K M Heinhuis1, W Ros1, M Kok2, N Steeghs3, J H Beijnen4, J H M Schellens5. 1. Divisions of Pharmacology, Utrecht University, Utrecht, The Netherlands. 2. Medical Oncology and Molecular Oncology & Immunology, Utrecht University, Utrecht, The Netherlands. 3. Medical Oncology, Department of Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands. 4. Divisions of Pharmacology, Utrecht University, Utrecht, The Netherlands; Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands; MC Slotervaart, Amsterdam, The Netherlands; Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 5. Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: j.schellens@gmail.com.
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.
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.
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