Immune Checkpoint Inhibitors and Infection: What Is the Interplay?

Function of ICIs

Immune checkpoint molecules comprise a group of inhibitory receptors expressed on immune cells, with a pivotal role in down-regulating and fine-tuning the adaptive immune response, thereby preventing collateral destruction of host tissue by effector cells (8). More specifically, activation of these self-inhibitory signaling pathways promotes T-cell exhaustion, a process characterized by impaired T-cell effector function (i.e., cytotoxicity or cytokine production), diminished proliferation, increased expression of co-inhibitory receptors and cell apoptosis (9).

CTLA-4 is an inhibitory receptor expressed on T-cells secondary to the binding of the CD28 T-cell receptor to the CD80/86 ligand on antigen-presenting cells (7). CTLA-4 binds to CD80/86 with greater affinity, minimizing T-cell effector function via inhibition of nuclear factor kappa light-chain enhancer of activated B-cells signaling and reducing IL-2 production (10). PD-1 is also a T-cell surface receptor which serves in down-regulating T-cell cytotoxic killing by binding to the protein programmed cell death ligand 1 (PD-L1) (11). PD-L1 expression in peripheral tissues is stimulated by interferon-gamma (IFN-γ) secretion by T-cells within the tumor microenvironment (9).

Tumors have been suggested to arise from already established cancer cell clones that have evolved to evade immune surveillance through a process termed immunoediting (12). The up-regulation of immune checkpoint molecules in the tumor microenvironment is one of the mechanisms cancer cells employ to evade active immune surveillance, with subsequent T-cell exhaustion having been suggested to play a critical role in tumor progression (13-15).

ICIs are agents developed to target known immune checkpoints [(PD-1/PD-L1, CTLA-4, T-cell immunoglobin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3)] and are designed to restore exhausted T-cell effector function with the aim of lifting the ‘immune breaks’ of cancer (15, 16). Ipilimumab, a human IgG1 antibody to CTLA-4, was the first agent approved by the US Food and Drug Administration in 2011 for first- or second-line treatment of unresectable melanoma (16, 17). Currently, nine checkpoint inhibitor of CTLA-4, PD-1/PD-L1 and LAG-3 have been approved by the Food and Drug Administration for various types of cancer (16, 18, 19). T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) constitutes another surface molecule that contributes to the complex mechanism of T-cell exhaustion (20). The combination of TIGIT and PD-1/PD-L1 targeting has been recognized to amplify the antitumor adaptive immune response and improve patient outcomes in both solid and hematological malignancies (21). ICIs facilitate the prospect of long-term survival in patients with advanced disease, but also they are being introduced in the early cancer treatment setting (22, 23).

ICI Administration and Risk of Infection

Infection due to immunosuppression administered to treat ICI-induced immune-related adverse effects. Although ICIs have altered the field of oncology, immune-related toxicities occur in a high percentage of patients with cancer, reported in approximately 40% of ICI-treated individuals (22). The exact mechanism of those immune-related adverse effects (irAEs) is not yet fully understood, although it has been heavily hypothesized that it is the same immune activation that provokes antitumor responses (23). Additionally, the wide variety of irAEs suggests the existence of different mechanisms, unrelated to tumor activity, such as viral factors, tissue-specific factors, or factors linked to the human microbiome (23). Modern clinical experience demonstrates that different ICIs have different and distinct toxicity profiles; for instance, CTLA-4 inhibition has a high incidence of dose-dependent toxicities, while the administration of PD-1 or PD-L1 ICIs is responsible for a lower incidence of clinically significant irAEs in a dose-independent way. Reasonably, the simultaneous administration of different ICIs enhances the risk of autoimmune toxicities (23). Although irAEs can affect any organ, they have been mostly reported to affect the skin, lungs, liver, gastrointestinal tract, thyroid gland, and joints (23). Interestingly, their onset can occur at any time from the initial administration of the ICI, sporadically even after treatment discontinuation, however, they are usually reported to appear within the first 5 months of therapy (9, 23).

Management of ICI-induced complications is heavily based on the administration of immunosuppressive agents. The first line of treatment involves the use of high-dose corticosteroids (i.e., the equivalent of 0.5 mg/kg/d of prednisone for mild irAEs and 1-2 mg/kg/d for severe irAEs), while irAEs that are refractory to corticosteroid administration can be treated with more potent immunosuppressive agents, for example tumor necrosis factor-α (TNF-α) inhibitors (9, 22, 24). However, it should be noted that such immunosuppressive interventions increase the risk of infection (24).

To date, sparse data exist on the risk of infection in ICI-treated patients (20). The most comprehensive study comes from the Memorial Sloan Kettering Cancer Center where 740 patients with melanoma were evaluated for the incidence of serious infection as a complication during the first year following ICI initiation (7). Interestingly, it was demonstrated that serious infections occurred in 7% of patients, while the majority of them (85%) were caused by bacteria (7), with pneumonia, intrabdominal and bloodstream infections being the most common infection types (7). Among the remaining infectious agents reported, viruses [varicella zoster, cytomegalovirus (CMV), and Epstein-Barr] and opportunistic fungi (Pneumocystis jirovecii, Aspergillus spp, and Candida spp) were also identified (7). Notably, corticosteroid exposure (≥10 mg/d of prednisone for ≥10 days) was reported in the majority of the patients with serious infections (7). Moreover, the discrepancy in the incidence of infection associated with the different ICIs was attributed to their different tendencies in provoking irAEs that would require immunosuppressive therapy (7).

Similar data emerged from other studies, which revealed that the rate of serious infections among patients receiving ICIs is correlated with the use of steroids (25). More specifically, it was demonstrated that bacterial infections were the main cause of infection after ICI administration, with the urinary tract being the most commonly affected site, followed by pneumonia and skin and soft-tissue infections (25). The use of corticosteroids to treat irAEs was significantly associated with the risk of these infections (25). Furthermore, the use of other immunosuppressive agents (e.g., alemtuzumab, abatacept) for the treatment of severe irAEs can also increase the risk of opportunistic infections and require the need for high clinical awareness (26, 27). In a study of patients with non-small cell lung cancer who received the PD-1 inhibitor nivolumab, the rate of infections was 19% (28), the most common being pulmonary infections typically caused by community-acquired bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus or viruses (influenza). Interestingly, the use of corticosteroids to treat irAEs (defined as ≥5 mg/d) was reported in approximately 50% of patients in the study and was not significantly associated with the development of infection (28). In addition, CMV infections have also been observed in patients with ICI-induced colitis that have been treated with corticosteroids and infliximab (22, 29) and have been described as refractory cases (29).

Whether ICI therapies predispose to the emergence of invasive fungal infection is a question that attracts clinical interest (30). Such infections are uncommon with the use of ICIs and most cases that have been described in the current literature have been attributed to invasive aspergillosis and pneumonocystis pneumonia (7, 28, 31). Such events occur mostly in the setting of the use of high doses of corticosteroids for the management of acute irAEs, which is a well-established risk factor for invasive fungal infection (31). Finally, in some cases, it is challenging for clinicians to discriminate irAEs from infections, while in other cases of administration of immunosuppressives for irAEs, appropriate use of antimicrobial prophylaxis wherever indicated is critical.

Infections directly due to ICI. The administration of ICIs per se does not appear to increase the overall risk of infection (32). However, their use may directly predispose to certain infections, such as tuberculosis, in a subgroup of patients (22). This has been supported in pre-clinical models, where PD-1-deficient animals were demonstrated to be highly susceptible to infection with Mycobacterium tuberculosis (22). Increased mortality in these animals is caused by excessive IFN-γ production by Th1 cells. The observation that the mice could be rescued by depletion of CD4⁺ T-cells combined with the well-known impact of Th1 cells in controlling M. tuberculosis, demonstrates the significance of the equilibrium between T-cell reactivation to mediate pathogen clearance and the simultaneous avoidance of collateral tissue immunopathology. Moreover, the PD-1 pathway has been suggested to be protective against M. tuberculosis infection. The blockade of the PD-1/PD-L1 axis in cancer therapy may disrupt the immune surveillance of such infections, resulting in the risk of tuberculosis emergence, even in patients who do not receive immunosuppressive treatment (33). Of note, both acute disease and reactivation of latent tuberculosis have been reported in patients receiving PD-1 ICI treatment (34). Quantifying the risk of M. tuberculosis reactivation during ICI administration in patients with cancer is confounded by the immunosuppressive effects of malignancy and chemotherapy (34). Additionally, the appearance of pneumonitis as an irAE during ICI therapy has an immunomodulatory effect on pulmonary T-cells and may contribute to increased susceptibility to M. tuberculosis infection (34). Collectively, it appears that tuberculosis reactivation and primary infection may represent a direct AE of ICI administration (33-35). However, existing data to support this association are as yet insufficient and the interplay between tuberculosis and the human immune system during ICI therapy has yet to be deciphered. Physicians should be aware of the risk of primary infection or reactivation of M. tuberculosis during ICI therapy. Routine screening for M. tuberculosis prior to ICI administration is considered an appropriate strategy (34).

Notably, a hypothesis has been proposed through which infections might in fact be stimulators of irAEs in the absence of immune suppression. Infections can either occur coincidentally or due to a dysregulated immune response provoked by ICIs (36). In this context, such infections have been characterized as “infections due to dysregulated immunity” (36). The Memorial Sloan Kettering Cancer Center study mentioned above demonstrated 10 cases of Clostridioides difficile-associated diarrhea (CDAD) in patients receiving ICIs (7). Complementary data from another case series (37), where four out of the five patients studied did not report any antibiotic exposure prior to CDAD occurrence, suggest a potential association of CDAD and immune-mediated colitis with ICI administration (37). However, questions still remain in exploring such an observation, as patients with cancer a priori have an elevated risk of C. difficile infection (38) while colitis itself increases susceptibility to CDAD (22, 39).

The use of ICIs has also been linked with hematological irAEs. ICI-induced neutropenia has been reported in 11 patients in the literature. Neutropenia was typically significant and in 55% of cases was complicated by infections (40). Immune-mediated neutropenia due to ICI therapy can also contribute to invasive fungal infection, although such events seem to be rare (31, 41).

Possible Use of ICIs in the Management of Infections

Many pathogens are able to evade host immune surveillance by stimulating inhibitory interactions between immune cells through checkpoint molecules in a similar way to tumor cells (42). Pre-clinical and secondarily clinical studies have been conducted in order to assess the possible positive therapeutic impact of checkpoint inhibitors on immune cell responses and pathogen clearance in acute and chronic infections (9, 43, 44). The purpose of these studies was to lay the groundwork for the design of future randomized controlled trials regarding the potential use of ICIs in patients with difficult-to-treat infections.

HIV infection. HIV infection remains a major cause of morbidity and mortality globally (45) and its treatment constitutes a significant challenge for clinicians because of the ability of the virus to persist in a latent phase in CD4⁺ T-cells and its rebound after interruption of antiretroviral therapy (ART) (46). The possible role of immune checkpoint blockade in HIV-latency reversal and reinvigoration of HIV-specific T-cell responses has been studied extensively (47-49). The rationale behind this research is that in HIV infection, up-regulation of expression of immune checkpoint molecules can lead to T-cell exhaustion and reduced cytolytic activity (50-52).

In vitro studies on HIV infection have shown that PD-1 overexpression on both CD4⁺ and CD8⁺ T-cells has been positively correlated with plasma HIV viral load, and inversely with HIV-specific CD8⁺ T-cell function and CD4⁺ T-cell count (51). Thus, PD-1 blockade can promote HIV-specific CD8⁺ T-cell survival and proliferation, leading to improved effector functions (52). In addition, inhibitory effects of PD-1 on T-cell activation can attenuate viral transcription and RNA translation, providing the basis for HIV latency (8). This is in accordance with ex vivo findings where blocking PD-1 in CD4⁺ T-cells from virally suppressed individuals enhanced HIV reactivation and latency reversal (47). It is also worth noting that blockade of the PD-1 pathway during experimental vaccination for the development of HIV vaccines had a positive effect on protection of macaques against Simian immunodeficiency virus (SIV), augmenting vaccine-induced SIV-specific T-cell responses (53).

In contrast to PD-1 expression, CTLA-4 is not up-regulated in HIV-specific CD8⁺ T-cells during HIV infection. However, its up-regulation is significantly enhanced in HIV-specific CD4⁺ T-cells in the presence of viremia, even in cases of suppression of viral load after use of ART. This overexpression has been correlated to disease progression, and CTLA-4 in vitro blockade has been shown to substantially increase HIV-specific T-cell proliferation (50). Furthermore, CTLA-4 blockade in SIV-infected macaques led to reduced viral RNA levels in lymph nodes and improvement of the effector function in SIV-specific CD4⁺ and CD8⁺ T-cells (54). Interestingly, inhibition of the CTLA-4 pathway in combination with an HIV virus-like particle vaccine in a mouse model resulted in increased CD4⁺ T-cell activation, modified HIV-specific B-cell responses and production of higher-avidity HIV antibodies, suitable for antibody-dependent cellular cytotoxicity (49).

Data on other checkpoint molecules that might possibly be targeted in the context of treating active HIV infection are limited. The expression of LAG-3 and TIM-3 is up-regulated in both CD4⁺ and CD8⁺ T-cells during HIV infection. This has been directly correlated with HIV viral load and with disease progression (55, 56). Moreover, co-expression of TIGIT with PD-1 or LAG-3 in CD4⁺ T-cells was significantly associated with a higher frequency of integrated HIV DNA in these cells (57).

Despite recent findings that ICIs may be safe and efficacious as antitumor treatment in people living with HIV (58), this subgroup of patients is usually excluded from cancer ICI trials, even if their viral load is effectively suppressed through ART (59). As a result, insufficient clinical data exist regarding the possible role of ICIs in HIV-specific T-cell function, HIV persistence or other outcomes. In a case of a patient living with HIV on ART who was treated with anti-CTLA-4 for metastatic melanoma, an increase in cell-associated unspliced HIV RNA was observed after the first and second infusions (60). In another HIV-infected patient on ART, anti-PD-1 treatment for lung cancer led to a transient increase in plasma HIV viral load, a significant and persistent decrease in cell-associated HIV-DNA, and modest T-cell activation (61). Moreover, in 32 people on ART living with HIV with cancer, administration of pembrolizumab (an anti-PD-1 agent) was associated with increased unspliced HIV RNA 1 week after infusion and a higher frequency of CD4⁺ T-cells with inducible virus after six cycles of treatment (62). In another study of 40 cancer and HIV-infected patients on ART who received anti-PD-1 as monotherapy or in combination with anti-CTLA-4, cell-associated HIV RNA increased after the first dose only in the subpopulation treated with combined blockade (63). Not only elevated levels of cell-associated unspliced HIV RNA but also a higher frequency of HIV-specific CD8⁺ T-cells producing IFN-γ, TNF-α and CD107a were noted in patients living with HIV who received anti-CTLA-4 in combination with anti-PD-1 for metastatic melanoma (64). As regards studies in people living with HIV without malignancy, administration of anti-CTLA-4 in viremic patients caused an increase in plasma HIV RNA after dosing (65). Other studies of ICIs in patients with HIV without cancer were precipitously interrupted because of possible irAEs (66, 67). However, in one study, the first evaluation after the first dose of anti-PD-L1 treatment indicated an increase in the mean percentage of HIV-1-specific CD8⁺ T-cells expressing IFN-γ in two patients (66). The above-mentioned clinical data are suggestive of a possible positive impact of ICIs predominately on reversal of HIV latency and secondarily on enhancing HIV-specific T-cell responses.

In conclusion, ICIs may potentially stimulate latently-infected CD4⁺ T-cells to release HIV, and HIV-specific CD8⁺ T-cells to eradicate the infected cells through lytic and non-lytic processes (Figure 1), indicating an additional therapeutic strategy to ART. Plenty of parameters affect the outcome, such as the baseline CD4 count and viral load of patients, concomitant ART, other co-morbidities, concurrent immunosuppressive medication, time of initiation of ICI, and the combination of different ICIs. Immune checkpoint blockade may consequently be effective only in a subset of patients. This is in accordance with the results of a systematic review regarding the effects of ICIs in people living with HIV, according to which the pattern of a transient increase in plasma viral load followed by augmented HIV-specific CD8⁺ T-cells and decrease in cell-associated HIV-DNA after ICI treatment was reported in only one patient among 176 participants, although related data were available for fewer than 10% of them (68). Better understanding of the immunopathology during HIV infection and ICI administration and larger cohort studies regarding the use of ICIs in people living with HIV are warranted in order to shed more light on the potential of these antibodies as an additional weapon against HIV infection.

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Figure 1.

Latency reversal and augmentation of HIV-specific CD8⁺ T-cell response through immune checkpoint blockade. Immune checkpoint molecules, such as programmed cell death-1 (PD-1), can inhibit T-cell activation and attenuate viral transcription and RNA translation during HIV infection, establishing one of the mechanisms for HIV latency in CD4⁺ T-cells. Anti-PD-1 treatment can activate these cells and promote viral replication and assembly, uncovering infected CD4⁺ T-cells and leading to the reversal of latency. It may also improve function of HIV-specific CD8⁺ T-cells, through increased secretion of cytokines, such as interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ) which promote antiviral and inflammatory responses, and through enhanced degranulation of perforin and granzymes, which target infected cells and eliminate them in a lytic manner.

John Cunningham virus. John Cunningham virus (JCV) usually remains in a latent phase in the cells of immunocompetent people. However, in the case of disorders of cellular immunity, viral genomic rearrangements can stimulate JCV to cause a potentially lethal central nervous system infection, progressive multifocal leukoencephalopathy (PML). Reversal of the immunocompromised state remains the cornerstone of PML management (69). For over a decade now, it has been clear that PD-1 expression is up-regulated on both CD4⁺ and CD8⁺ T-cells in patients with PML, and that PD-1 blockade enhances JCV-specific T-cell responses in a subset of these patients (70). PD-1 is overexpressed on lymphocytes in blood and in cerebrospinal fluid (71). These observations led to increased scientific interest regarding the use of PD-1 ICI to improve viral clearance in PML. In a small study of eight patients with PML treated with pembrolizumab, five had reduced JCV load, clinical and radiological improvement or stabilization and increased in vitro anti-JCV activity after treatment (71). Pembrolizumab, as a therapeutic strategy in PML, has also been described in many case reports, with encouraging results in some cases (72) and unfavorable in others (73). These controversial outcomes could be associated with several factors, such as time of diagnosis, underlying immunodeficiency, baseline JCV load, severity of neurological deficits before therapy, dose of pembrolizumab and time of treatment initiation. Thus, more well-designed studies are necessary to clarify the role of PD-1 blockade in PML.

Hepatitis B virus. Hepatitis B virus (HBV) enters hepatocytes and releases its DNA, which is converted to a more stable form and is integrated into the host genome in the nucleus, constituting a reservoir for viral replication and establishing chronic infection. Chronic HBV infection remains a major healthcare problem worldwide, with a high risk of progression to cirrhosis and hepatocellular carcinoma (74). PD-1 expression is up-regulated on peripheral and intrahepatic CD8⁺ T-cells during acute HBV infection (75). In chronic infection, HBV-specific CD8⁺ T-cells express high levels of PD-1, CTLA-4, and TIM-3 (43, 76, 77), whereas in CD4⁺ T-cells, only the PD-1 pathway is overexpressed (78). The up-regulation of CTLA-4 has been associated with apoptosis of cytotoxic lymphocytes (78). The ex vivo inhibition of these checkpoint molecules enhances HBV-specific T-cell responses (76-78). Specifically for the in vivo blockade of the PD-1 pathway, a study in woodchuck hepatitis virus-infected animals showed that anti-PD-L1 treatment in combination with entecavir and therapeutic DNA vaccination led to reinvigoration of T-cell function and persistent suppression of woodchuck hepatitis virus replication (79).

In a phase 1/2 clinical trial regarding the use of nivolumab in adults with advanced hepatocellular carcinoma with or without HBV or hepatitis C virus (HCV) infection, a feasible safety profile of this checkpoint inhibitor was demonstrated, with comparable results regarding AEs among patients (80). Furthermore, in virally suppressed patients with chronic HBV infection, nivolumab treatment, with or without HBV therapeutic vaccination, was correlated with a decline in hepatitis B surface antigen (HBsAg) titers in most patients and seroconversion in one patient, in whom maximal T-cell responses were also observed (81). In another study in HBsAg-positive patients on ICIs, 24 patients were evaluated and only one had HBV reactivation, whereas in 15 patients, a decrease in the amount of HBsAg from baseline was shown 48 weeks after treatment (82).

More clinical trials are needed to validate the potential role of ICIs in viral clearance during chronic HBV infection and the possible risk of severe liver inflammation or even fulminant hepatitis, as a result of alterations in immunopathology by these molecules.

Hepatitis C virus. PD-1 expression is significantly elevated on circulating and especially intrahepatic HCV-specific CD8⁺ and CD4⁺ T-cells during acute and chronic HCV infection, leading to T-cell exhaustion (83). This situation is reversible, as in vitro blockade of the PD-1 pathway restores HCV-specific T-cell proliferation and function (84). These data led to an increased interest in examining possible virological effects of ICIs in patients with cancer and HCV infection. Notably, AE rates in patients with untreated or resolved HCV infection treated with ICIs for cancer are comparable to those observed in patients without HCV infection (85).

In a clinical trial of 20 patients with chronic HCV infection who received anti-CTLA-4 treatment for hepatocellular carcinoma, a manageable safety profile, a substantial decline in viral load, and an augmented specific anti-HCV immune response were reported (86). In another, randomized, double-blind, placebo-controlled study, in a cohort of 45 patients with chronic HCV infection treated with a monoclonal antibody to PD-1, HCV RNA reductions were observed in 11.1% of participants who received this treatment (44). Further investigation will provide more information regarding the role of ICIs alone or in combination with antiviral therapy in the treatment of HCV-infected patients.

Other infections. Insufficient data are available regarding a possible positive impact of ICIs on other viral, bacterial, fungal, or parasitic infections. Current evidence, principally based on preclinical models, suggests that immune checkpoint blockade could potentially have a beneficial effect on pathogen clearance and restoration of immune function in several infectious diseases, such as herpes simplex virus 1 (87), CMV (88), influenza A virus (89), malaria (90) and histoplasmosis (91). Regarding clinical data, a case was reported in 2017 of a patient with extensive abdominal mucormycosis who was treated successfully with nivolumab in combination with IFN-γ (92). The design of future clinical trials will offer the possibility to translate the effects of ICIs from animal models to humans.

Sepsis. The definition of sepsis has changed over time and sepsis is now defined as a life-threatening organ failure caused by the host’s inappropriate response to infection (93). Mitigation of sepsis-induced immunosuppression through ICIs might be an additional therapeutic strategy against sepsis, leading to reduced morbidity and mortality (94). Overexpression of PD-1 in CD8⁺ T-cells and concurrent reduced production of IFN-γ and IL-2, as well as up-regulation of PD-L1 expression in monocytes have been observed in blood obtained from patients with sepsis. In vitro blockade of the PD-1/PD-L1 pathway led to reduced apoptosis of these cells and restored immune cell function during sepsis (95). Moreover, in a mouse model, expression of CTLA-4 on CD4⁺, CD8⁺ and regulatory T-cells increased during sepsis. Anti-CTLA-4 treatment reduced sepsis-induced apoptosis of lymphocytes, whereas it had only a minor effect on cytokine production. Lower doses of this treatment were associated with significantly improved survival, although higher doses were correlated with a worsened outcome, indicating that survival of mice with sepsis was a result of a delicate balance between pro- and anti-inflammatory immune responses (96). In a meta-analysis of preclinical studies about ICI therapy in mice with sepsis, a possible benefit was reported, as this treatment generally increased the odds for survival. However, these results must be considered encouraging with caution, as preclinical models have several limitations (97).

In a phase 1, randomized, placebo-controlled, dose-escalation study of anti-PD-L1 therapy in patients with sepsis, ICI administration was well tolerated, there was no indication of cytokine storm, and, at the highest doses, an association with an increase in monocyte human leukocyte antigen DR isotype expression over 28 days was observed, demonstrating a state of increased immune surveillance (98). A multicenter, open-label, phase 1/2 study in Japanese patients with sepsis treated with nivolumab reported an acceptable drug tolerance and an association of length of treatment with an increase in absolute lymphocyte count and level of monocyte human leukocyte antigen DR isotype expression (99). However, in another study of patients with cancer admitted to the intensive care unit, prior ICI therapy did not appear to significantly improve mortality caused by septic shock (100). An individualized approach concerning the time of ICI administration, severity of sepsis, concomitant organ failure, type of bacterial or fungal infection and concurrent antimicrobial use, and larger clinical trials examining these factors, may provide answers to whether ICIs can constitute an adjunctive therapeutic perspective to conventional strategies in sepsis management.

In summary, pre-clinical and clinical data suggest the existence of therapeutic potential of ICIs against some infectious diseases, especially in the case of persistent viral infections, opportunistic infections such as PML, and sepsis. The challenge is that only a subgroup of patients suffering from these infections will probably benefit from this treatment, and individualized therapy is essential. As a result, further clinical studies are required to examine the role of ICIs in the management of infections, in combination with other parameters, such as the time of treatment initiation, dosing, accompanying antimicrobial therapy, the host microbiome, ICI-related AEs, and other comorbidities.