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Updated: Feb 15, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model
Álvaro Padrón1, Vincent Hurez1, Harshita B Gupta1
1Department of Medicine, University of Texas Health San Antonio, TX 78229, United States.
Abstract:
Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed, with six distinct agents approved since 2011 for a wide variety of cancers. Although age is the biggest risk factor for cancer (aside from selected early-onset pediatric cancers), these agents were tested pre-clinically in young hosts, and there is remarkably little published on the effects of host age on treatment outcomes in pre-clinical studies or human clinical trials. The three principal immune checkpoints against which blocking antibodies have been FDA-approved for human use are CTLA-4, PD-1 and PD-L1. We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies. All three agents were highly effective in treating young tumor-bearing hosts as expected. Anti-PD-L1 as a single agent had no effect on tumor growth in aged hosts, anti-CTLA-4 had detectable, modest effects and anti-PD-1 was essentially as effective in aged as in young hosts, the first single agent we have identified not to lose efficacy with age in this model. Other important differences in young versus aged hosts included lack of anti-CTLA-4-mediated depletion of intratumor regulatory T cells in aged hosts and poorer ability of all three agents to activate T cells in aged versus young hosts. Anti-CTLA-4 efficacy appeared to improve when combined with anti-PD-L1. Regulatory T cell depletion with FDA-approved denileukin diftitox did not improve treatment by any single agent. Aged mice tolerated treatments as well as young mice without obvious toxicities at equivalent doses.
Insights
Cancer immunotherapy agents like anti-PD-1 remain effective in aged mice, unlike anti-CTLA-4 and anti-PD-L1, highlighting age-related differences in treatment outcomes.
Area of Science:
- Immunology
- Oncology
- Gerontology
Background:
- Cancer immunotherapy, particularly immune checkpoint blocking antibodies, has revolutionized cancer treatment.
- Age is a significant risk factor for cancer, yet pre-clinical and clinical data on age-related treatment efficacy are limited.
- Key immune checkpoints targeted by approved therapies include CTLA-4, PD-1, and PD-L1.
Purpose of the Study:
- To investigate the impact of host age on the efficacy of anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies in a pre-clinical cancer model.
- To identify potential age-related mechanisms influencing immunotherapy response.
- To evaluate combination therapies and their efficacy in aged hosts.
Main Methods:
- Utilized a transplantable, orthotopic B16 melanoma mouse model.
- Administered single-agent treatments with anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies to young and aged mice.
- Assessed tumor growth, T cell activation, and regulatory T cell populations.
Main Results:
- Anti-PD-1 maintained efficacy in aged hosts, while anti-PD-L1 and anti-CTLA-4 showed reduced or modest effects, respectively.
- Aged hosts exhibited impaired T cell activation and lacked anti-CTLA-4-mediated depletion of intratumoral regulatory T cells.
- Combination therapy of anti-CTLA-4 and anti-PD-L1 showed improved efficacy in aged mice.
- Aged mice tolerated immunotherapy treatments well, with no observed increase in toxicity.
Conclusions:
- Host age significantly influences the efficacy of certain cancer immunotherapies, with anti-PD-1 demonstrating preserved effectiveness in aged models.
- Age-related changes in immune cell function may underlie differential treatment responses.
- Further research into age-specific immunotherapy strategies is warranted to optimize cancer treatment for older populations.
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