Acetaminophen may reduce immunotherapy efficacy in patients with cancer
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CHICAGO — Acetaminophen suppressed antitumor immunity in a cohort of patients with cancer, according to study results presented during ASCO Annual Meeting.
Researchers recommended caution when prescribing acetaminophen among patients with cancer who are treated with immune checkpoint inhibitors.
Rationale and methods
“Acetaminophen is the first-line strategy to manage mild-to-moderate pain among patients with advanced cancer,” Antoine Italiano, MD, PhD, professor and head of the early phase trials and sarcoma units at Institute Bergonié in Bordeaux, France, said during his presentation. “However, preclinical studies have demonstrated that acetaminophen inhibits the proliferation of immune cells and the T cell-dependent antibody response. In addition, randomized studies have shown that acetaminophen has a negative impact on vaccination response, with decreased antibody levels in individuals receiving acetaminophen for fever prophylaxis.”
Italiano and colleagues sought to assess the effect of acetaminophen on the efficacy of immunotherapy among patients with cancer included in three previously published study cohorts: the CheckMate 025 trial (n = 297), the institutional biomarker program BIP (n = 34) and the institutional biomarker program PREMIS (n = 297).
Researchers additionally evaluated the immunomodulatory effects of acetaminophen on a preclinical tumor model and on human peripheral blood mononuclear cells from otherwise healthy donors.
Key findings
Researchers found patients with detectable plasma acetaminophen levels at onset of treatment with immune checkpoint inhibitors had significantly worse clinical outcomes (HR for PFS = 1.43; 95% CI, 1.07-1.91; and HR for OS = 1.78; 95% CI, 1.18-2.68), independent of age, performance status, number of previous lines of treatment, tumor type, number of metastatic sites and presence of liver metastases.
Researchers also observed decreased immune checkpoint inhibitor efficacy in the preclinical model and decreased efficacy of PD-1 blockade-associated interferon-gamma secretion by human peripheral blood mononuclear cells.
Decreased efficacy of immune checkpoint inhibitors in vivo was associated with increased tumor infiltration by regulatory T cells, and acetaminophen administered over a 24-hour period induced significant expansion of peripheral regulatory T cells among the cohort of otherwise healthy individuals.
Moreover, patients who received acetaminophen also experienced upregulation of interleukin-10 upon treatment with immune checkpoint inhibitors.
Looking ahead
“This is the first comprehensive picture of the immunomodulatory effects of acetaminophen, which showed the drug is associated with decreased efficacy of immune checkpoint inhibitors in patients with advanced cancer,” Italiano said. “Future research will examine the direct or indirect effect of the association of acetaminophen on [regulatory T cells].”
For more information:
Antoine Italiano, MD, PhD, can be reached at a.italiano@bordeaux.unicancer.fr.
Perspective
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Ryan J. Sullivan, MD
This study does a great job of highlighting something that could dramatically change the way we manage our patients who are on immunotherapy, and it is concerning because acetaminophen is so commonly used for patients with cancer.
The study includes a number analysis of clinical data from multiple trials, functional analysis of immune cell subsets from patients and volunteers, and preclinical animal modeling, which support the conclusion that acetaminophen diminishes the benefit of cancer immunotherapy. One of the strengths of this abstract is that the researchers did not just use patients’ recall as to whether they were or were not taking acetaminophen, but measured blood levels of acetaminophen and its metabolites.
Certainly, further study is needed before we radically change the way we manage patients with cancer-related pain or fevers. However, if confirmed, it could dramatically alter the way we think about treating patients with cancer who are being treated with immunotherapy. It is a bit sobering to have a finding like this with a drug that we use all the time with our patients. The findings are thought-provoking and potentially game-changing.
The potential limitation of this work is that it is hard to know whether the researchers measured and compared other metabolites of other drugs — that was not a part of their multivariate analysis and could be a confounding variable. For example, there are data to suggest metformin, certain beta-blockers and angiotensin II receptor blockers are associated with better outcomes with immunotherapy. Thus, it would be important to carefully look at all the other medications detected in patients’ blood that are potentially associated with better or worse outcomes with checkpoint inhibitors and make sure that those confounding factors are at least identified and controlled for, if possible.
Ultimately, the data are strong and I think they will indeed change the way we think about acetaminophen when treating our patients — but until the data are validated, I don’t think it should change how we use it. And yet, it is definitely a wake-up call and another variable to consider when managing our patients treated with immune checkpoint inhibitors.
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Bessede A, et al. Abstract LBA12000. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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