Effects of COVID-19 vaccination on irAEs and prognosis in lung cancer patients receive PD-(L)1 inhibitors.

Introduction
Several immune checkpoint inhibitors (ICIs) have been approved for the treatment of non-small cell lung cancer, breast cancer, relapsed/refractory malignant lymphoma and other malignancies.1,2 ICIs currently used in clinic mainly include programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and Lymphocyte activation gene 3 (LAG3) antibodies.3,4 ICIs have resulted in significant clinical benefit, but as the population of patients receiving immunotherapy continues to grow, immune-related adverse (irAEs) events have become increasingly prominent during clinical use.5,6 The clinical manifestations of irAEs are often similar to those of autoinflammatory or autoimmune diseases.7 It is believed that the driving mechanism of irAEs mainly includes the following four aspects: T-cell activation and tumor antigen cross-reactivity leading to normal tissue destruction; Autoantibody production mediated by B cell; T cells secrete a lot of cytokines and direct action of monoclonal antibodies.8,9 The occurrence time of irAEs is significantly different from that of traditional antitumor drugs.10 The peak of immune-related adverse events typically occurs 9 to 12 weeks after ICIs monotherapy (average of four treatment cycles), and irAEs have been reported to appear as early as the first treatment cycle. irAEs can also occur after treatment or even several months after the end of treatment, and the peak of irAEs in ICIs combination therapy is generally earlier than monotherapy.11,12
With the spread of coronaviruses, COVID-19 vaccination has become one of the key concerns for cancer patients,13 as the cohort is generally immunocompromised, making them susceptible to infection and serious disease. However, whether the COVID-19 vaccine influences the efficacy of treatment for ICIs is unclear, and vaccination may be a risk factor for the development of irAEs in cancer patients. ICIs therapy improves the function of immune cells by blocking PD-(L)1/CTLA-4 on them and induces tumor immunity.14,15 At the same time, the goal of vaccination is also to enhance tumor immunity. Vaccination is also aimed at enhancing the immune response, albeit against viral antigens rather than tumor cells, both of which can independently stimulate the immune system and have a significant impact on growth of tumor cells. Although directed against viral antigens rather than tumor cells, both can independently stimulate the immune system, with potential implications for the development of irAEs.
As a major global health threat, lung cancer has been an important cause of high morbidity and mortality from malignant tumors worldwide. In 2022, about 2.5 million new cases of lung cancer were diagnosed globally, accounting for 12.4% of the total number of malignant tumors, making it the most common malignant tumor; and about 1.8 million deaths were attributed to lung cancer, accounting for 18.7% of the total number of deaths from malignant tumors, making it the leading cause of deaths from malignant tumors.16 Multiple phase 3 clinical studies conducted to explore the efficacy and safety of combining chemotherapy with antibodies that block PD-1 or PD-L1 in advanced lung cancer have shown that combining a standard first-line chemotherapy regimen with atezolizumab or pembrolizumab improves the efficacy of treatment and improves the prognosis for survival in patients with advanced lung cancer.17–20 In this study, we investigated the effects of COVID-19 vaccination on the development of irAEs and prognosis in lung cancer patients receiving PD-(L)1 inhibitors.

Materials and methods

Study population
The 394 lung cancer patients receiving PD-(L)1 inhibitors in this study were recruited at Xiangya Hospital from 2020 to 2022. All patients were older than 18 y old with histopathological diagnosis of lung cancer and had received at least one cycle of anti-PD-(L)1 checkpoint antibody monotherapy or combination therapy. Each patient’s medical history was examined and investigated in detail. Exclude patients with serious concomitant diseases that may seriously affect their physical condition. Telephone follow-up was conducted to collect information on patients receiving COVID-19 vaccine. The inclusion criteria were as follows: Patients were vaccinated with COVID-19 vaccines, including mRNA vaccine (Anhui Zhifei) and inactivated vaccine, prior to treatment with PD-(L)1 inhibitors. All subjects received informed consent. The analysis of the retrospective data was approved by the ethics committee of the Medical Faculty of Xiangya Hospital (Ethics approval number: 2022100970).

Data collection and patient outcomes
We used electronic medical records to retrospectively collect clinical information of the patients, including gender, age, and smoking status, pathological type, disease stage, complications concomitant diseases, and the type of PD-(L)1 inhibitor received. Lung cancer comorbidities mainly include chronic pulmonary inflammation, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, bronchiectasis, etc., which are closely related to the occurrence, prognosis and efficacy of lung cancer.21 Follow-up is usually semiannual, and the termination date for PFS collection was January 22, 2023. Progression-free survival (PFS) was defined as the time from initiation of PD-(L)1 inhibitor therapy to death or recurrence or metastasis. IrAE outcomes were assessed by NCCN or CSCO guidelines of Management of Immunotherapy-related Toxicities, and the severity of irAEs was evaluated by Common Terminology Criteria for Adverse Events (CTCAE version 5.0).

Statistical analysis
Descriptive statistics of baseline demographic and clinical characteristics were composed both for the vaccinated and for the unvaccinated group. Continuous variables were summarized using means and 95% CIs and categorical variables were summarized using frequencies and proportions. Analysis of variance was performed using chi-square tests. The association between COVID-19 vaccination and prognosis was analyzed by using Cox proportional hazards regression model. All analyses were performed using IBM SPSS 26.0 software, and P < .05 was considered statistically significant.

Results

The characteristics and COVID-19 vaccination of participants
This study assembled a cohort of 394 lung cancer patients who received PD-(L)1 inhibitors. In total, 150 of the patients received COVID-19 vaccination before initiation of ICIs treatment and 244 of patients without COVID-19 vaccination. The clinical characteristics of the patients were summarized in Table 1. Of the 394 patients, 338 (85.79%) were males, and the majority were smokers (77.66%). About 180 (45.68%) patients were squamous carcinoma, 137 (34.77%) were adenocarcinomas, 60 (15.23%) were small cell carcinomas, and 17 (4.31%) were other pathological types. Most of the patients were in advanced stage. We conducted statistical analysis on general clinical data, including ICIs treatment cycle, age, gender, smoking status, case type, disease stage, PD-(L)1 inhibitor type, and concomitant disease, between the COVID-19 vaccination and non-COVID-19 vaccination groups. There was a significant difference in the cycles of treatment, histology, stage and PD-(L)1 inhibitor type (Table 1). These factors would be used as covariates in analyzing the association of COVID-19 vaccination with irAEs and prognosis of the patients.

Immune-related adverse events
Among the 394 lung cancer patients, 44% (171 cases) experienced multiple irAEs, 29% (114 cases) experienced one type of irAE, and 27% (108 cases) had no adverse reactions (Figure 1A). The most frequent irAEs were thyroid-related events (hypothyroidism (18%) and hyperthyroidism (11%)) and skin toxicity (16%), followed by cardiovascular toxicity (14%), skeletal muscle toxicity (8%), glycemic endocrine toxicity (7%), and pneumonia (6%). The incidence of pituitary endocrine toxicity was 2%, while hepatic gastrointestinal toxicity, inflammatory arthritis, enteritis gastrointestinal toxicity, and nephrotoxicity were 3%, 5%, 4%, and 5%, respectively (Figure 1B). There was a high prevalence of irAEs at the G1-G2 level for most types of irAEs. Severe grades of irAEs were observed for pneumonia, skin toxicity, and gastrointestinal toxicity (Table 2).

Association of COVID-19 vaccination with irAEs
To investigate the effect of COVID-19 vaccination on the occurrence of irAEs in lung cancer patients, we conducted univariate and multivariate logistic regression analyses while adjustment with confounding factors (treatment cycles, histology, stage and PD-(L)1 inhibitor type). In the univariate logistic analysis, the occurrence of Dermatitis/rash (OR = 0.54, 95%CI: 0.32–0.89, P = .016), inflammatory arthritis (OR = 0.18, 95%CI: 0.05–0.61, P = .006), and cardiovascular toxicity (OR = 0.41, 95% CI: 0.24–0.71, P = .001) was significantly associated with COVID-19 vaccination. The multivariate analysis results showed that COVID-19 vaccination was significantly associated with inflammatory arthritis toxicity (OR = 0.22, 95%CI: 0.07–0.76, P = .016) and cardiovascular toxicity (OR = 0.48, 95%CI: 0.27–0.84, P = .010), which indicated that COVID-19 vaccination might significantly decrease the prevalence of arthritis and cardiovascular toxicity in lung cancer patients received PD-(L)1 inhibitors.

Association of COVID-19 vaccination with PFS
To investigate the correlation between COVID-19 vaccination and PFS of lung cancer patients, we conducted univariate and multivariate analyses on variables of COVID-19 vaccination, gender, age, smoking status, histology, PD-(L)1 inhibitor type, treatment cycle, and stage. The results revealed that the correlation between COVID-19 vaccination and PFS was not significant in both univariate (HR = 0.95, 95% CI: 0.68–1.33, p = .761) (Figure 2) and multivariate analysis after adjustment for other variables (HR = 0.89, 95% CI: 0.61–1.29, p = .529). Gender, age, smoking status, PD-(L)1 inhibitor type, treatment cycles and stage were not found to be significant factors on PFS, but histological type was significantly related to PFS (Table 3).

Discussion
Our study found that the COVID-19 vaccination could decrease the incidence of immune related arthritis and myocarditis in lung cancer patients with ICIs treatment. Other irAEs such as pneumonia, dermatitis/rash, myositis, oculopathy, diabetes, colitis, nephritis, hypothyroidism, hyperthyroidism, hypophysitis and transaminitis were not affected by COVID-19 vaccination. Furthermore, COVID-19 vaccination had no effect on PFS of lung cancer patient received ICIs treatment.
The global morbidity, mortality and social disruption caused by the COVID-19 pandemic have accelerated clinical vaccine development and has been shown to reduce the risk of severe COVID-19.22 Cancer patients are prioritized for vaccination according to vaccination strategies due to their weakened immune systems and high risk of infection.23 However, there are concerns about potential interactions between COVID-19 and its vaccines and ongoing systemic cancer treatments, particularly immunotherapy. The number of CD4+ and CD8+ T cells is reduced in patients with severe COVID-19.24 Whereas PD-(L)1-based ICIs unleash the brakes on immune tolerance mechanisms, CD4+ and CD8+ T cells are among the key immune cells for an effective anti-tumor response.25 Therefore, COVID-19 infection may have a potential impact on the prognosis of patients receiving ICIs. On the other hand, immunotherapy and the COVID-19 vaccine can simultaneously enhance the body’s systemic immune response,26 and the potential overlapping immune enhancement present in these two treatments could lead to an increase in irAEs. COVID-19 vaccine may trigger cytokine release syndrome during ICI treatment.27 PD-1 inhibitor may enhance vaccine efficacy against infectious diseases by reversing T cell exhaustion in cancer patients and increased risk of immune-related adverse effects (irAEs) due to immune system overstimulation during vaccination.28
Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs. Studies showed that the incidence of irAEs was not elevated following vaccination treated with ICIs in melanoma patients,29 and there was no significant increase in the incidence of irAEs in patient with colorectal cancer within 90 d after COVID-19 mRNA vaccination such as BNT162b2 and mRNA-1273.30 In solid tumor subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.31 The meta-analysis32 showed that the incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was 21.96% and 14.88%, respectively. Among 408 patients with cancer receiving ICI therapy, administration of a COVID-19 mRNA vaccine within 90 d of ICI treatment was not associated with an increased incidence of irAEs.33 The above studies show that ICI treatment after COVID-19 vaccination has good efficacy and safety.
Our study revealed that COVID-19 vaccination was not associated with most types of irAEs and PFS in lung cancer patients with ICIs treatment, but it may decrease prevalence of immune related arthritis and myocarditis. This may be explained by the protective nature of the COVID-19 vaccination against arthritis and myocarditis, and future prospective randomized studies in this population are needed. Recent observations also report a protective role for flu vaccination (FV) in the development of ICIs myocarditis and major adverse cardiac events (MACE). FV was also associated with a lower rate of ICI-related pneumonitis, and myocarditis cases had lower troponin levels and lower rates of cumulative MACE at follow-up in the FV population.34 There were some limitations in our study. Firstly, according to most of the patients received inactivated vaccines, and only 22 patients received mRNA vaccine, further studies are still needed to determine whether the vaccine types resulting in differences in the incidence of irAEs. Secondly, the study is conducted with data collected in a single center, and the sample size of our study is not large enough. The results might need to be verified in a larger independent cohort.
In conclusion, COVID-19 vaccination neither increase the incidence of irAEs nor affect PFS of lung cancer patients receiving ICIs treatment.