Review articleImmunotherapy comes of age: Immune aging & checkpoint inhibitors
Introduction
Despite decades of effort aimed at harnessing the immune system to treat cancer, until recently clinical results have been limited in general and particularly so for older adults. Early attempts to harness the immune system to fight cancer included efforts to generally increase inflammatory responses in a non-specific manner with agents such as BCG or levamisole. Following this, use of cytokines [e.g. interleukin-2 (IL-2) or interferon alpha (IFN α)] which drive many aspects of immunity was tried with some benefit in certain cancers but with substantial toxicity. The relatively small impact of these efforts led to questions of the viability of immune enhancement as a broad-based approach to cancer therapy. Based on novel approaches, however, we now appear to be on the threshold of a revolution in immune based cancer therapy. Current exciting treatments known as immune checkpoint inhibitors (ICIs) are based on the more sophisticated understanding that there are multilayered checks and balances which can be manipulated to unleash already existing, but paralyzed, immune responses to cancer. In most cases, these agents are safer and more efficacious than classic cytotoxic drugs making them a very attractive therapeutic option, especially in older adults. On the other hand, aging is associated with a decline in the immune system or “immunosenescence” which theoretically can reduce the efficacy of these immune based therapies.
In this paper, we will review the mechanism of action of ICIs, current clinical data on their use in older adults, and age-associated immune changes that might have a direct impact on their activity in this population. We chose to focus on mainly adaptive cellular immunity, and especially on components of the immune system that are implicated directly in the immune checkpoint process. However, it should be noted that innate immune cells play important roles in cancer control or progression and these cells also have altered function with age (e.g. see discussion below of myeloid derived suppressor cells).
Section snippets
Mechanisms of Action of Checkpoint Inhibitor Antibodies
Immune checkpoints are essential for self-tolerance and protection of tissues from excessive immune related damage. Tumors can use these checkpoints as a pathway to escape immune response. Two immune-checkpoint receptors are currently the focus of cancer immunotherapy, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1).
CTLA-4 antibodies act mainly by enhancing the interaction between antigen-presenting cells (APCs) and T lymphocytes (Fig. 1). APCs are
Clinical Trial Data on Use of ICIs in Older Adults
There have been no trials focused specifically on the use of ICIs in older adults. However, several papers have reviewed results of the limited number of older adults included in larger trials and found no clear evidence of age-associated difference in the effectiveness of ICIs, although a concern about higher toxicity has been raised. Elias et al. reviewed efficacy and safety of checkpoint inhibitors based on data from key clinical trials that lead to approval of ipilimumab, nivolumab and
Declining Function of Function of Key Immune Cells with Age
Table 1 summarizes major age-associated changes in immune cell function that might impact ICIs.
Conclusions
It is clear from this review that anti-tumor immunity is a highly complex process and that our understanding of this process is rapidly expanding. As we understand more about the immune response, we can delineate in much more detail how anti-tumor immunity is impaired with aging. This knowledge may help us to understand why many cancers increase in incidence or have different natural histories in older adults. It is not yet clear how these age-related immune impairments impact the effectiveness
Disclosures and Conflict of Interest Statements
The authors have no conflicts of interest to disclose.
Author Contributions
Concept and design: R. Elias.
Data collection: R. Elias.
Analysis and interpretation of data: R. Elias, T. Karantanos, E. Sira.
Manuscript writing and approval: R. Elias, K. Hartshorn.
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