Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy

Abstract

Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or growth stasis. However, certain cytotoxic cancer chemotherapeutic drugs, including doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway, which activates robust innate and adaptive anti-tumor immune responses and has the potential to greatly increase the efficacy of chemotherapy. Here, we review studies on chemotherapeutic drug-induced immunogenic cell death, focusing on how the choice of a conventional cytotoxic agent and its dose and schedule impact anti-tumor immune responses. We propose a strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which we term medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti-cancer activity. We also discuss strategies for combination chemo-immunotherapy, and we outline approaches to identify new immunogenic chemotherapeutic agents for drug development.

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics‐Based Combination Antitumor Therapy

“…Chemotherapeutics not only directly kill the tumor cells, but also have the potential to increase tumor immunogenicity by activating immunogenic cell death . However, the undesirable toxicity of many chemotherapeutic drugs to T cells, natural killer (NK) cells, and dendritic cells (DCs) limits their combination with immunotherapeutics . To address the above challenges, several injectable hydrogel‐based depot systems have been designed to co‐deliver chemotherapeutics and immunotherapeutics for localized combination cancer therapy .…”

“…[46] However, the undesirable toxicity of many chemotherapeutic drugs to T cells, natural killer (NK) cells, and dendritic cells (DCs) limits their combination with immunotherapeutics. [80] To address the above challenges, several injectable hydrogel-based depot systems have been designed to co-deliver chemotherapeutics and immunotherapeutics for localized combination cancer therapy. [25,46,[81][82][83] The combination delivery systems are expected to not only maintain effective drug concentrations by prolonging the drug residence time at the tumor site, but also protect bioactive molecules against denaturation or degradation.…”

Delicate balances in cancer chemotherapy: Modeling immune recruitment and emergence of systemic drug resistance

“…The ability of drugs to induce anti-tumor immune responses is not sufficient by itself to insure a successful therapeutic response, as the effect on various compartments of the immune system, and thus on overall tumor burden can vary dramatically depending on dose, schedule and tumor type. Scheduling and dosing of an ICD drug is of critical importance in instigating an immune response, which relates to the concept of "getting things just right" [13,57]. For instance, administration of cyclophosphamide on a 6-day repeating schedule (Q6D) at 140 mg/kg per dose, dramatically improves the therapeutic outcome for murine GL261 gliomas through immunomodulatory mechanisms [9,10,11].…”

“…It is clear that much remains to understand about the underlying mechanisms of ICD action including the impact of chemotherapy dose and schedule on the many factors linked to the ICD response [13]. In particular, we explore the use of well-designed mathematical models, which can help elucidate the complex interplay between the various players, making these models an invaluable complementary tool to in vivo experimental results for designing better treatments.…”

“…Indeed, high frequency low dose drug administration, also known as metronomic chemotherapy, can in some cases strike the right balance and induce immunogenic cell death (ICD) in tumor tissue by selecting an appropriate choice of drug, dose, and time interval between treatments [6,7,8,9,10,11,12]. Successful achievement of ICD-based therapeutic outcomes during anticancer therapy is dependent on complex interactions between the drug, the tumor, and the host immune system, the nature of which is still being uncovered [13].…”