Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors

Abstract

Background: Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors.Patients and methods: This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy.Results: Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms. Conclusion:Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…Nevertheless, several concurrent chemotherapy regimens with immune checkpoint blockade have been proven to have superior outcomes compared to either modality alone, with combined regimens now approved for first‐line squamous and non‐squamous NSCLC, as well as triple‐negative breast cancer (Table ). Numerous clinical trials of chemotherapy with ICIs are ongoing in a variety of solid tumors …”

“…Numerous clinical trials of chemotherapy with ICIs are ongoing in a variety of solid tumors. 46 In sarcomas, ongoing clinical trials are exploring the alkylating agent trabectedin with ipilimumab/nivolumab (NCT03138161), pembrolizumab plus doxorubicin (NCT02888665 and NCT03056001), and gemcitabine plus pembrolizumab (NCT03123276). Our group is currently developing a trial of doxorubicin plus dual CTLA-4/ PD-1 blockade.…”

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

“…These have included empirically combining well-characterised and commonly used chemotherapeutic classes (such as anti-metabolites, anti-microtubule and crosslinking agents) with novel ICB treatments to improve outcome [10]. Our data suggests there may be a rationale for combining topo-II inhibitors with ICB agents.…”

“…In recent years, following the use of single agent immune checkpoint inhibitors in clinical trials, efforts have been made to identify combination therapies, which provide maximal benefit to patients. This has focused on combining well-characterised and commonly used chemotherapeutic classes (such as anti-metabolites, anti-microtubule, and crosslinking agents) with novel ICB treatments to improve outcome [10]. However, the majority of these combinations are empirically based on currently used regimens.…”

“…An extensive number of clinical trials are in progress using combinations of ICB with various chemotherapeutic agents in a number of solid tumours, resulting in mixed outcomes [10].…”