Tuberculosis following PD-1 blockade for cancer immunotherapy

Barber DL, Sakai S, Kudchadkar RR, Fling SP, Day TA, Vergara JA, Ashkin D, Cheng JH, Lundgren LM, Raabe VN, Kraft CS, Nieva JJ, Cheever MA, Nghiem PT, Sharon E

Sci Transl Med. 2019 Jan 16;11(475). pii: eaat2702. doi: 10.1126/scitranslmed.aat2702.

PMID: 30651320

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Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models, Mtb-infected PD-1-/- mice mount exaggerated TH1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific TH17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting TH1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.

Sci Transl Med. 2019 Jan 16;11(475). pii: eaat2702. doi: 10.1126/scitranslmed.aat2702.