Overcoming the logistics of immune monitoring of cancer patients during clinical trials

Abstract

Cancer is a collection of complex diseases with shared and unique molecular pathways of carcinogenesis, invasion and metastases [1]. The interface between cancer and the host stroma and immune system also share unique interactions [2–4]. Cancer therapeutics attempts to leverage the differences between malignant and normal tissues and the host response to cancer: chemotherapy inhibits cell division or metabolic pathways; targeted therapy exploits the cancer-activated molecular growth pathways; antiangiogenesis treatment takes advantage of cancer-induced neovascularization; differentiation therapy drives cancer stem cells into terminal differentiation; and immune therapy focuses on regulating the inflammatory and regulatory pathways to induce an anticancer immune response. Understanding each of these pathways in vivo in humans will improve benefit and outcome for cancer patients. Thus, immune monitoring of patients undergoing therapy is critical to expanding this knowledge. Immune therapy has had a long history in the treatment of cancer patients. Its roots are established in the late 19th century with the use of nonspecific bacterial stimulants pioneered by William Coley [5]. The development of antibodies as the ‘magic bullets’ was hypothesized by Paul Ehrlich about the same time [6]. In the mid-20th century, the first identification of an inflammatory cytokine, interferon, was published by Nagano and Kojima and subsequently confirmed by Isaacs and Lindenmann [7–8]. Since then, many cytokines, chemokines and regulator molecules have been discovered and used in clinical trials. Cytotoxic T cells were first described by Govaerts in 1960 and, subsequently, tumor-specific cytotoxic T cells were identified by the Boon laboratory [9–11]. Regulation of cellular immune response by T cells was first proposed by Gershon in 1970, but it was not until 2000 that Sakaguchi described the CD4CD25 regulatory cell [12,13]. The cellular regulatory pathways now include a variety of additional components including regulatory dendritic cells, CD8 regulatory cells, suppressor B-cells, myeloid suppressor cells and numerous regulatory molecules [12]. The growing complexity of immune pathways is rich with new therapeutic targets and provides novel approaches to treating patients with cancer. Although the promise of cancer immune therapy is being realized, we have not yet been able to associate the ‘on-target effects’ of these agents and the clinical outcome. It is through fully understanding the human in vivo mechanism of action of these agents that we will be able to truly unlock the promise of cancer immune therapy. Immune monitoring during carefully designed clinical trials provides this knowledge. Nevertheless, monitoring of the immune system in cancer patients has its own limitations, which bear on our interpretation of the data. “It is through fully understanding the human in vivo mechanism of action of these agents that we will be able to truly unlock the promise of cancer immune therapy”