Immune Checkpoint Inhibitor Therapy and Risk of Tuberculosis Exacerbation

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Immune checkpoint therapy with programmed cell death-1 (PD-1) inhibitors was linked to activation of latent Mycobacterium tuberculosis (Mtb) infection in 2 patients.
Immune checkpoint therapy with programmed cell death-1 (PD-1) inhibitors was linked to activation of latent Mycobacterium tuberculosis (Mtb) infection in 2 patients.

Immune checkpoint therapy with programmed cell death-1 (PD-1) inhibitors was linked to activation of latent Mycobacterium tuberculosis (Mtb) infection in 2 patients, according to a case study report published in Science Translational Medicine.  

Two patients, a 59-year old man with metastatic nasopharyngeal carcinoma receiving nivolumab and an 83-year old man with metastatic Merkel cell carcinoma receiving pembrolizumab, developed active Mtb infection while receiving anti-PD-1 therapy. Given factors that include patient age, travel history, contact (or lack thereof) with patients with tuberculosis, as well as Mtb strain, the authors concluded that both cases of MtB were likely to be associated with pre-existing latent infections. Both patients were treated with standard tuberculosis regimens.

An analysis of peripheral blood mononuclear cells obtained prior to immune blockade therapy initiation and at treatment cycles 5, 8, 11, and 14 in the patient with Merkel cell carcinoma showed an increase in the production of interferon-gamma producing-Mtb-specific CD4 cells following administration of pembrolizumab. Previously published preclinical studies have shown that high levels of interferon gamma were associated with increased risk of early death and exacerbation of Mtb infection in PD-1 knockout mice.  

The use of host-directed therapy, such as PD-1 inhibitors, to unleash the immune system for the treatment of chronic infections, such as tuberculosis, is an active area of research. During active Mtb infection, Mtb-specific CD4 T cells have been shown to express PD-1, and PD-1 levels on these cells have been found to decrease after Mtb infection has been cleared. Hence, the use of host-directed therapy with PD-1 inhibitors has been suggested as a possible alternative to standard tuberculosis treatment regimens which are complicated, require long-term administration, and can induce development of drug-resistant Mtb strains. 

Nevertheless, the authors cautioned that “these cases highlight that treatment with an anti-PD-1 in a patient with latent or active TB may have deleterious outcomes.” They concluded the article by stating that screening for tuberculosis before the initiation of checkpoint therapy may be a warranted treatment strategy.

Reference

  1. Barber DL, Sakai S, Kudchadkar RR, et al. Tuberculosis following PD-1 blockade for cancer immunotherapy [published online January 16, 2019]. Sci Transl Med. doi: 10.1126/scitranslmed.aat2702

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