 In contrast, patients with a high NLR can be less likely good candidates for ICIs but might be chosen for cytotoxic chemotherapy.…”