ICIs Effective Regardless of Patients' Age, But Key Immune Phenotype Differences May Enable Tailored Regimens
A study in Nature Communications found that older cancer patients have similar outcomes with immune checkpoint inhibitors as younger patients, despite having different baseline immune profiles, suggesting potential for age-tailored therapies.
Microscopic view of a cancer cell being destroyed by a targeted therapy treatment, representing the latest advancements in medical research towards a cancer cure: © Sirinporn - stock.adobe.com
Older patients with cancer have similar outcomes as younger patients when treated with immune checkpoint inhibitors (ICIs); however, patients who are over 65 years of age have divergent immune phenotypes at baseline than their younger counterparts. Findings may help tailor approaches to improve ICI outcomes for aged vs younger patients with cancer, according to investigators in a study published in Nature Communications.
Investigators identified some key differences, notably cytokine dynamics, circulating immune composition, and immune cell phenotype dynamics at baseline. These may guide more personalized therapeutic approaches for patients with cancer.
“Older patients do just as well, sometimes better than younger patients with immunotherapy treatments,” senior author Daniel Zabransky, MD, PhD, assistant professor of oncology at the Johns Hopkins University School of Medicine, Baltimore, Maryland, said in a release. “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 or allow us to use current therapies in all patients more effectively.”
Study Design
A total of 124 patients were enrolled and received ICIs as standard-of-care treatment for solid tumors and were prospectively followed for at least 6 months during this observational study. Among these patients, 104 provided peripheral blood samples at baseline and about 1 to 5 months after initiation of ICI therapy.
Patients with pathologically confirmed solid tumors were treated with ICIs consisting of anti-PD-1/PD-L1 blockade (nivolumab [Opdivo], pembrolizumab [Keytruda], atezolizumab [Tecentriq], cemiplimab [Libtayo], durvalumab [Imfinzi], and avelumab [Bavencio]), combination ICI blockade with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab [Yervoy]), or in combination with targeted therapy or chemotherapy.
The median age of all patients was 65 years (range, 20-over 90) and there were 54 patients who were 65 years and older (range, 65-90 or older) and 50 patients who were younger than 65 years (range, 20-64). Overall, the cohort was predominantly male (67.3%), White (64.4%), and treated with ICI monotherapy (42.3%).
Cancer Types and Disease Stage
Among patients with cancer aged 65 and older, gastrointestinal (40.7%) and genitourinary (37.0%) cancers were most common, followed by skin (9.3%), other malignancies (9.3%), and upper aerodigestive (UAD; 3.7%) cancers. In the younger group, gastrointestinal (32.0%) and genitourinary (28.0%) cancers also predominated, with higher rates of UAD (16.0%) and other cancers (18.0%).
Most patients with cancer had advanced or metastatic disease at baseline: 92.3% overall, 96.3% in patients 65 years and older, and 88.0% in patients 65 years and younger.
Age-Related Responses
Among the 104 patients, 95 patients had available on-treatment samples to assess the cytokine changes that occur after ICI exposure. The majority had on-treatment samples collected withing 2 months (83.2%), after 2 months but within 3 months (13.7%), 3 to 5 months post initiation of ICI therapy (3.2%).
With regards to immune response, investigators noted differences in the baseline and on-treatment levels of multiple cytokines (IL-2, IL-12p70, IL-17a, CCL2, IL-1α, VEGF-α, and sCD40L). While aged patients had smaller increases in CCL2 expression after ICI treatment, interestingly, an increased fold change in CCL2 levels predicted nonresponse in young patients but response in aged patients (adjusted interaction P =.02).
ICI clinical outcomes are comparable between aged (65 or more years) and younger (65 years or younger) patients in a diverse pan-tumor cohort. However, aged patients have lower proportions of naive cytotoxic (TcN) and helper T (ThN) cells, B cells, and double negative T (DNT) cells, and a higher proportion of natural killer (NK) cells before and after ICI treatment. Aged patients also display diminished circulating cytokine responses after treatment.
Next Steps
For next steps in research, Zabransky and his team plan to investigate immune cells found inside tumors and compare them across age groups to see how they react to immunotherapies. They hope that by understanding age-related differences in immune responses to cancer therapies, they can either develop new cancer therapies better tailored to different age groups’ needs or find new ways to combine existing treatments to improve care. It’s imperative, he notes, to find ways to boost therapy effectiveness in older patients without triggering toxicities or other adverse events that can lead to poor outcomes.
“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,” Zabransky said. “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.”
