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\begin{document}

\title{Efficacy and safety of PD-1 immune checkpoint inhibitors in locally
advanced and advanced non-small cell lung cancer patients with chronic
viral infection}



\author[1]{Zhiting Zhao}%
\author[1]{Ran Hu}%
\author[2]{Yan Chen}%
\author[2]{Guoren Zhou}%
\author[2]{Shaorong Yu}%
\author[2]{Jifeng Feng}%
\affil[1]{Jiangsu Cancer Hospital}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract Immune checkpoint inhibitors (ICIs) have become new research
hotspots in the treatment of non-small cell lung cancer, but the
efficacy and safety of immunotherapy for patients with chronic viral
infection are still unclear, because existing clinical trials often
exclude those patients. Materials and Methods We identified 78 locally
advanced or advanced NSCLC patients with chronic viral infection treated
with PD-1/PD-L1 inhibitors alone or combined with the
chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with
hepatitis C, and 16 with syphilis. Objective response rates were
assessed using the RECIST v1.1. Adverse events were graded following the
National Cancer Institute Common Terminology Criteria for Adverse Events
v5.0. Results Objective responses were observed in 19 out of 78(24.36\%)
patients, and the disease control rate (DCR) was 69.23\% (54/78). No
patient achieved a complete response. The median progression-free
survival (PFS) was 6.49 months (95\% CI:3.71-9.27). PFS was 1.44 months
(95\%CI:0.00-4.34) for monotherapy versus 7.34 months
(95\%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the
first-line treatment group revealed relatively higher ORR and longer PFS
(ORR: 48.00\% vs. 13.20\%, P = 0.001; PFS: 7.67 months vs. 5.57 months,
P = 0.129). Patients with combined radiotherapy showed longer PFS than
those without combined radiotherapy (14.07 vs.4.62, P=0.027). The
incidence of adverse events of any grade was 73.07\% (57/78), among
which there were 7 cases of grade 4 adverse events. The incidence of
leukopenia in any grade of adverse reactions was the highest (57.69\%),
followed by anemia (25.64\%), elevated alanine aminotransferase or
aspartate aminotransferase (24.36\%) and fatigue (21.79\%). Hepatic
transaminase increased in 26.7\% (16/60) of HBV-infected patients, and
remained unchanged in 63.3\% (38/60) patients. Conclusions The PD-1
inhibitor showed an acceptable toxicity profile and moderate efficacy on
NSCLC patients with chronic viral infection, but still has the potential
to increase the incidence of hepatitis.%
\end{abstract}%



\sloppy


\textbf{Efficacy and safety of PD-1 immune checkpoint inhibitors in
locally advanced and advancednon-small cell lung cancer patients with
chronic viral infection}

\textbf{Abstract}

Immune checkpoint inhibitors (ICIs) have become new research hotspots in
the treatment of non-small cell lung cancer, but the efficacy and safety
of immunotherapy for patients with chronic viral infection are still
unclear, because existing clinical trials often exclude those patients.

\textbf{Materials and Methods}

We identified 78 locally advanced or advanced NSCLC patients with
chronic viral infection treated with PD-1/PD-L1 inhibitors alone or
combined with the chemotherapy/bevacizumab therapy, of whom 60 with
hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective
response rates were assessed using the RECIST v1.1. Adverse events were
graded following the National Cancer Institute Common Terminology
Criteria for Adverse Events v5.0.

\textbf{Results}

Objective responses were observed in 19 out of 78(24.36\%) patients, and
the disease control rate (DCR) was 69.23\% (54/78). No patient achieved
a complete response. The median progression-free survival (PFS) was 6.49
months (95\% CI:3.71-9.27). PFS was 1.44 months (95\%CI:0.00-4.34) for
monotherapy versus 7.34 months (95\%CI:4.50-10.18) for combination
therapy (P=0.053). Patients in the first-line treatment group revealed
relatively higher ORR and longer PFS (ORR: 48.00\% vs. 13.20\%, P =
0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with
combined radiotherapy showed longer PFS than those without combined
radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events
of any grade was 73.07\% (57/78), among which there were 7 cases of
grade 4 adverse events. The incidence of leukopenia in any grade of
adverse reactions was the highest (57.69\%), followed by anemia
(25.64\%), elevated alanine aminotransferase or aspartate
aminotransferase (24.36\%) and fatigue (21.79\%). Hepatic transaminase
increased in 26.7\% (16/60) of HBV-infected patients, and remained
unchanged in 63.3\% (38/60) patients.

\textbf{Conclusions}

The PD-1 inhibitor showed an acceptable toxicity profile and moderate
efficacy on NSCLC patients with chronic viral infection, but still has
the potential to increase the incidence of hepatitis.

\textbf{Keywords} : immune checkpoint inhibitors; A history of
infection; Non-small cell lung cancer; Programmed cell death-1

\textbf{WHAT'S KNOWN?}

Successful anti-PD-1 / PD-L1 immunotherapy requires an adequate number
of specific T cells in the tumor microenvironment. Similar to the tumor
microenvironment, the chronic viral infection is a strong
immunosuppression environment, leading to specific T cells exhausting,
in theory, it may influence the effect of ICI which has reversed the
role of T cell failure at the same time and undermine the balance
between the host immune system and virus control that has caused the
risk of liver damage. But there is not any consensus yet and appropriate
strategy of ICIs in this population needs in depth assessment. In the
existing published articles about safety and efficacy of ICIs in
patients with chronic viral infection and advanced-stage cancer, the
types of cancer involved are not comprehensive, with liver cancer and
melanoma accounting for the majority and NSCLC accounting for less than
five percent. In one retrospective study of PD-1 inhibitors for NSCLC
with special issues involving 32 HBV-infected patients, four of nine
patients experienced severe AST/ALT elevation (grade 3 or higher) were
HBV patients. And three patients developed viral reactivations or
flares, despite receiving anti-HBV therapy prior to the immunotherapy.

\textbf{WHAT'S NEW?}

By expanding the sample size, we found that the PD-1 inhibitor showed an
acceptable toxicity profile on NSCLC patients with chronic viral
infection. There is no big difference between the adverse reaction
spectrum and the incidence of adverse reactions in such patients and
those of patients without infectious diseases, but it is worth observing
that the proportion of hepatic transaminase elevating was increased.
Hepatic transaminase increased in 26.7\% (16/60) of hepatitis B
patients. All five patients with reduced viral load received antiviral
therapy. Of the 14 patients who did not receive antiviral therapy, 3
patients had grade 3 or 4 adverse events, but in all three patients, the
adverse events were reversed with steroids and ICIs were not
discontinued, so the side effects were considered acceptable. And
immunotherapy combined with antiviral therapy can effectively improve
safety. Therefore, we recommend close monitoring for such patients in
consultation with a hepatologist and to treat those with active viral
hepatitis with antiviral therapy prior to the immunotherapy. The
efficacy of PD-1/PD-L1 immune checkpoint inhibitors on locally advanced
and advanced NSCLC patients with a history of infectious diseases was
acceptable and such patients can benefit from immunotherapy. In subgroup
analysis, first-line treatment group, immunotherapy combined with
radiotherapy group, immunotherapy combined with chemotherapy and
antiangiogenic agents group showed better efficacy.

\textbf{Introduction}

Lung cancer is one of the leading causes of cancer-related deaths
worldwide \textsuperscript{1}, and non-small cell lung cancer (NSCLC)
accounts for more than 80\% of all lung cancers. Despite the existence
of various treatment methods such as new chemotherapeutics and
gene-targeted drugs, still patients with lung cancer have below 5-year
survival rate and high mortality rate. In recent years, immunotherapy,
especially PD-1/PD-L1 immune checkpoint inhibitors, has achieved a great
success in the clinical application of various tumors by inhibiting the
PD-1/PD-L1 signaling pathway and activating the immune system.
Therefore, it has fetched much attentions of the researchers recently.

However, existing clinical trials often exclude patients with viral
infections (patients with hepatitis B, hepatitis C, syphilis, etc.), and
the efficacy and safety of immunotherapy for such patients are still
unclear. There is a high occurrence of hepatitis B in China and the
current hepatitis B surface antigen carrying rate of people under 60 is
7.2\% \textsuperscript{2}. There are about 93 million chronic HBV
infections, of which more than 20 million are patients with active
hepatitis B \textsuperscript{3}. The purpose of current investigation is
to retrospectively analyze the efficacy and safety of PD-1 immune
checkpoint inhibitors for locally advanced and advanced NSCLC patients
with chronic viral infection, to provide a reference for clinical
decision-making.

\textbf{Patients and Methods}

\textbf{Patients}

We studied the medical records of all locally advanced and advanced
NSCLC patients treated at the Jiangsu Cancer Hospital between May 2018
and March 2021 and identified patients who received the PD-1 inhibitor
alone or in combination with the chemotherapy and/or the bevacizumab
therapy and screened patients who met one or more of the following
criteria: positive for hepatitis B surface antigen; HCV - RNA positive;
Syphilis antibody positive. All patients included in this study had at
least one measurable disease. This study was approved by the Academic
Ethics Committee of Jiangsu Cancer Hospital.

\textbf{Data collection and response assessment}

Medical records were examined and separated on clinical pathologic
features and treatment histories. Data and follow-up records were
updated as of March 1, 2021. The best response to PD-1 inhibitor-based
therapy, defined as a complete or partial response and stable disease
achieved at least once during therapy, was assessed using the RECIST v
1.1 criteria. The PFS was defined from the time of treatment initiation
to clinical or radiographic progression or death. Adverse events (AEs)
were graded by the National Cancer Institute Common Terminology Criteria
for Adverse Events v5.0.

\textbf{Statistical analysis}

Survival data were estimated using the Kaplan--Meier method and compared
using the log-rank test in the overall cohort and other subgroups.
Statistical analyses were performed using the SPSS version 25.0 (SPSS,
Inc). P [?] 0.05 was considered to indicate statistical significance.

\textbf{Results}

\textbf{Patients' characteristics}

In this study, we considered 78 patients with chronic viral infection
who were treated at Jiangsu Cancer Hospital with the PD-1 inhibitor
alone or in combination with the chemotherapy and/or the bevacizumab
therapy, and their clinical and pathological baseline characteristics
are shown in Table 1. The median age of the 78 patients was 65 years,
including 62 males and 16 females. Adenocarcinoma was the most common
pathological type (56.4\%), followed by squamous cell carcinoma
(35.9\%). Most of the patients (88.5\%) were clinically diagnosed with
stage IV lung cancer. Out of 78 patients, 60 were suffering from NSCLC
with a history of hepatitis B (including 57 patients with past hepatitis
B and 3 patients with chronic hepatitis B), 2 NSCLC patients had the
record of hepatitis C, and 16 with syphilis. All patients received
PD-1/PD-L1 immune checkpoint inhibitors, including 10 patients were
treated with monotherapy and 68 patients were prescribed with the
combination chemotherapy/bevacizumab. Most of the patients (67.9\%)
received the PD-1 inhibitor-based therapy as second- or late-line
therapy and most of the patients (87.2\%) did not received combined
radiotherapy. Most patients (85.9\%) had an ECOG performance status of 0
or 1.

\textbf{Overall clinical outcomes}

As shown in Figure 1A, Objective Radiographic Responses (ORR) was
observed in 19 of 78(24.36\%) patients, and the disease control rate
(DCR) was 69.23\% (54/78). No patient achieved a complete response. The
median PFS was 6.49 months with a 95\% CI of 3.71-9.27 months (Figure
1B). Among those 19 patients who achieved a partial response, 17 were
treated with the combination chemotherapy/bevacizumab and only 2 had the
PD-1 inhibitor monotherapy, but the results showed no statistically
significant difference.

\textbf{Subgroup analyses}

As displayed in Figure 1C , all 10 patients in the combined radiotherapy
group were in a more stable condition than that in the non-combined
radiotherapy group (DCR=100.00\%) (P \textless{} 0.05) ,and patients
with better performance status exhibited a trend of higher DCR than
those with poorer performance status (88.23\% vs.74.00\% vs.18.18\%) (P
\textless{} 0.05). Patients in the first-line treatment group
(ORR=48.0\%) revealed relatively higher ORR and longer PFS than those
treated with the PD-1 inhibitor-based therapy as second- or late-line
therapy (ORR: 48.00\% vs. 13.20\%, P = 0.001, Figure 1D ; PFS: 7.67
months vs. 5.57 months, P = 0.129, Figure 2A). As shown in Figure 2B,
PFS was 1.44 months (95\%CI:0.00-4.34) for monotherapy versus 7.34
months (95\%CI:4.50-10.18) for combination therapy (P=0.053), which was
not statistically significant, but it was worth observing that 17 out of
the 19 (89.47\%) patients who achieved a partial response were on
combination therapy. Significant difference was observed in the PFS of
different combination groups (PD-1 antibody alone vs. PD-1 antibody
combined with the chemotherapy vs. PD-1 antibody combined with the
bevacizumab vs. PD-1 antibody combined with the chemotherapy and the
bevacizumab groups: 1.44 vs.5.67 vs.1.67 vs.14.13, Figure 2C). Patients
with combined radiotherapy showed longer PFS than those without combined
radiotherapy (14.07 vs.4.62, P=0.027) (Figure 2D). The evaluation of
lesion for the efficacy of ICI therapy and irradiation site were the
same sites in all the patients treated with radiotherapy, and the
treatment processes are presented in Table 2.

\textbf{Safety}

As shown in the Table 3, the incidence of any grade treatment-related
AEs was 73.07\% (57/78), including 7 cases of grade 4 adverse reactions,
3 cases of myelosuppression, 2 cases of pneumonia, 1 case of superior
vena cava occlusion, and 1 case of ketoacidosis. No fatal effects
happened. Among the treatment-related AEs, the incidence of leukopenia
was the highest (57.69\%), followed by anemia (25.64\%), elevated
alanine aminotransferase or aspartate aminotransferase (24.36\%) and
fatigue (24.59\%).

\textbf{Discussion}

In this retrospective study, we have evaluated the efficacy and the
safety of the PD-1 inhibitor on locally advanced and advanced NSCLC
patients with chronic viral infection. Results show that the PD-1
inhibitor-based therapy, especially combined with chemotherapy and
bevacizumab, had moderate efficacy on this population. Notably, the
incidence of elevated hepatic transaminase was higher in them than those
without chronic viral infection and other toxicity profile was
acceptable.

In recent past, immunotherapy, especially PD-1/PD-L1 immune checkpoint
inhibitors, has brought new hope for lung cancer patients by activating
the autoimmune system to achieve the effect of killing tumors.
Successful anti-PD-1 / PD-L1 immunotherapy requires an adequate number
of specific T cells in the tumor microenvironment. Similar to the tumor
microenvironment, the chronic viral infection is a strong
immunosuppression environment, leading to specific T cells
exhausting\textsuperscript{4}, in theory, it may influence the effect of
ICI which has reversed the role of T cell failure at the same time and
undermine the balance between the host immune system and virus control
that has caused the risk of liver damage. In China the incidence of
hepatitis B is higher. At present, the hepatitis B surface antigen
carrying rate among people aged 1-59 is 7.2\%. There are about 93
million chronic HBV infected people in China, among which more than 20
million active hepatitis B patients require proper treatment. The
efficacy and safety of immunotherapy for these patients need to be
clarified, but existing clinical trials tend to exclude patients with
co-viral infection\textsuperscript{5}.Thus there is not any consensus
yet and appropriate strategy of ICIs in this population needs in depth
assessment.

In the existing published articles about safety and efficacy of ICIs in
patients with chronic viral infection and advanced-stage cancer, the
types of cancer involved are not comprehensive, with liver cancer and
melanoma accounting for the majority and NSCLC accounting for less than
five percent \textsuperscript{6}. In one retrospective study of PD-1
inhibitors for NSCLC with special issues involving 32 HBV-infected
patients, four of nine patients experienced severe AST/ALT elevation
(grade 3 or higher) were HBV patients. And three patients developed
viral reactivations or flares, despite receiving anti-HBV therapy prior
to the immunotherapy. In our study, the incidence of elevated ALT/AST
and increased virus-load was lower than in that study. Differences in
ECOG performance status, prior lines of therapy, and agents combined
with PD-1 antibody of the patients may contribute to the differences
between the two studies\textsuperscript{7}. Given the unavailability of
such information and the limited number of patients in that study, the
results of the two studies were not comparable.

Among 78 patients included in the study, the objective response rate
(ORR) was 24.36\% (19/78), and the disease control rate (DCR) was
69.23\% (54/78). Comparing the phase III clinical trial Keynote-042 in
the Chinese subgroup study\textsuperscript{8}, the exclusion criteria of
which included patients with a history of infectious diseases, the
overall objective response rate of the immunotherapy group was similar
to the results of this study (24.36\% vs. 32.80\%) (P=0.250), indicating
that the history of infectious diseases does not affect the short-term
efficacy. In terms of long-term efficacy, the median progression-free
survival (PFS) reached 6.49 months (95\% CI :3.71-9.27). Among them, the
first-line treatment shows better efficacy than the second-line and
later treatment (7.67 months vs. 5.57 months, P = 0.129). Previous
studies have proved that the median progression-free survival of
advanced NSCLC who received pembrolizumab as the first-line
immunotherapy was about 8 months\textsuperscript{9,10}, which is similar
to our study, and that of advanced NSCLC who received nivolumab as the
second-line immunotherapy was about 3 months\textsuperscript{11,12}. In
our study, the median PFS of second- and later-line treatment group
seems improved than the previous studies. This phenomenon may be because
the patients' constitutions are different. In our study, 11.5\% of
patients were clinically diagnosed with stage IIIB lung cancer, which
may have improved the results.

In our group analysis, the short-term efficacy of patients in the
first-line treatment group was significantly better than that in the
second-and multi-line treatment groups (48.00\% vs. 13.20\%)
(P\textless{}0.05). The reason may be that patients in the first-line
treatment group have not received other treatments, and there are more
specific T cells in the tumor microenvironment than in second-line and
multi-line patients, which promote the immune system to recover to a
greater extent. The ECOG score of group 0 and group 1 was significantly
higher than that of group 2 (88.23\% vs.74.00\% vs.18.18\%)
(P\textless{}0.05), indicating that patients with better physical
conditions are more likely to benefit. The ECOG score of group 2 has
poor efficacy, but no deaths related to adverse reactions of
immunotherapy occurred, and the safety was fair. The 10 patients in the
combined radiotherapy group were all in stable condition, which was
better than the non-radiotherapy group, and the PFS was also
significantly longer than the patients without combined radiotherapy
(14.07 vs.4.62, P=0.027). Because local radiotherapy has a synergistic
effect with immunotherapy by enhancing the uptake of antigen by APC,
promoting DC activation and migration, and tumor-associated antigen
cross-presentation\textsuperscript{13}. We divided patients into four
groups in accordance with the different agents that were used to combine
with the PD-1 inhibitor, drawing the conclusion that patients who
received the PD-1 inhibitor in combination with the chemotherapy and the
bevacizumab therapy obtained the longest PFS (PD-1 antibody alone vs.
PD-1 antibody combined with the chemotherapy vs. PD-1 antibody combined
with the bevacizumab vs. PD-1 antibody combined with the chemotherapy
and the bevacizumab groups: 1.44 vs.5.67 vs.1.67 vs.14.13, P=0.002),
which is consistent with previous research.

The incidence of adverse events of any group among 78 patients was
73.07\% (57/78), including 7 cases of grade 4 adverse reactions, 3 cases
of bone marrow suppression, 2 cases of pneumonia, 1 case of superior
vena cava obstruction, and 1 case of ketoacidosis. 3 patients who died
due to respiratory failure after receiving immunotherapy for 2 months
were considered to be affected by rapid tumor progression. The incidence
of leukopenia in any grade of adverse reactions was the highest
(57.69\%), followed by anemia (25.64\%), hepatic transaminase elevating
(24.36\%) and fatigue (21.79\%). There is no big difference between the
adverse reaction spectrum and the incidence of adverse reactions in
patients with infectious diseases and those of patients without
infectious diseases, but it is worth observing that the proportion of
hepatic transaminase elevating was increased. In the clinical phase III
trials of Keynote001, the proportion of alanine aminotransferase (ALT)
elevating and aspartate aminotransferase (AST) elevating were
respectively 2.2\% and 3.0\% in the treatment of
pembrolizumab.\textsuperscript{14} Compared with patients without a
history of infectious diseases, the patients in this study displayed a
higher incidence of hepatotoxicity. Hepatic transaminase increased in
26.7\% (16/60) of hepatitis B patients, and remained unchanged in 63.3\%
(38/60) patients, as is shown in Table 4. Notably, 5\% of hepatitis B
patients showed a decrease in hepatic transaminase. Of the 60 patients
with hepatitis B, viral load remained unchanged in 53, viral load
increased in 2, and viral load decreased in 5. All five patients with
reduced viral load received antiviral therapy. Of the 14 patients who
did not receive antiviral therapy, 3 patients had grade 3 or 4 adverse
events, but in all three patients, the adverse events were reversed with
steroids and ICIs were not discontinued, so the side effects were
considered acceptable. In summary, there was no significant increase in
the incidence of these adverse events in patients with a history of
infectious diseases. Considering the retrospective nature of our study
and small sample size, data from phase IV studies with relaxed inclusion
criteria or from further prospective series are needed to shed more
light on the safety and efficacy of ICIs in this challenging population.

In this retrospective analysis, the efficacy of PD-1/PD-L1 immune
checkpoint inhibitors on locally advanced and advanced NSCLC patients
with a history of infectious diseases was acceptable, safe, and the
clinical outcome was not affected by the history of infectious diseases.
Such patients can benefit from immunotherapy. However, considering that
the incidence of hepatic transaminase elevating has increased, we
recommend close monitoring for such patients in consultation with a
hepatologist and to treat those with active viral hepatitis with
antiviral therapy prior to the immunotherapy.

\textbf{Acknowledgments}

This work was supported by the National Natural Science Foundation of
China {[}81871873{]}; the Project of Invigorating Health Care through
Science, Technology, and Education, Jiangsu Provincial Medical Youth
Talent {[}QNRC2016646{]}; China Postdoctoral Science Foundation
{[}2017M621680{]}; Six talent peaks project in Jiangsu Province
(WSN-039) and the talents program of Jiangsu Cancer Hospital
(YC201807).Research Project of Jiangsu Cancer Hospital (No. ZM202007).

\textbf{Conflicts of interest:} All authors have completed the ICMJE
uniform disclosure form. The authors have no conflicts of interest to
declare.

\textbf{Figure legend}

\textbf{Figure 1.} Clinical outcomes. A, ORR (objective response rate)
and DCR (disease control rate) of all patients. B, PFS (progression-free
survival) of all patients. C, DCR of patients with or without
radiotherapy and DCR of patients with different ECOG performance status.
D, ORR of patients treated with ICIs as first-line or later treatment.
*: p\textless{}0.05

\textbf{Figure 2.} Kaplan-Meier curves. A, PFS of patients treated with
ICIs as first-line or later treatment. B, PFS of patients treated with
ICIs alone or in combination with other drugs. C, PFS of different
combination groups. D, PFS of patients with or without radiotherapy.

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\includegraphics[width=0.70\columnwidth]{figures/figure1/figure1}

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\includegraphics[width=0.70\columnwidth]{figures/Jifeng-Feng-figure-2/Jifeng-Feng-figure-2}

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\textbf{Hosted file}

\verb`Table 1 .docx`  available at \url{https://authorea.com/users/360005/articles/530986-efficacy-and-safety-of-pd-1-immune-checkpoint-inhibitors-in-locally-advanced-and-advanced-non-small-cell-lung-cancer-patients-with-chronic-viral-infection}

\textbf{Hosted file}

\verb`Table 2 .docx`  available at \url{https://authorea.com/users/360005/articles/530986-efficacy-and-safety-of-pd-1-immune-checkpoint-inhibitors-in-locally-advanced-and-advanced-non-small-cell-lung-cancer-patients-with-chronic-viral-infection}

\textbf{Hosted file}

\verb`Table 3 .docx`  available at \url{https://authorea.com/users/360005/articles/530986-efficacy-and-safety-of-pd-1-immune-checkpoint-inhibitors-in-locally-advanced-and-advanced-non-small-cell-lung-cancer-patients-with-chronic-viral-infection}

\textbf{Hosted file}

\verb`Table 4 .docx`  available at \url{https://authorea.com/users/360005/articles/530986-efficacy-and-safety-of-pd-1-immune-checkpoint-inhibitors-in-locally-advanced-and-advanced-non-small-cell-lung-cancer-patients-with-chronic-viral-infection}

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