More than 47.8 million people in the U.S. are 65 years of age or older. As the proportion of the U.S. population that is older rises, we can expect cancer incidence to increase. The NCI's Surveillance, Epidemiology, and End Results Program reports that the median age of diagnosis of cancer at any site is 66, and that of death from cancer is 72. Though currently more than 50 percent of all cancers are diagnosed in patients older than 65, in the next decade, that percentage will grow to 70 percent (Semin Oncol 2004;31(2):128-136).
Some define elderly as being older than 65 years of age, although many argue the cut point should be older than 75 years because of the physiologic and pharmacologic processing changes that occur around that time (Cancer J 2017;23(4):219-222). In fact, of all age groups, the one 75-84 years of age records the highest percentage (26.6%) of cancer deaths. There are many reasons why cancer develops in the elderly population, but one significant reason is the modification of the immune system.
That one reason may be immunosenescence, a term that refers to changes that occur in the immune system with increasing age. These changes may play a role in elders' response to immunotherapy treatments, such as those therapies relying on PD-1, PD-L1, and cytotoxic T lymphocyte antigen-4 (CTLA-4).
Despite robust data with immunotherapy drugs in various cancers, older and very elderly patients are often underrepresented in clinical trials (J Clin Oncol 2004;22(22):4626-4631). In addition, elderly patients in clinical trials may not necessarily represent the elderly population overall, given that patients in clinical trials generally have good health status and adequate organ function (Eur J Cancer 2017;82:155-166). The focus here is on changes aging imposes on the immune system and what current data can tell us about immunotherapy use in elderly patients with cancer.
Immunosenescence in the Elderly
Senescence is a physiological process characterized by gradual organ function alterations attributable to age. Cell senescence is associated with modifications of the chromatin structure, loss of growth factor responsiveness, accumulation of DNA damage, oncogene activation, metabolic modification, and mitochondrial dysfunctions (Eur J Immunol 2016;46(10):2286-2301).
Studies from peripheral blood have shown a markedly lower number and frequency of naïve CD8+ T cells and a slightly lower frequency of naïve CD4+ T cells in the elderly population than in younger adults (Brain Behav Immun 2014;39:8-22). These differences are believed to be the result of a lifetime of exposure to immune stimulation, mostly by pathogens but also possibly from autoantigens and cancer antigens. These exposures convert naïve cells to memory cells over time. The accumulation of most of these cells is likely the result of infection with herpes virus or cytomegalovirus, with which the majority of elderly people are infected (ASCO-SITC Clinical Immuno-Oncology Symposium 2017; https://immunosym.org/daily-news/aging-and-immunity).
The role of these viruses in response rates to immunotherapy is still unclear. In a review, Hurez, et al, discuss how the effects of age on immunity extend far beyond simple declines in functions or reductions in cell numbers (Clin Exp Immunol 2017;187(1):53-63). They propose the term age-related immune dysfunction to encompass the full range of age-related alterations in immunity as populations age.
Accumulations of myeloid-derived suppressor cells (MDSCs) also have been described in the aging immune system, as well as observed as a change frequently seen in the immune systems of patients with cancer (Age (Dordr) 2014;36(6):9729). MDSCs are a redirected population of myeloid cells that promote contradictory immune suppressive activities, and a reduction of these cells has been achieved with ipilimumab therapy (Curr Oncol Rep 2018;20(2):20, J Leukoc Biol 2017;102(2):381-391).
Immunotherapy in the Elderly
Immune checkpoint inhibitors have become one of the most successful immunotherapy strategies for various cancers (J Exp Med 2012;209(2):201-209, Nat Rev Cancer 2012;12(4):252-264). Another treatment generating excitement is chimeric antigen receptor (CAR) T-cell therapy, which uses adoptive cell therapy to improve the adaptive immune response.
Data primarily drawn from immunotherapy studies in elderly patients with cancer are limited. Much of this limitation is due to lack of specific trials utilizing immunotherapy solely in the elderly. Most of the data regarding efficacy and safety are from population subgroup analyses in trials leading to FDA approval of immune checkpoint inhibitors. Patients who are 65-69 years of age in 2013 made up 17 percent of clinical trial participants. Patients 75-79 years of age and 80 years and older made up only 8 percent and 4 percent, respectively, of clinical trial participants that same year (J Clin Oncol 2017;35(Suppl):abstract 10009).
In a review, Marrone, et al, summarized phase III trial results in FDA-approved immune checkpoint inhibition by age (Cancer J 2017;23(4):219-222). Many trials had few patients older than 65 years and even fewer older than 75 years. Daste, et al, reviewed efficacy and safety of immune therapies in older patients (Eur J Cancer 2017;82:155-166). An overview of these reports shows the diminution of the number of subjects in their 60s, 70s, and 80s and the difficulty of having sufficient numbers for reliable analysis in the oldest cohort (Table 1).
Overall, immune checkpoint inhibitors are better tolerated than cytotoxic chemotherapy, but few clinical trials describe toxicity in elderly populations. In one study, grade 3-5 adverse events were recorded less often in patients younger than 65 years of age (360/616, or 58.4%) than in patients 70 years of age or older (152/212, or 71.7%) (J Clin Oncol 2016;34(Suppl):abstract 10010). Findings suggested occurrence of diarrhea/colitis and rash was lower in the younger group than in the elderly group (5.2% and 10.4% vs. 2.4% and 7.6%, respectively).
Immunotherapy is certainly tolerated by elderly patients; however, response rates and side effects may not be similar to findings in most studies. As immune function changes with age, it is likely that elderly patients may have an increased rate of adverse events. Close monitoring of symptoms is absolutely necessary.
The immune system changes elderly patients experience are complex. There has been some insight into the pathophysiology of immunosenescence; however, other factors like the tumor microenvironment, proinflammatory effects, the patient's microbiome, and others must also be considered (Clin Exp Immunol 2017;187(1):53-63).
In contrast, mammalian target of rapamycin inhibition may improve immune function in older patients (Sci Transl Med 2014;6(268):268ra179) and perhaps even reverse some components of immunosenescence, which may help improve responses to checkpoint inhibitors.
Predicting response to immune checkpoint inhibitors has been tested using tumor mutational burden (TMB) as a marker (Science 2015;348(6230):124-128). In a recent analysis of 1,638 patients, a higher TMB (at least 20 mutations/mb) predicted a favorable outcome to PD-1/PD-L1 blockade across diverse tumors (Mol Cancer Ther 2017;16(11):2598-2608). Future clinical trials may incorporate various immune markers as well as TMB to help identify elderly patients who may respond to immunotherapy.
Older age is a primary risk factor for cancer in adults. The median age of diagnosis with cancer at any site is 66 years. The immune system also changes as patients get older, perhaps influencing a patient's ability to respond to immunotherapy.
Despite the abundant prevalence of cancer in men and women older than 65 years of age, they and the subset population of those more than 75 years of age are underrepresented in clinical trials.
To help physicians and researchers achieve a clearer understanding of how the immune system changes with aging and how those changes could influence the success of immunotherapy, future studies should examine biomarkers in elderly patients who have responded to immunotherapy to help identify a population for whom this type of treatment is more meaningful.
In addition, clinical trials should incorporate a more representative elderly population, including patients with multiple comorbidities and those with diminished performance status, to typify the general population better, to make findings more generalizable, and to serve those in the population most likely to be diagnosed with cancer.
ANKUR R. PARIKH, DO, is Medical Director of Precision Medicine at Cancer Treatment Centers of America.