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.

Keywords: Anti-cancer drug scheduling; Anti-tumor immunity; Drug development; Immune memory; Immune suppression.

Fig. 1. Cancer chemotherapy: Immune effects of low-dose, medium-dose, high-dose options

Cancer chemotherapeutic drugs may be non-immunogenic (yellow rectangles) or immunogenic; the latter may be further divided into three categories based on the dose and schedule: Low-dose daily metronomic chemotherapy (blue), medium-dose and intermediate-length intermittent chemotherapy schedule (MEDIC, a modified form of metronomic chemotherapy, red), and high-dose with long drug-free break schedule (MTD, green). The impact of each treatment regimen on tumor cell killing and immune responses is shown.

Fig. 2. Chemo-immunotherapy schedules

(A) A single injection of a cancer chemotherapeutic drug may induce multiple events, including changes in the number of tumor-tolerant immune cells (a, black line), chemotherapy treatment-induced drug cytotoxicity (b, brown cone), which is often followed by lymphopenia (c, blue line) and immune-stimulatory signals (d, pink line). The immune stimulatory signals activate anti-tumor immune responses (e, red line), which are followed by increased immune suppression and drug resistance (f, green line). (B) An optimal drug-free break allows for an overall increase in anti-tumor immune response. A second treatment with chemotherapy may have greater effect than the first treatment due to synergism with the anti-tumor immune responses activated by the first drug treatment, and can circumvent or interrupt the emergence of immune suppression. (C) A drug-free break that is too long may enable the development of immune suppression and the emergence of drug resistance, thereby countering the effectiveness of the second drug treatment; (D) A drug-free break that is too short ablates anti-tumor immune responses prematurely, thereby reducing the efficacy of subsequent treatments with chemotherapy.

Fig. 3. Four strategies for cancer chemotherapeutic drug combinations

(A) Drug A synergizes with Drug B by minimizing the survival of drug-resistant tumor cell clones. (B) Drug A and Drug B can each stimulate or induce different anti-tumor immune populations. (C) Drug A inhibits tumor growth by its intrinsic anti-tumor cytotoxicity or by an anti-angiogenic mechanism, while Drug B complements Drug A by activating ICD. (D) Drug A normalizes the tumor vasculature and thereby improves the uptake of Drug B, which activates ICD.