Abstract and Introduction
Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers.
The involvement of the immune system in tumor control is now accepted. The ability of innate and adaptive immune cells to detect and eliminate tumor cells was termed 'cancer immunosurveillance'. However, subsequent studies have shown that immune cells could also facilitate cancer progression by promoting the growth of tumor clones resistant to anticancer immunity. The term 'cancer immunoediting' encapsulates the dual activity of the immune system on tumors. The positive effect of the immune system on the control of tumor growth is underlined by the observation that HIV infection or immunosuppressive states induced by genetic deficiency or immunosuppression increase the frequency of solid cancers and hematological malignancies in mice and humans.[2–5] Recent data show that growing tumors are frequently infiltrated by immune cells, notably CD8 T cells and these cells probably contribute to the control of tumor growth in humans because their presence is associated with better outcomes.[6–8] This anti-tumor immune response can be manipulated to enhance tumor immune attack, leading to clinical benefits for cancer patients. Challenging the presiding view that chemotherapeutic agents were immunosuppressive,[9–14] we and others have shown that some chemotherapeutic agents could elicit an immunogenic form of tumor cell death that enhances anticancer immune responses and contributes to the clinical efficacy of these chemotherapies.[15–18] Although the demonstration of immunogenic cell death (ICD) relies on mouse models of intratumor injection of chemotherapy or only one systemic injection of chemotherapy which do not mimic the clinical setting of repetitive systemic injections of high doses of chemotherapy, the findings that patients with genetic deficiencies in molecules involved in the detection of ICD have poorer prognosis under chemotherapeutic treatment underscore the clinical relevance of this concept.[15–17] Recently, the use of monoclonal antibodies (mAbs) blocking key inhibitory receptors of T cells such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) has led to robust anti-tumor immune responses and has yielded clinical benefits across multiple tumor types. In addition, impressive clinical responses were observed upon adoptive transfer of tumor-specific autologous T cells using the generation of T cells that expressed cloned T-cell receptors (TCRs) or chimeric antigen receptors (CAR). However, despite these recent successes, many patients are not cured. Emerging evidence suggest that combination strategies may be important to achieve deeper tumor responses. Although combination of immune therapy with some conventional cytotoxic chemotherapies can be envisioned, the important question of how to integrate these novel immunotherapy treatments with the current clinical strategy still remains. In this review, we will summarize our knowledge on the immune-mediated effects of chemotherapies and on the mechanisms of action of novel immunotherapies and propose a rationale for the design of synergistic anticancer combinations.
Ann Oncol. 2015;26(9):1813-1823. © 2015 Oxford University Press
Copyright European Society for Medical Oncology. Published by Oxford University Press. All rights reserved.