A groundbreaking study published in Nature Communications has revealed that immune checkpoint inhibitors (ICIs) demonstrate comparable efficacy in cancer patients regardless of age, despite significant differences in baseline immune phenotypes between older and younger patients.
The research, led by scientists at Johns Hopkins University School of Medicine, challenges assumptions about immunotherapy effectiveness in older populations, whose immune systems typically show age-related decline.
"Older patients do just as well, sometimes better than younger patients with immunotherapy treatments," said senior author Dr. Daniel Zabransky, assistant professor of oncology at Johns Hopkins University School of Medicine. "We found clues about important pathways mediating the immune system response to immunotherapies in younger versus older patients that may help us improve the next generation of therapies."
Study Design and Patient Demographics
The observational study enrolled 124 patients with solid tumors who received ICIs as standard-of-care treatment and were followed for at least six months. Of these, 104 patients provided peripheral blood samples at baseline and approximately 1-5 months after initiating ICI therapy.
The patient cohort had a median age of 65 years (range 20-90+), with 54 patients aged 65 and older and 50 patients younger than 65. The study population was predominantly male (67.3%) and White (64.4%), with most patients (42.3%) receiving ICI monotherapy.
Patients received various ICIs, including anti-PD-1/PD-L1 agents (nivolumab, pembrolizumab, atezolizumab, cemiplimab, durvalumab, and avelumab), combination therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), or ICIs in combination with targeted therapy or chemotherapy.
Cancer Types and Disease Characteristics
The most common malignancies in both age groups were gastrointestinal and genitourinary cancers. Among patients 65 and older, 40.7% had gastrointestinal cancers and 37.0% had genitourinary cancers, followed by skin (9.3%), other malignancies (9.3%), and upper aerodigestive (3.7%) cancers.
In the younger cohort, gastrointestinal (32.0%) and genitourinary (28.0%) cancers also predominated, though with higher rates of upper aerodigestive (16.0%) and other cancers (18.0%).
The vast majority of patients had advanced or metastatic disease at baseline: 92.3% overall, with 96.3% in the older group and 88.0% in the younger group.
Key Immune Phenotype Differences
Despite similar clinical outcomes, researchers identified significant differences in immune responses between age groups. Among the 95 patients with available on-treatment samples, investigators observed variations in baseline and post-treatment levels of multiple cytokines, including IL-2, IL-12p70, IL-17a, CCL2, IL-1α, VEGF-α, and sCD40L.
Notably, older patients showed smaller increases in CCL2 expression after ICI treatment. Interestingly, increased CCL2 levels predicted nonresponse in younger patients but response in older patients (adjusted interaction P=.02), suggesting fundamentally different immune dynamics based on age.
The study also revealed that older patients had lower proportions of naive cytotoxic T cells, helper T cells, B cells, and double negative T cells, while showing higher proportions of natural killer (NK) cells both before and after ICI treatment. Additionally, aged patients displayed diminished circulating cytokine responses following treatment.
Implications for Personalized Immunotherapy
These findings suggest that while ICIs work effectively across age groups, the underlying mechanisms may differ significantly, pointing to opportunities for age-tailored therapeutic approaches.
"Right now, we give immune checkpoint inhibitors to patients in the same way without major consideration about how their age may influence how the immune system may recognize cancer cells," Dr. Zabransky explained. "By better understanding age-related changes that we all experience over our lifespan, we hope to identify new strategies and personalize our therapies even further based on those important patient-level factors."
Future Research Directions
The Johns Hopkins team plans to extend their research by investigating immune cells within tumors themselves, comparing them across age groups to better understand how they respond to immunotherapies.
Their goal is to develop new cancer therapies better tailored to different age groups or to find innovative ways to combine existing treatments to improve outcomes. This is particularly important for enhancing therapy effectiveness in older patients without triggering toxicities or adverse events that could lead to poor outcomes.
The study addresses a critical gap in cancer treatment research, as most new cancer diagnoses occur in people 65 and older, who typically experience worse cancer treatment outcomes. By demonstrating that immunotherapy can be equally effective regardless of age while identifying the specific immune differences between age groups, this research opens new avenues for optimizing cancer treatment across the age spectrum.
