Elsevier

The Lancet Oncology

Volume 21, Issue 1, January 2020, Pages e55-e65
The Lancet Oncology

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Immune checkpoint inhibitors and tuberculosis: an old disease in a new context

https://doi.org/10.1016/S1470-2045(19)30674-6Get rights and content

Summary

Tuberculosis, the leading cause of infection-related death in developing regions, is a leading cause of morbidity and mortality worldwide. Screening for, and treatment of, latent Mycobacterium tuberculosis infection is routine before initiation of anti-tumour necrosis factor α (anti-TNFα) agents in the management of psoriasis, Crohn's disease, and rheumatoid arthritis. By contrast, screening for latent tuberculosis before immune checkpoint inhibitor treatment in cancer is not routine, despite the increasing number of reports of primary infection with M tuberculosis or reactivation of latent M tuberculosis infection during such treatment. We present our experience with M tuberculosis screening in 70 patients who underwent immune checkpoint inhibitor therapy for metastatic skin cancer. Based on our understanding of the interaction between M tuberculosis and the immune system, we present the argument for tuberculosis screening before immune checkpoint inhibitor therapy and its use when considering anti-TNFα treatment for severe immune-related adverse events. We call for increased vigilance during immune checkpoint inhibition until its effects on tuberculosis pathophysiology are fully ascertained.

Introduction

Tuberculosis represents a major disease burden worldwide, with 9 million new cases per year and 1·5 million deaths annually.1 Multidrug resistance, particularly in the context of concomitant HIV infection, also poses a substantial health-care challenge.2 Additional risk factors for Mycobacterium tuberculosis infections are smoking, immunosuppression, diabetes, obesity, visiting or living in endemic areas, living in overcrowded areas, poor nutrition, and being male.1 In fact, tuberculosis has been referred to as the disease without boundaries3 and although living in a developing country is a risk factor for infection, mass migration means that the disease is by no means restricted to these areas.4

The use of monoclonal antibody therapies for several chronic inflammatory diseases (eg, psoriasis, inflammatory bowel disease, and rheumatoid arthritis) has resulted in routine screening for, and treatment of, latent M tuberculosis infection to prevent potentially fatal reactivation; particularly before treatment with tumour necrosis α (TNFα) blocking agents.

By contrast, screening for latent M tuberculosis before the initiation of immune checkpoint inhibition for the treatment of cancer is not routine. The risk of reactivation of latent M tuberculosis or primary infection during immune checkpoint inhibition is currently unknown. Quantifying the extent of this risk is complicated by the presence of pre-existing risk factors for M tuberculosis infection or reactivation, including the immunosuppressive effects of malignancy and previous chemotherapy.5 The situation is even more complicated in the treatment of lung cancer, in which immune checkpoint inhibition is increasingly used. Specifically, the development of pleural effusions must be carefully evaluated to establish whether they are due to disease progression or pleural M tuberculosis infection to avoid potentially fatal treatment delays.5, 6 Pneumonitis during immune checkpoint inhibitor therapy (particularly anti- PD-1 therapy)7 is a well recognised immune-related adverse event, which suggests an immunomodulatory effect on pulmonary T cells. Whether pneumonitis contributes to an increased susceptibly to M tuberculosis infection or reactivation is unknown and requires evaluation.

The use of immune checkpoint inhibitors that primarily block PD-1, PD-L1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) signalling, has drastically transformed the therapeutic landscape for the treatment of metastatic melanoma and other cancers. Indeed, with the increasing use of neoadjuvant and adjuvant melanoma immunotherapy for patients in tumour stage III and IV,8 the number of patients who will benefit from immune checkpoint inhibition is set to increase. The consequence is that increases in progression-free survival and overall survival, particularly in metastatic melanoma, will result in more patients who could potentially develop severe and lasting immune checkpoint inhibitor therapy-induced organ-specific immune-related adverse events.

Despite the well grounded enthusiasm for using immune checkpoint-based immunotherapy in both the adjuvant and metastatic setting, either as monotherapy or as combined treatment, organ-specific, immune-related adverse events are frequent and potentially fatal.9 Therefore, the risks associated with immune checkpoint-based immunotherapy must be carefully balanced against the benefits of treatment, particularly when used in the adjuvant setting.

Central to minimising the risks associated with immune checkpoint-based immunotherapy is the development of comprehensive guidelines that detail the necessary pre-treatment investigations and appropriate monitoring strategies; facilitating early recognition of immune-related adverse events to initiate timely treatment. To this end, Champiat and colleagues10 delivered a position statement detailing a five-point model based on prevention, anticipation, detection, treatment, and monitoring of immunotherapy-mediated side-effects and toxicities. As part of the baseline immunotherapy blood test, the authors recommended the IFNγ release assay (IGRA) or the tuberculin sensitivity test in patients with a known previous exposure, to screen for latent M tuberculosis infection. Although the effect on immune checkpoint inhibition on the pathophysiology of M tuberculosis infection is only partly understood, evidence suggests that immune checkpoints do play a role in M tuberculosis infection, which we discuss in the important considerations section.

Section snippets

The PD-1–PD-L1 signalling pathway

To date, the role of the PD-1–PD-L1 signalling pathway in establishing an effective immune response to infection with M tuberculosis is unclear. An initial murine study in Pd1 knockout mice reported drastically reduced survival after aerosol infection with M tuberculosis compared with wild-type mice, reflected by an increased mycobacterial load.11 Moreover, the infected Pd1 knockout mice developed severe necrotic pneumonia, characterised by neutrophil infiltration and reduced numbers of

Evidence

In fact, both acute and reactivated tuberculosis have been described in patients undergoing treatment with PD-1 checkpoint inhibitors. Lee and colleagues19 reported the first case of M tuberculosis reactivation during the treatment of relapsed Hodgkin lymphoma with pembrolizumab. The reactivation developed after five cycles of treatment, accompanied by fever and weight loss, and M tuberculosis was cultured from the patient's sputum. Pembrolizumab treatment was discontinued.

Subsequently, Fujita

Experience in a dermato-oncology cohort

Given the reports of M tuberculosis infection or reactivation, we retrospectively reviewed the case notes of all patients who had undergone immunotherapy in our department (Department of Dermatology, University of Lübeck, Lübeck, Germany), including anti-PD-1 monotherapy, combined anti-PD-1 and CTLA-4 treatment and anti-PD-L1 treatment, between Jan 1, 2017, and Dec 31, 2018, to determine our adherence to tuberculosis screening. Screening from Mtb forms part of our internal immunotherapy

Important considerations

Although the interplay between tuberculosis and the human immune system during immune checkpoint inhibition has yet to be clarified, clinicians must be aware of the risk of primary infection with M tuberculosis or reactivation of infection during immune checkpoint inhibition therapy to facilitate early recognition and treatment. In particular, there are several other aspects of the development of tuberculosis during immune checkpoint inhibitor therapies that deserve attention, such as

Tuberculosis mimicking tumour progression or tumour pseudoprogression

Primary infection or reactivation of latent tuberculosis can initially mimic disease progression. For example, myocardial thickening, described in a patient reported by Chu and colleagues,22 was initially interpreted as tumour infiltration. Indeed, the situation is further complicated by trying to distinguish infection with M tuberculosis from the occurrence of tumour pseudoprogression (transient radiographic evidence of progression after the initiation of immune therapy), true tumour

Pre-therapeutic IGRA testing

Although acute tuberculosis infection is diagnosed on the basis of the clinical presentation, chest x-ray, and sputum culture or PCR, the initial presenting symptoms and radiographic findings might not enable the differentiation between patients with tumour progression, M tuberculosis infection, and immune-therapy mediated sarcoidosis. The IGRA is primarily useful to exclude latent infection with M tuberculosis, although the test result can be positive during acute infection and should be done

Anti-TNFα treatment in the setting of immune-related adverse events

Knowledge of a patient's previous exposure to M tuberculosis, risk factors for M tuberculosis infection, and IGRA result is of paramount importance when considering anti-TNFα treatment for immune checkpoint-mediated adverse events. Although firm data for the use of anti-TNFα agents for the treatment of severe and refractory immune-related adverse events are not available, infliximab should be considered for the management of severe, therapy resistant, immune checkpoint-associated colitis45 and

Treatment of the underlying tumour

As evidenced by published studies to date, there is no general consensus on whether immune checkpoint inhibitor therapy should be continued, temporarily interrupted, or permanently stopped in the context of acute M tuberculosis infection or reactivation. In six of the 14 published studies, immune therapy was discontinued, it was either temporarily interrupted, continued, or not specified in the remaining studies. Given the small number of studies, it is not possible to determine whether the

Antimicrobial prophylaxis and the microbiome

At present, there are no official recommendations regarding antimicrobial prophylaxis for patients with latent tuberculosis who undergo immune checkpoint inhibitor therapy or anti-TNFα treatment for immune checkpoint-mediated toxicities. Although routine antimicrobial prophylaxis for all patients with suspected latent tuberculosis scheduled to undergo immune checkpoint inhibitor therapy is questionable, it would be reasonable and well advised to simultaneously administer antimicrobial

Conclusion

Clinicians should be aware that acute M tuberculosis infection and reactivation of latent disease can both occur during immune checkpoint inhibition, with potentially fatal consequences. Given that a quarter of the world's population is infected with M tuberculosis, latent infection is not only an issue for endemic areas.71 Although persistent cough, unexpected weight loss, fever, and breathlessness are the typical presenting symptoms, infection with M tuberculosis could present in the absence

Search strategy and selection criteria

We did a PubMed literature search with the search terms “tuberculosis”, “immune checkpoint”, “PD-1”, “PD-L1”, “pembrolizumab”, “nivolumab”, “melanoma”, and “lung cancer”, between Jan 7 and Sept 12, 2019. Only articles published in English were selected. Both human and animal studies were included for review.

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