The Safety and Efficacy of Immunotherapy With Anti-programmed Cell Death 1 Monoclonal Antibody for Lung Cancer Complicated With Mycobacterium Tuberculosis Infection

Jinpeng Shi; Jiayu Li; Qi Wang; Xiaomin Cheng; He Du; Ruoshuang Han; Xuefei Li; Chao Zhao; Guanghui Gao; Yayi He; Xiaoxia Chen; Chunxia Su; Shengxiang Ren; Fengying Wu; Zhemin Zhang; Caicun Zhou

Disclosures

Transl Lung Cancer Res. 2021;10(10):3929-3942.

Abstract and Introduction

Abstract

Background: Anti-programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy has boosted the prognosis in advanced lung cancer. Meanwhile, accumulating cases showed the correlation between tuberculosis (TB) reactivation and anti-PD-1/PD-L1 immunotherapy. However, the safety and efficacy of anti-PD-1/PD-L1 immunotherapy for lung cancer complicated with TB infection could only be learned from real-world data.

Methods: We retrospectively analyzed 562 patients with advanced lung cancer who received anti-PD-1/PD-L1 immunotherapy at Shanghai Pulmonary Hospital from 2015 to 2019, including 13 patients with TB infection. Besides, relevant literature reviews were performed online to analyze the safety and efficacy of immunotherapy and to explore the appropriate treatment strategies in this specific population.

Results: In our cohort, the initiation of anti-PD-1/PD-L1 immunotherapy was from June 2015 to December 2019. Among them, 13 patients had TB infection prior to immunotherapy including 11 latent TB and 2 active TB, and all of them were treated with anti-PD-1 immunotherapy. Patients with active TB infection were treated with concurrent anti-TB and anti-PD-1 treatments, and the remaining received either mono-immunotherapy or combined immunotherapy. Neither reactivation of latent TB nor progression of active TB was monitored in our cohort during immunotherapy. Severe immune-related adverse events (irAEs) were diagnosed in two patients. Treatment strategies such as discontinuation of immunotherapy and administration of corticosteroids were provided timely, and one with latent TB infection got gradually improved, but the other one with active TB died quickly. The median progression-free survival (PFS) was 5.5 months for tumor immunotherapy in our cohort. However, the PFS of immunotherapy was merely 2.1 and 2.2 months in lung cancer patients with active TB infection.

Conclusions: Immunotherapy is relatively safe for lung cancer patients complicated with previously treated latent TB, and the efficacy of immunotherapy in this specified population is not inferior to that in lung cancer patients without TB infection. TB screening before anti-PD-1/PD-L1 immunotherapy is strongly recommended, and irAEs should be monitored more cautiously in lung cancer patients with active TB infection.

Introduction

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand (PD-L1) have shifted the paradigm in various solid malignancies, especially in non-small cell lung cancer (NSCLC).^[1–6] It is well known that the binding of co-inhibitory receptor PD-1 with its ligand PD-L1 will attenuate the priming, the proliferation and the cytotoxic capacity of T cells.^[7,8] Therefore, tumor cells evade host immune surveillance and escape tumor neutralization through the PD-1/PD-L1 axis.^[9] In recent years, immunotherapy with anti-PD-1/PD-L1 monoclonal antibodies (mAbs) has made a breakthrough in NSCLC, and the 5-year survival rate of advanced NSCLC has significantly increased from less than 5% to 23.2%.^[10,11]

Immune checkpoint molecules on T cells, such as PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4) will also be up-regulated during chronic infectious diseases. The success of immunotherapy in cancer, especially anti-PD-1/PD-L1 mAbs which can restore and enhance the function of T cells, has aroused people's interest in trying immunotherapy to treat chronic infectious diseases.^[12] However, growing evidences show anti-PD-1/PD-L1 immunotherapy leads to tuberculosis (TB) reactivation,^[13–28] which arouse the awareness of physicians about the safety of immunotherapy and immune-related adverse events (irAEs).

According to the 2020 World Health Organization (WHO) global TB report (https://www.who.int/teams/global-tuberculosis-programme/data), in 2019, an estimated 10.0 million people fell ill with TB, 1.2 million TB deaths among human immunodeficiency virus (HIV)-negative people, and an additional 208,000 deaths among HIV-positive people. China is the second highest TB burden country, accounting for 8.4% cases in total globally. Accumulating data support the view that TB is a risk factor for the development of lung cancer,^[29–32] and in China where both TB and lung cancer are prevalent, the co-existence of TB with lung cancer is not rare, which brings great challenges to the treatment of patients, especially in the era of tumor immunotherapy. In clinical practice, the following issues are worth noting. Will the excessive activation of T cells and the release of cytokines induced by anti-PD-1/PD-L1 mAbs activate the latent TB lesions leading to TB recurrence, or deterioration the current TB situation? Will anti-TB therapy increase the incidence of irAEs? There have been many clinical trials on immunotherapy for lung cancer, nonetheless, patients with TB are usually excluded from existing trials resulting in a lack of experience in the above-mentioned issues.

Thus, we retrospectively analyzed 562 patients with advanced lung cancer who received anti-PD-1/PD-L1 immunotherapy in our hospital from 2015 to 2019, including 13 patients with TB infection prior to immunotherapy (either latent or active TB infection), and analyzed the safety and efficacy of immunotherapy among these patients.

We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-524).

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Patient characteristics and immunotherapy
	Age(years)	Sex	Smoking	Cancer	Gene*	PD-L1	TNM Stage	PS	Previous therapies	Time since TB diagnosis to initiation of ICIs (years)	ICIs	Line	Overall duration (months)^#	PFS (months)^#	irAEs	Treatment of irAEs
P1	62	M	Never	LUSC	WT	NA	IV	2	None	0.7	Pembrolizumab	1	2.1	2.1	Renal dysfunction, III°	Discontinuation of ICI + corticosteroids
P2	68	M	Never	LUSC	WT	NA	Recurrent	1	None	12.3	Pembrolizumab	1	9.9	5.6	None	None
P3	68	M	Never	LUAD	20ins	30%	Recurrent	1	None	0.2	Pembrolizumab	1	2.2	2.2	Liver dysfunction, I°	Monitor liver function
P4	61	M	Smoker	LUSC	NA	0	IV	1	TC (8 cycles)	12.2	Camrelizumab	2	3.8	3.8	None	None
P5	66	M	Smoker	LUAD	WT	NA	IV	1	None	5.7	Camrelizumab	1	7.0	5.6	None	None
P6	79	M	Never	LUSC	WT	80%	Recurrent	1	None	53.4	Toripalimab	1	1.8+	1.8+	None	None
P7	42	F	Never	LUAD	19del	40%	IIIb	1	1st line: afatinib (1 month) 2nd line: AC (4 cycles)	7.4	Toripalimab	3	2.1	2.1	None	None
P8	68	M	Smoker	LUSC	NA	0	IV	1	None	27.8	Pembrolizumab	1	5.6+	5.6+	Exfoliative dermatitis, III°	Discontinuation of ICI + corticosteroids
P9	59	M	Smoker	LUSC	NA	30%	Recurrent	1	None	10.2	Pembrolizumab	1	1.3	1.3	None	None
P10	52	M	Smoker	LUAD	WT	0	IIIc	1	GP (4 cycles)	27.2	Tislelizumab	2	5.5	5.5	None	None
P11	45	F	Never	LUAD	WT	30%	IV	1	None	5.8	Pembrolizumab	1	3.6	3.6	None	None
P12	67	M	Smoker	LUSC	WT	0	IIIb	1	1st line: NP (4 cycles) 2nd line: docetaxel (2 cycles)	5.2	Camrelizumab	3	12.5	12.5	None	None
P13	43	M	Never	LUSC	NA	5%	Recurrent	1	GP (6 cycles)	4.1	Pembrolizumab	2	15.3	14.4	None	None

Gene*: Driver oncogene alteration. ^#, numbers followed by '+': patients who were still responding to immunotherapy at the censor date (March 1, 2021) or who were lost to follow-up were censored at the last date of follow-up. PS, Eastern Cooperative Oncology Group performance status; TB, tuberculosis; ICIs, immune checkpoint inhibitors; PFS, progression-free survival; irAEs, immune-related adverse effects; M, male; F, female; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; WT, wild type; NA, not available; TC, paclitaxel + carboplatin; AC, pemetrexed + carboplatin; GP, gemcitabine + cisplatin; NP, vinorelbine + cisplatin.

Table 2. Diagnosis and treatment of TB
	TB lesions (organ, locations)	TB-Ab	T-SPOT	TB confirmation	Calcification	TB cavity	Active/latent TB	TB treatment	Follow-up* (months)
P1	Lung, bilateral diffuse lesions	(+)	(+)	Sputum AFB (+)	No	Yes	Active	4HREZ/4PaReEZLfx	4.2
P2	Lung, left upper	NS	NS	History + radiology	Yes	No	Latent	NS	17.3
P3	Lung, right lower	(–)	(–)	Resected tissue AFB (+)	Yes	No	Active	2HRELfx/4HR	1.5
P4	Lung, bilateral upper and right lower	NS	NS	History + radiology	No	No	Latent	2HREZ/4HR	8.1
P5	Lung, bilateral upper	NS	NS	History + radiology	No	No	Latent	2HREZ/4HR	12.0
P6	Lung, bilateral upper and right lower	NS	NS	History + radiology	No	No	Latent	2HREZ/4HR	1.8
P7	Lung, left upper	(+)	NS	History + radiology	No	No	Latent	naïve	7.2
P8	Lung, bilateral upper	(–)	(+)	History + radiology	Yes	Yes	Latent	naïve	5.7
P9	Lung, right upper	(–)	NS	History + radiology	No	No	Latent	NS	9.3
P10	Pleura, left lower	NS	NS	History + radiology	Yes	No	Latent	3HREZ/9HR	21.5
P11	Lung, right upper	NS	NS	History + radiology	Yes	No	Latent	2HREZ/4HR	3.7
P12	Bone, left hip joint	(–)	(–)	History	NS	NS	Latent	3HREZ/9HR	18.4
P13	Lung, left upper	(–)	(+)	History + radiology	Yes	No	Latent	NS	23.8

Follow-up*, the time from ICI initiation to the last chest CT with confirmation that there was no deterioration of active TB or reactivation of latent TB at that point of time. TB, tuberculosis; Ab, antibody; NS, not specified; AFB, acid-fast bacillus; H, isoniazid; R, rifampicin; E, ethambutol; Z, pyrazinamide; Pa, pasiniazid; Re, rifapentine; Lfx, levofloxacin.

Table 3. Summary of literature reviews
No.	Study	Sex	Age	Ethnicity	Cancer type	Stage	ICIs	Line^†	Cycles^‡	TB lesions	TB treatment	ICIs discontinuation	TB response	Corticosteroids
1	Fujita et al. (15) (2016)	Male	72	Japanese	LUSC	IV	Nivolumab	3	8	Lung	NS	Yes	NS	NS
2	Chu et al. (13) (2017)	Male	59	Chinese	LUAD	IV	Nivolumab	NS	6	Pericardium	6-month treatment	Interrupted, resumed after one-month prednisolone	pericardial & pleural effusion regressed	Prednisolone, 1 mg/kg for 1 month
3	Picchi et al. (23) (2018)	Male	64	Caucasian	NOS	NS	Nivolumab	NS	2	Bone	4-drug regimen	Yes	rapid death after a second operation for spinal cord compression	NS
4	Jensen et al. (19) (2018)	Male	56	Caucasian	LUAD	IIIC	Nivolumab	3	12	Lung	NS	Yes	NS	NS
5	Takata et al. (25) (2019)	Male	75	Japanese	LUAD	IV	Nivolumab	NS	15	Lung	2HREZ/7HR	Interrupted for 3.5 months	negative sputum culture conversion + pulmonary lesions disappeared	Prednisolone, 30 mg/d for 1 month
6	Inthasot et al. (18) (2020)	Male	69	NS	LUAD	NS	Nivolumab	2	18	Lung	NS	NS	NS	NS
7	van Eeden et al. (26) (2019)	Female	56	Caucasian	LUAD	IV	Nivolumab	3	NS	Lung	HREZ	Interrupted, and failed to resume (dead shortly after PD)	improved clinically	Corticosteroids, i.v., NS
8	Crawley et al. (14) (2020)	Male	58	Caucasian	LUAD	IV	Pembrolizumab+ AC	1	2	Lung	HREZ	Interrupted for a period, NS	improved clinically within 48 hours	Prednisolone, p.o., 40 mg/d (high-dose dexamethasone was given before ICI treatment)
9	Im et al. (17) (2020)	Male	63	Korean	LUAD	NS	Nivolumab	4	41	Lung	HREZ	No	NS	No
10	Im et al. (17) (2020)	Male	79	Korean	LUSC	NS	Pembrolizumab	2	14	Lung	HREZ	Yes	NS	Prednisolone, p.o., 30 mg/d for1 month
11	Suliman et al. (24) (2021)	Female	58	Caucasian	LUAD	IV	Pembrolizumab	1	6	Lung	4-drug regimen	Yes	negative sputum AFB conversion after 6 weeks following anti-TB	No
12	Zhang et al. (28) (2020)	Male	57	Chinese	LUAD	IV	Pembrolizumab	1	4	Pleura	HRE	Interrupted for 2 months, and failed to resume (tumor PD)	controlled by medication	NS
13	Murakami et al. (22) (2021)	Male	73	Japanese	LUAD	IV	Pembrolizumab	1	5	Lung	HREZ	Interrupted over one year	controlled by medication	Prednisolone, p.o., 15 mg/d for 2 weeks due to myositis after the 5th cyclePrednisolone, 0.5 mg/kg/d for 3 months due to suspected CIP
14	Fujita et al. (16) (2020)	Female	79	Japanese	LUAD	IV	Nivolumab	3	5	Knee joint	NS	NS	NS	NS
15	Fujita et al. (16) (2020)	Male	74	Japanese	LUSC	IIIB	Pembrolizumab	2	4	Lung	NS	NS	NS	NS
16	Fujita et al. (16) (2020)	Male	79	Japanese	NOS	IV	Nivolumab	2	4	Lung	NS	NS	NS	NS
17	Fujita et al. (16) (2020)	Male	64	Japanese	LUSC	IIIB	Pembrolizumab	2	3	Lung	NS	NS	NS	NS

^†, lines of ICIs used; ^‡, numbers of cycles of ICIs used till TB diagnosis. LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; NOS, not otherwise specified; NS, not specified; WT, wild type; NA, not available; ICIs, immune checkpoint inhibitors; AC, pemetrexed + carboplatin; PR, partial response; SD, stable disease; PD, progression disease; H, isoniazid; R, rifampicin; E, ethambutol; Z, pyrazinamide; AFB, acid-fast bacillus; i.v., injectio venosa; p.o., per os; CIP, checkpoint inhibitor-related pneumonitis.