Multiple approaches to immunotherapy - the new pillar of cancer treatment
In this Special Feature, we present a series of reviews that highlight some of the recent advances in practice and theory concerning the more effective means to mobilize effective host immunity to cancer. The diversity of approaches covered represents only a small minority of the enormous efforts being undertaken by clinicians, academics and pharmaceutical companies world-wide to explore the potentially broad applicability of cancer immunotherapy in cancer treatment.
Mounting evidence suggests that the major barrier to more successful cancer immunotherapy is the tumour microenvironment (TME), where chronic inflammation may play a significant role in tumour immunosuppression, tumour survival and proliferation, and angiogenesis. Our understanding of cancer-related inflammation has significantly improved, and now we have a number of new therapeutic options tailored to interfering with inflammation in the TME. These strategies include the following: re-educating the TME, inhibiting inflammatory mediators or their downstream signalling molecules, blocking the recruitment of myeloid cells, and modulating immunosuppressive functions in myeloid cells. In the review by Nakamura et al.1, the role of cancer-related inflammation (intrinsic and extrinsic regulators) as a potential target in the era of immunotherapy is discussed.
Tumour cells use various ways to evade anti-tumour immune responses. Adenosine, a potent immunosuppressive metabolite, is often found elevated in the extracellular TME. Therefore, targeting adenosine-generating enzymes (CD39 and CD73) or adenosine receptors has emerged as a novel means to stimulate anti-tumour immunity. This is a large field, but Allard et al.2 nicely focus on the therapeutic potential of targeting the adenosine A2 receptors. They present a comprehensive review of A2 receptor signalling, A2 receptor expression, the role of A2 receptor in immunity and cancer progression, and the development of highly specific A2 receptor antagonists for use in cancer treatment alone and in combination with immune checkpoint blockade antibodies. Targeted therapies directed against A2a, A2b or against upstream ecto-nucleotidases CD39 and CD73 responsible for adenosine catabolism have proven to be effective in various pre-clinical cancer models. Combinations with other treatments, including immune checkpoint inhibitors, chemotherapy and adoptive cell therapy, have also demonstrated therapeutic synergy. The first results with A2A receptor antagonists in advanced cancer patients will be available early this year. These will be awaited with great anticipation.
Antibodies are increasingly important vehicles for targeting elements of the immune system in tumours. One of the most obvious, but surprisingly poorly recognized, mechanisms of antibody activity is via its Fc portion. Stunning experiments in mice using antibodies with a variety of Fc isotypes and mice gene-targeted for various Fc receptors have highlighted the critical role that Fc-FcR cross-linking plays in the therapeutic activity of antibodies that target host immune cells (for example, anti-CTLA-4, anti-GITR and antibodies reactive with the TNF superfamily of receptors). In these instances, mechanisms may include depletion of immune cells expressing the antigen by antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis or FcR cross-linking, and signalling or antigen internalization. Barnhardt and Quigley3 and Ochoa et al.4 present two wonderful reviews on this subject area, with Ochoa et al. particularly focusing on ADCC and the means to enhance the function of NK cells in cancer.