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Development of Mycobacterium avium complex lung disease in patients with lung cancer on immune checkpoint inhibitors

Development of Mycobacterium avium complex lung disease in patients with lung cancer on immune... Immunotherapy with immune checkpoint inhibitors (ICIs), though ameliorates lung cancer, can cause infectious diseases, including tuberculosis, in addition to immune-related non-infectious complications. In clinical setting, efficacy of ICIs to treat mycobacterial infection remains controversial. We report three cases of acute Mycobacterium avium complex lung disease during immunotherapy with ICIs. Keywords: Mycobacterium avium complex, lung cancer, immune checkpoint inhibitors, nontuberculous mycobacteria Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Introduction Recent advances in immunotherapy with immune checkpoint inhibitors has improved the outcomes of patients with lung cancer [1, 2]. Although immune checkpoint inhibitors manifest drastic effects, unique adverse events, including skin rash, hepatotoxicity, and endocrine disturbances, are known to occur during treatment. These events are termed immune-related adverse events (irAEs). Among the several types of irAEs, cases of infectious diseases have been increasing steadily [3]. Cases of mycobacterial infection have been particularly alarming because of multiple reported cases [4-7]. We experienced three cases of acute development of Mycobacterium avium complex lung disease (MAC-LD) in patients with lung cancer on immune checkpoint inhibitors. These may emerge as thought-provoking cases. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case presentation and summary Case 1. A 66-year-old woman underwent surgical resection of the right lower lobe lung adenocarcinoma. Her adenocarcinoma recurred after 12 years. Computed tomography (CT) images acquired at that time showed no bronchiectasis or nodules in the bilateral lobes. She received 60-Gy stereotactic radiotherapy. On disease progression, she received one cycle of combined carboplatin and pemetrexed as initial therapy. Because of adverse events, her chemotherapy regimen was revised to gemcitabine. rd However, her disease progressed. She received nivolumab as the 3 line therapy. After 15 cycles of nivolumab, she developed wet cough with excessive sputum. CT images showed infiltration in the upper left lung lobe and lingula. Two consecutive sputum cultures were positive for Mycobacterium th intracellulare at 17 cycle of nivolumab therapy. A diagnosis of MAC-LD was established and specific treatment for MAC was initiated along with continued nivolumab therapy. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case 2. An 80-year-old man was diagnosed with stage 3a right upper lobe non-small cell lung cancer by bronchoscopy. Although lung cancer was diagnosed, CT images only showed bilateral emphysema but no bronchiectasis or nodules. Sequential chemoradiotherapy was initiated. He received one cycle of combined carboplatin and nanoparticle albumin-bound paclitaxel (nabPTX) therapy, followed by radiotherapy (66 Gy). He attained 3 years of progression-free survival. However, the cancer recurred because of a single brain metastasis and multiple lower left nodules. He underwent gamma knife nd therapy for brain metastasis and was initiated on 2 line systemic immunotherapy with atezolizumab. rd At 23 cycle of atezolizumab therapy, he developed wet cough and excessive sputum production. CT images revealed multiple reticulonodular infiltrates in the lower left lung lobe. Two consecutive th sputum cultures at 24 cycle of atezolizumab were positive for M. avium and M. intracellulare. He was diagnosed with MAC-LD; specific treatment was initiated for MAC alongside the atezolizumab therapy. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case 3. A 66-year-old man was diagnosed with stage 4a advanced squamous cell carcinoma of the right upper lung lobe. Although lung cancer was diagnosed, CT images showed bilateral emphysemas but no bronchiectasis or nodules. He received initial therapy with 6 cycles of combined carboplatin and nabPTX. However, tumor progression was confirmed after 3 months. Second line therapy with nivolumab was initiated. However, disease progression was confirmed after 6 cycles of nivolumab rd th therapy. As the 3 line therapy, he received 7 cycles of docetaxel, and subsequently, 4 line therapy with atezolizumab after docetaxel failure. Concomitantly, he experienced right main bronchus stenosis because of tumor progression, and palliative radiotherapy (37.5 Gy) was administered. CT images acquired during atezolizumab therapy revealed rapidly worsening right lower lobe infiltration. th Two consecutive sputum cultures at the 4 cycle of atezolizumab therapy were positive for M. intracellulare, and a diagnosis of MAC-LD was established. However, because of severe debilitation, treatment for MAC-LD was not initiated and atezolizumab immunotherapy was discontinued. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Summary of cases Table 1 shows the summary of all 3 cases. In this study, CT images were retrospectively reviewed to assess possible changes of MAC-LD predating ICI immunotherapy. All patients had advanced lung cancer and received cytotoxic chemotherapy before treatment with ICIs. Moreover, they received thoracic radiotherapy before the pathogenesis of MAC-LD. ICI immunotherapy was continued in two patients after they were diagnosed with MAC-LD. The median time to MAC-LD diagnosis from induction of initial ICI were 17 months (range, 17–19 months). Discussion We experienced three acute cases of MAC-LD during ICI immunotherapy. Previous reports indicate that development of tuberculosis during ICI immunotherapy has become an emerging concern [4-7]. Multiple cases of tuberculosis were suspected reactivation of latent infection. Some authors have suggested the development of tuberculosis to be similar to immune reconstitution inflammatory syndrome [4, 7]. A similar presentation is expected of nontuberculous mycobacterial infection; Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 however, till date, no paper had reported the development of nontuberculous mycobacterial infection. In our three cases, no fibro-cavitary or reticulonodular shadow was noted that could indicate nontuberculous mycobacteria (NTM) infection at the initial diagnosis of lung cancer. Therefore, it is unclear whether MAC-LD developed from reactivation of existing disease or whether it was a de novo infection. Although the precise mechanisms underlying MAC-LD are unknown, anti-PD-1/PD-L1 antibodies are known to have possible anti-microbial effects that are mediated by upregulation of T cell- mediated immunity [8]. A previous report suggested favorable effect of nivolumab for the treatment of Mycobacterium abscessus lung disease [9]. Our present cases might partly reflect this paradoxical reaction, i.e., overresponse to mycobacteria. In contrast, Barber et al. reported that PD-1/PD-L1 knockout mice displayed increased susceptibility to tuberculosis through enhanced CD4 T cell- mediated tissue destruction [10]. In patients receiving ICIs, Barber et al. also discovered similar profiles for CD4 T cell, CD8 T cell, and T cell-mediated cytokine dynamics[11]. These data suggested that Th1 function with anti-PD-1/PD-L1 antibodies might cause the development of tuberculosis. In actual clinical settings, treatment with anti-PD-1/PD-L1 antibodies is expected to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 show similar responses. Therefore, the effects of ICIs with regard to mycobacterial diseases in clinical setting remains controversial. Alternatively, ICI immunotherapy might initiate a state of autoimmunity that mimics diseases like rheumatoid arthritis, which are known to be strongly associated with NTM-LD. Well-designed population-based studies are required to investigate such causal associations. Cumulative experience will reveal the complete picture. Presently, all patients had advanced stage lung cancer and received relatively long-term treatment, including cytotoxic chemotherapy; therefore, the influence of both the cancer and the treatment in the development of MAC-LD cannot be ignored. Furthermore, cytotoxic chemotherapy can exacerbate NTM disease [12]. Previous cytotoxic chemotherapy before induction of ICIs might favor the clinical outcome moderately. The following alternate interpretation is also important. Japan has one of the highest burdens of NTM globally [13, 14]. Moreover, ICI immunotherapy is becoming popular in Japan. Therefore, physicians in high burden of NTM should pay more attention to the development of MAC-LD during immunotherapy regimens with ICIs. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Conclusion Physicians should be cautious towards the development of MAC-LD in patients on immunotherapy with ICIs, especially in countries such as Japan, which has a high burden of NTM. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Conflicts of interest All authors declare no conflicts of interest. Patients consent We have obtained written consent forms from all patients described in this study. Financial support This case study was partly supported by a Grant-in-Aid for Young Scientists (B), KAKENHI, Japan Society for the Promotion of Science, Japan. (Grant Number, 17K16067) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 References (1) Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450-461. (2) Granier C, De Guillebon E, Blanc C, Roussel H, Badoual C, Colin E, Saldmann A, Gey A, Oudard S, Tartour E. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2017;2:e000213-2017. (3) Fujita K, Kim YH, Kanai O, Yoshida H, Mio T, Hirai T. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy. Respir Med 2019;146:66-70. (4) Fujita K, Terashima T, Mio T. Anti-PD1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. J Thorac Oncol 2016;11:2238-2240. (5) Chu YC, Fang KC, Chen HC, Yeh YC, Tseng CE, Chou TY, Lai CL. Pericardial Tamponade Caused by a Hypersensitivity Response to Tuberculosis Reactivation after Anti- Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 PD-1 Treatment in a Patient with Advanced Pulmonary Adenocarcinoma. J Thorac Oncol 2017;12:e111-e114. (6) Picchi H, Mateus C, Chouaid C, Besse B, Marabelle A, Michot JM, Champiat S, Voisin AL, Lambotte O. Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment. Clin Microbiol Infect 2018;24:216-218. (7) Takata S, Koh G, Han Y, Yoshida H, Shiroyama T, Takada H, Masuhiro K, Nasu S, Morita S, Tanaka A, Hashimoto S, Uriu K, Suzuki H, Tamura Y, Okamoto N, Nagai T, Hirashima T. Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents. J Infect Chemother 2019;25:54-58. (8) Rao M, Valentini D, Dodoo E, Zumla A, Maeurer M. Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm. Int J Infect Dis 2017;56:221-228. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 (9) Ishii S, Tamiya A, Taniguchi Y, Tanaka T, Abe Y, Isa SI, Tsuyuguchi K, Suzuki K, Atagi S. Improvement of Mycobacterium abscessus Pulmonary Disease after Nivolumab Administration in a Patient with Advanced Non-small Cell Lung Cancer. Intern Med 2018;57:3625-3629. (10) Barber DL, Mayer-Barber KD, Feng CG, Sharpe AH, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 2011;186:1598-1607. (11) 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. Tuberculosis following PD-1 blockade for cancer immunotherapy. Sci Transl Med 2019;11:10.1126/scitranslmed.aat2702. (12) Tsuji T, Tsuyuguchi K, Tachibana K, Kimura Y, Kobayashi T, Minomo S, Atagi S, Matsumura A, Hayashi S, Suzuki K. Analysis of the impact of lung cancer treatment on nontuberculous mycobacterial lung diseases. Respir Investig 2017;55:45-50. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 (13) Morimoto K, Iwai K, Uchimura K, Okumura M, Yoshiyama T, Yoshimori K, Ogata H, Kurashima A, Gemma A, Kudoh S. A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan. Ann Am Thorac Soc 2014;11:1-8. (14) Namkoong H, Kurashima A, Morimoto K, Hoshino Y, Hasegawa N, Ato M, Mitarai S. Epidemiology of Pulmonary Nontuberculous Mycobacterial Disease, Japan. Emerg Infect Dis 2016;22:1116-1117. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Table 1. Characteristics of the patients who developed Mycobacterium avium complex lung disease Case 1 Case 2 Case 3 Age at diagnosis of MAC, years 78 80 66 Sex Female Male Male Smoking status (pack-year) Never 45 20 Cavities/Bronchiectasis before ICI None None None Histopathology Adenocarcinoma Not otherwise specified Squamous cell carcinoma Staging at diagnosis Post-operative recurrence cT1bN2M0; stage 3a cT4N2M1a; stage 4a Driver oncogene alteration wild type wild type NE PD-L1 expression NE NE <1% Type of ICI Nivolumab Atezolizumab Nivolumab + Atezolizumab Infected MAC strain M. intracellulare M. avium + M. intracellulare M. intracellulare Time to MAC-LD diagnosis*, month 17 17 19** Cycles of ICI, number 38 24 6 (nivolumab) + 4 (atezolizumab) Prior radiotherapy 60 Gy 60 Gy 37.5 Gy Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Prior chemotherapy 1st line Carboplatin + Pemetrexed Carboplatin + nabPTX Carboplatin + nabPTX 2nd line Gemcitabine - Nivolumab 3rd line - - Docetaxel Response to MAC treatment Good Fair No medication MAC, Mycobacterium avium complex; NE, not evaluated; PD-L1, programmed cell death-ligand 1; ICI, immune checkpoint inhibitor; nabPTX, nanoparticle albumin-bound paclitaxel *Time from initiation of immune checkpoint inhibitor therapy to diagnosis of Mycobacterium avium complex lung disease **Duration included that of docetaxel treatment Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Development of Mycobacterium avium complex lung disease in patients with lung cancer on immune checkpoint inhibitors

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Oxford University Press
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© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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2328-8957
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10.1093/ofid/ofaa067
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Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs), though ameliorates lung cancer, can cause infectious diseases, including tuberculosis, in addition to immune-related non-infectious complications. In clinical setting, efficacy of ICIs to treat mycobacterial infection remains controversial. We report three cases of acute Mycobacterium avium complex lung disease during immunotherapy with ICIs. Keywords: Mycobacterium avium complex, lung cancer, immune checkpoint inhibitors, nontuberculous mycobacteria Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Introduction Recent advances in immunotherapy with immune checkpoint inhibitors has improved the outcomes of patients with lung cancer [1, 2]. Although immune checkpoint inhibitors manifest drastic effects, unique adverse events, including skin rash, hepatotoxicity, and endocrine disturbances, are known to occur during treatment. These events are termed immune-related adverse events (irAEs). Among the several types of irAEs, cases of infectious diseases have been increasing steadily [3]. Cases of mycobacterial infection have been particularly alarming because of multiple reported cases [4-7]. We experienced three cases of acute development of Mycobacterium avium complex lung disease (MAC-LD) in patients with lung cancer on immune checkpoint inhibitors. These may emerge as thought-provoking cases. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case presentation and summary Case 1. A 66-year-old woman underwent surgical resection of the right lower lobe lung adenocarcinoma. Her adenocarcinoma recurred after 12 years. Computed tomography (CT) images acquired at that time showed no bronchiectasis or nodules in the bilateral lobes. She received 60-Gy stereotactic radiotherapy. On disease progression, she received one cycle of combined carboplatin and pemetrexed as initial therapy. Because of adverse events, her chemotherapy regimen was revised to gemcitabine. rd However, her disease progressed. She received nivolumab as the 3 line therapy. After 15 cycles of nivolumab, she developed wet cough with excessive sputum. CT images showed infiltration in the upper left lung lobe and lingula. Two consecutive sputum cultures were positive for Mycobacterium th intracellulare at 17 cycle of nivolumab therapy. A diagnosis of MAC-LD was established and specific treatment for MAC was initiated along with continued nivolumab therapy. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case 2. An 80-year-old man was diagnosed with stage 3a right upper lobe non-small cell lung cancer by bronchoscopy. Although lung cancer was diagnosed, CT images only showed bilateral emphysema but no bronchiectasis or nodules. Sequential chemoradiotherapy was initiated. He received one cycle of combined carboplatin and nanoparticle albumin-bound paclitaxel (nabPTX) therapy, followed by radiotherapy (66 Gy). He attained 3 years of progression-free survival. However, the cancer recurred because of a single brain metastasis and multiple lower left nodules. He underwent gamma knife nd therapy for brain metastasis and was initiated on 2 line systemic immunotherapy with atezolizumab. rd At 23 cycle of atezolizumab therapy, he developed wet cough and excessive sputum production. CT images revealed multiple reticulonodular infiltrates in the lower left lung lobe. Two consecutive th sputum cultures at 24 cycle of atezolizumab were positive for M. avium and M. intracellulare. He was diagnosed with MAC-LD; specific treatment was initiated for MAC alongside the atezolizumab therapy. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Case 3. A 66-year-old man was diagnosed with stage 4a advanced squamous cell carcinoma of the right upper lung lobe. Although lung cancer was diagnosed, CT images showed bilateral emphysemas but no bronchiectasis or nodules. He received initial therapy with 6 cycles of combined carboplatin and nabPTX. However, tumor progression was confirmed after 3 months. Second line therapy with nivolumab was initiated. However, disease progression was confirmed after 6 cycles of nivolumab rd th therapy. As the 3 line therapy, he received 7 cycles of docetaxel, and subsequently, 4 line therapy with atezolizumab after docetaxel failure. Concomitantly, he experienced right main bronchus stenosis because of tumor progression, and palliative radiotherapy (37.5 Gy) was administered. CT images acquired during atezolizumab therapy revealed rapidly worsening right lower lobe infiltration. th Two consecutive sputum cultures at the 4 cycle of atezolizumab therapy were positive for M. intracellulare, and a diagnosis of MAC-LD was established. However, because of severe debilitation, treatment for MAC-LD was not initiated and atezolizumab immunotherapy was discontinued. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Summary of cases Table 1 shows the summary of all 3 cases. In this study, CT images were retrospectively reviewed to assess possible changes of MAC-LD predating ICI immunotherapy. All patients had advanced lung cancer and received cytotoxic chemotherapy before treatment with ICIs. Moreover, they received thoracic radiotherapy before the pathogenesis of MAC-LD. ICI immunotherapy was continued in two patients after they were diagnosed with MAC-LD. The median time to MAC-LD diagnosis from induction of initial ICI were 17 months (range, 17–19 months). Discussion We experienced three acute cases of MAC-LD during ICI immunotherapy. Previous reports indicate that development of tuberculosis during ICI immunotherapy has become an emerging concern [4-7]. Multiple cases of tuberculosis were suspected reactivation of latent infection. Some authors have suggested the development of tuberculosis to be similar to immune reconstitution inflammatory syndrome [4, 7]. A similar presentation is expected of nontuberculous mycobacterial infection; Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 however, till date, no paper had reported the development of nontuberculous mycobacterial infection. In our three cases, no fibro-cavitary or reticulonodular shadow was noted that could indicate nontuberculous mycobacteria (NTM) infection at the initial diagnosis of lung cancer. Therefore, it is unclear whether MAC-LD developed from reactivation of existing disease or whether it was a de novo infection. Although the precise mechanisms underlying MAC-LD are unknown, anti-PD-1/PD-L1 antibodies are known to have possible anti-microbial effects that are mediated by upregulation of T cell- mediated immunity [8]. A previous report suggested favorable effect of nivolumab for the treatment of Mycobacterium abscessus lung disease [9]. Our present cases might partly reflect this paradoxical reaction, i.e., overresponse to mycobacteria. In contrast, Barber et al. reported that PD-1/PD-L1 knockout mice displayed increased susceptibility to tuberculosis through enhanced CD4 T cell- mediated tissue destruction [10]. In patients receiving ICIs, Barber et al. also discovered similar profiles for CD4 T cell, CD8 T cell, and T cell-mediated cytokine dynamics[11]. These data suggested that Th1 function with anti-PD-1/PD-L1 antibodies might cause the development of tuberculosis. In actual clinical settings, treatment with anti-PD-1/PD-L1 antibodies is expected to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 show similar responses. Therefore, the effects of ICIs with regard to mycobacterial diseases in clinical setting remains controversial. Alternatively, ICI immunotherapy might initiate a state of autoimmunity that mimics diseases like rheumatoid arthritis, which are known to be strongly associated with NTM-LD. Well-designed population-based studies are required to investigate such causal associations. Cumulative experience will reveal the complete picture. Presently, all patients had advanced stage lung cancer and received relatively long-term treatment, including cytotoxic chemotherapy; therefore, the influence of both the cancer and the treatment in the development of MAC-LD cannot be ignored. Furthermore, cytotoxic chemotherapy can exacerbate NTM disease [12]. Previous cytotoxic chemotherapy before induction of ICIs might favor the clinical outcome moderately. The following alternate interpretation is also important. Japan has one of the highest burdens of NTM globally [13, 14]. Moreover, ICI immunotherapy is becoming popular in Japan. Therefore, physicians in high burden of NTM should pay more attention to the development of MAC-LD during immunotherapy regimens with ICIs. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Conclusion Physicians should be cautious towards the development of MAC-LD in patients on immunotherapy with ICIs, especially in countries such as Japan, which has a high burden of NTM. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Conflicts of interest All authors declare no conflicts of interest. Patients consent We have obtained written consent forms from all patients described in this study. Financial support This case study was partly supported by a Grant-in-Aid for Young Scientists (B), KAKENHI, Japan Society for the Promotion of Science, Japan. (Grant Number, 17K16067) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 References (1) Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450-461. (2) Granier C, De Guillebon E, Blanc C, Roussel H, Badoual C, Colin E, Saldmann A, Gey A, Oudard S, Tartour E. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2017;2:e000213-2017. (3) Fujita K, Kim YH, Kanai O, Yoshida H, Mio T, Hirai T. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy. Respir Med 2019;146:66-70. (4) Fujita K, Terashima T, Mio T. Anti-PD1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. J Thorac Oncol 2016;11:2238-2240. (5) Chu YC, Fang KC, Chen HC, Yeh YC, Tseng CE, Chou TY, Lai CL. Pericardial Tamponade Caused by a Hypersensitivity Response to Tuberculosis Reactivation after Anti- Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 PD-1 Treatment in a Patient with Advanced Pulmonary Adenocarcinoma. J Thorac Oncol 2017;12:e111-e114. (6) Picchi H, Mateus C, Chouaid C, Besse B, Marabelle A, Michot JM, Champiat S, Voisin AL, Lambotte O. Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment. Clin Microbiol Infect 2018;24:216-218. (7) Takata S, Koh G, Han Y, Yoshida H, Shiroyama T, Takada H, Masuhiro K, Nasu S, Morita S, Tanaka A, Hashimoto S, Uriu K, Suzuki H, Tamura Y, Okamoto N, Nagai T, Hirashima T. Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents. J Infect Chemother 2019;25:54-58. (8) Rao M, Valentini D, Dodoo E, Zumla A, Maeurer M. Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm. Int J Infect Dis 2017;56:221-228. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 (9) Ishii S, Tamiya A, Taniguchi Y, Tanaka T, Abe Y, Isa SI, Tsuyuguchi K, Suzuki K, Atagi S. Improvement of Mycobacterium abscessus Pulmonary Disease after Nivolumab Administration in a Patient with Advanced Non-small Cell Lung Cancer. Intern Med 2018;57:3625-3629. (10) Barber DL, Mayer-Barber KD, Feng CG, Sharpe AH, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 2011;186:1598-1607. (11) 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. Tuberculosis following PD-1 blockade for cancer immunotherapy. Sci Transl Med 2019;11:10.1126/scitranslmed.aat2702. (12) Tsuji T, Tsuyuguchi K, Tachibana K, Kimura Y, Kobayashi T, Minomo S, Atagi S, Matsumura A, Hayashi S, Suzuki K. Analysis of the impact of lung cancer treatment on nontuberculous mycobacterial lung diseases. Respir Investig 2017;55:45-50. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 (13) Morimoto K, Iwai K, Uchimura K, Okumura M, Yoshiyama T, Yoshimori K, Ogata H, Kurashima A, Gemma A, Kudoh S. A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan. Ann Am Thorac Soc 2014;11:1-8. (14) Namkoong H, Kurashima A, Morimoto K, Hoshino Y, Hasegawa N, Ato M, Mitarai S. Epidemiology of Pulmonary Nontuberculous Mycobacterial Disease, Japan. Emerg Infect Dis 2016;22:1116-1117. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Table 1. Characteristics of the patients who developed Mycobacterium avium complex lung disease Case 1 Case 2 Case 3 Age at diagnosis of MAC, years 78 80 66 Sex Female Male Male Smoking status (pack-year) Never 45 20 Cavities/Bronchiectasis before ICI None None None Histopathology Adenocarcinoma Not otherwise specified Squamous cell carcinoma Staging at diagnosis Post-operative recurrence cT1bN2M0; stage 3a cT4N2M1a; stage 4a Driver oncogene alteration wild type wild type NE PD-L1 expression NE NE <1% Type of ICI Nivolumab Atezolizumab Nivolumab + Atezolizumab Infected MAC strain M. intracellulare M. avium + M. intracellulare M. intracellulare Time to MAC-LD diagnosis*, month 17 17 19** Cycles of ICI, number 38 24 6 (nivolumab) + 4 (atezolizumab) Prior radiotherapy 60 Gy 60 Gy 37.5 Gy Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa067/5760760 by guest on 05 March 2020 Prior chemotherapy 1st line Carboplatin + Pemetrexed Carboplatin + nabPTX Carboplatin + nabPTX 2nd line Gemcitabine - Nivolumab 3rd line - - Docetaxel Response to MAC treatment Good Fair No medication MAC, Mycobacterium avium complex; NE, not evaluated; PD-L1, programmed cell death-ligand 1; ICI, immune checkpoint inhibitor; nabPTX, nanoparticle albumin-bound paclitaxel *Time from initiation of immune checkpoint inhibitor therapy to diagnosis of Mycobacterium avium complex lung disease **Duration included that of docetaxel treatment Accepted Manuscript

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Open Forum Infectious Diseases – Oxford University Press

Published: Mar 1, 2020

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