Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model

Álvaro Padrón, Vincent Hurez, Harshita B. Gupta, Curtis A. Clark, Sri Lakshmi Pandeswara, Bin Yuan, Robert Svatek, Mary Jo Turk, Justin M. Drerup, Rong Li, Tyler J Curiel

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
JournalExperimental Gerontology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Melanoma
T-cells
Neoplasms
Blocking Antibodies
Regulatory T-Lymphocytes
Therapeutics
Tumors
Bearings (structural)
Experimental Melanomas
Pediatrics
Immunotherapy
Toxicity
Clinical Trials
T-Lymphocytes
Antibodies
Growth

Keywords

  • Aging
  • Cancer
  • Immune checkpoint
  • Immunity
  • Immunotherapy
  • Melanoma

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

Cite this

Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. / Padrón, Álvaro; Hurez, Vincent; Gupta, Harshita B.; Clark, Curtis A.; Pandeswara, Sri Lakshmi; Yuan, Bin; Svatek, Robert; Turk, Mary Jo; Drerup, Justin M.; Li, Rong; Curiel, Tyler J.

In: Experimental Gerontology, 01.01.2018.

Research output: Contribution to journalArticle

Padrón, Álvaro ; Hurez, Vincent ; Gupta, Harshita B. ; Clark, Curtis A. ; Pandeswara, Sri Lakshmi ; Yuan, Bin ; Svatek, Robert ; Turk, Mary Jo ; Drerup, Justin M. ; Li, Rong ; Curiel, Tyler J. / Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. In: Experimental Gerontology. 2018.
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