Immune checkpoint inhibitors (ICIs) have revolutionized the care of several groups of patients with advanced cancers [1]. These therapies are approved for use among patients with metastatic melanoma, non-small cell lung cancer, squamous carcinoma of the head and neck, renal cell carcinoma, Hodgkin’s lymphoma, liver cancer, squamous cell of the skin and bladder cancer [2–8]. Checkpoint inhibitors are predominantly approved in late stage patients but, due to efficacy, are being expanded to adjuvant settings [9–13]. They work by releasing negative regulators of immune activation, thus facilitating the recognition of tumors by the immune system. As anticipated, activation of the immune system may result in immune-mediated adverse effects (irAEs) [14]. Myocarditis is an uncommon but serious immune complication of ICIs [15–22], myocarditis related to an ICI occurs early after initiation of ICIs [15] and the development of myocarditis after ICIs is associated with significant morbidity and mortality [15, 20–24]. The risk factors for the development of myocarditis among patients on ICI therapy are poorly understood [16, 25] and an improved understanding is needed. In this submission, we tested the effect of administration of the FV on the development of myocarditis. By way of background, there is controversy as to whether it is safe to administer the influenza vaccine to patients receiving immunotherapy and there are data in patients at risk of cardiovascular disease that the influenza vaccine may be protective. The national comprehensive cancer network (NCCN) guidelines recommend the FV in patients with hematologic or solid tumor malignancies, but there are no guidelines specific to those on immune therapy [26]. In a recent study, with 23 lung cancer patients on ICI (cases) and 11 age-matched healthy controls, influenza vaccination was associated with a heightened immune and inflammatory response resulting in a high rate of general irAEs (52.2%) [27]. In contrast, in a multi-center study with a broad range of cancers, FV administration was associated with a non-significant increase in overall survival among patients on ICI’s [28] and in a single center retrospective study of over 500 patients, a similar rate of general irAEs were noted between vaccinated (37.4%) and unvaccinated patients (42.6%) [29]. However, the majority of the irAEs in that study (87%) were ICI- related pneumonitis and there are no studies to date testing the association of the FV and development of ICI related myocarditis [29]. Therefore, the goal of this study is to test the association between FV and the development of myocarditis among patients on ICI’s. This relationship between FV status and the development of myocarditis may be of additional importance as the development of influenza infection is also, albeit rarely, associated itself with an increased risk for myocarditis and major adverse cardiovascular events [30–32]. Additional goals included testing the effect of FV status on outcomes among those patients who develop myocarditis.

We tested the association between FV and the development of myocarditis among patients on ICIs, and the effect of FV status on presentation and outcomes among patients who develop ICI-myocarditis. In our retrospective study of 101 ICI-related myocarditis cases, we found that 25% were vaccinated against influenza. In comparison, rate of vaccination for influenza was higher (40%) among 201 control patients on ICIs who did not develop myocarditis. This first analysis included those administered the FV from 6 months prior to commencing ICI therapy or during therapy. Similar findings of lower rates of vaccination against flu among myocarditis cases were noted when using a 3-month cut-off or, when restricting FV to administration during ICI therapy only and restricting to cases from the same institution from where the controls were derived. Among myocarditis cases, serum troponin, a measure of myocardial injury used to detect myocarditis, was 3-fold higher among myocarditis cases not administered the FV. This increase in serum troponin among unvaccinated myocarditis cases was associated with an increase in subsequent major adverse cardiac events. Specifically, during follow up, the rate of cumulative MACE among unvaccinated cases was more than double the adverse event rate seen among myocarditis cases administered the FV. Additional parallel findings of importance related to pneumonitis were noted that were not the primary focus of this paper. As compared to controls who did not develop myocarditis, the rates of pneumonitis were higher among myocarditis cases; and in analyses restricted to myocarditis cases, the rates of pneumonitis were higher among those cases not administered the FV.

Data testing the association between FV status and immune-mediated adverse events among patients on ICI therapy have provided conflicting results. In a single center study among patients with lung cancer, influenza vaccination during treatment with anti-PD1 induced an adequate serological protection from influenza, an increased inflammatory response and heightened the risk for immune-related adverse events [27]. There are differences in our study and that prior study that may explain the discordant findings. Specifically, we included patients with all types of cancers who were on an ICI, we included all types of ICI therapies and we only primarily focused on one type of adverse event, myocarditis. We focused on myocarditis for the following four reasons: 1) myocarditis is an uncommon but serious complication of ICI therapy, 2) myocarditis can occur among patients with active influenza infection, 3) vaccination against influenza has been associated with a reduction in cardiovascular events in broad populations [40, 41], 4) the risk for cardiovascular events is increased broadly among patients with cancer, Data among broad populations showing a beneficial effect of FV on cardiovascular events are robust. For example, in a large meta-analysis of randomized controlled trials of nearly 7000 patients, the administration of FV was associated with a lower risk of MACE [30]. Other studies have also suggested that the use of the FV vaccine may be safe among patients on an ICI. Specifically, a recent single center study suggested that the seasonal influenza vaccination is safe and may be beneficial for patients on ICI with reduced rates of hospital admissions from flu-related and immunotherapy-related adverse events [29]. This latter study also included patients with all types of cancer and ICI therapies.

In supportive findings of a protective effect of FV among patients on an ICI, we found that biomarkers of risk in general myocarditis and for adverse events among patients who develop ICI myocarditis were higher among unvaccinated cases. We previously noted that serum troponin, a sensitive marker for myocardial injury is elevated among most patients with ICI myocarditis and the degree of elevation of serum troponin is a predictor of adverse cardiovascular events among patients who develop myocarditis on an ICI [15]. In this current study, troponin levels were higher among unvaccinated cases with ICI myocarditis compared to cases with myocarditis who were administered the FV. We also noted that serious adverse cardiac events were increased among patients who developed ICI myocarditis and were not previously administered the FV.

Although not the primary focus of this paper our findings regarding other immune-related adverse events, specifically pneumonitis, merit discussion. Our rates of any grade of other irAEs were 36 and 55% in the vaccinated and unvaccinated cases, respectively. These are comparable to the 37% irAEs in the vaccinated group and 43% in the unvaccinated group reported in the discussed single center study showing a protective effect of FV [29]. However, these rates are still lower than the rate of 52.2% of previously vaccinated patients developing any grade irAEs in the study of Läubli and colleagues [27]. We found higher rates of pneumonitis in the population without FV, Pneumonitis and pneumonia are important causes of influenza-associated morbidity and mortality among broad populations [42, 43] and FV has been shown to reduce morbidity and mortality among at-risk individuals [40, 43], including patients with cancer [44–46]. In our cohort, vaccinated cases had lower rates of immune-related pneumonitis compared to unvaccinated cases. This may be explained by the protective nature of the FV against pneumonitis and pneumonia and support the need for prospective randomized studies in this at-risk population.

This study has some limitations that merit discussion. This is the largest registry of patients with ICI-myocarditis; however, this was a retrospective case-control study where cases were derived from multiple institutions and controls were derived from a single institution. To address this, we also compared the rates of FV within cases and controls from the same institution and found similar results of a lower rate of FV among patients on an ICI who got myocarditis. Additionally, as this was a retrospective study, the type of influenza vaccination, the specific antibody titers and measures of inflammatory response were not recorded. Also, the choice of whether patients were administered the FV was at the discretion of the clinician involved in their care, which differed between the centers but also locally within each center. Ideally to test the association of the FV and ICI myocarditis, a prospective study comparing all ICI patients with and without FV who develop myocarditis, or a randomized clinical trial would be warranted. However, with a low incidence rate of ICI-myocarditis (~ 0.5–1.0% or less) [14, 15, 20, 21], to test this association adequately, a large cohort of subjects would be required. In addition, there are currently no available systematic screening approaches for myocarditis among patients on ICIs and diagnosis is based on physician’s suspicion. Therefore, a prospective approach may also lead to an underestimation in the incidence of myocarditis and the effect of the FV. Finally, this study does not provide a mechanism by which the FV may be protective. Indeed, the mechanism underlying the protective effect of the FV against cardiovascular events in the general population is also unclear [30], but potential mechanisms include rupture of a vulnerable atherosclerotic plaque, heart failure, or, relevant to this study, myocarditis [32, 47–49]. Direct involvement of influenza in the myocardium, leading to myocarditis, is uncommon with rates of up to 10% reported depending on methods of detection used [31] and influenza infection can cause myocarditis by direct cytolysis of the myocyte causing necrosis, but also the host immune response to the virus may play an important role [50].

In summary, the administration of the FV was not associated with an increased risk of subsequent myocarditis among patients on ICI. In contrast, rates of influenza vaccination were lower among patients who did develop myocarditis on ICI, and the influenza vaccine was associated with a lower rate of ICI-related pneumonitis. At presentation, myocarditis cases administered the FV had lower troponin levels and, in follow-up, had lower rates of cumulative MACE. There is a clear need to establish the safety status of influenza vaccination among cancer patients treated with ICIs, as our data suggest that it may be protective. Further large studies are warranted to test and validate these important findings.