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New anticancer therapeutics impact fungal pathobiology, infection dynamics, and outcome

  • Julia R. Palmucci ,

    Roles Conceptualization, Investigation, Project administration, Writing – original draft, Writing – review & editing

    julia.palmucci@duke.edu

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

    ⨯
  • Julia A. Messina,

    Roles Conceptualization, Investigation, Writing – review & editing

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

    ⨯
  • Jennifer L. Tenor,

    Roles Conceptualization, Investigation, Writing – review & editing

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

    ⨯
  • John R. Perfect

    Roles Conceptualization, Resources, Supervision, Writing – review & editing

    julia.palmucci@duke.edu

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

    ⨯

Citation: Palmucci JR, Messina JA, Tenor JL, Perfect JR (2023) New anticancer therapeutics impact fungal pathobiology, infection dynamics, and outcome. PLoS Pathog 19(12): e1011845. https://doi.org/10.1371/journal.ppat.1011845

Editor: Anuradha Chowdhary, Vallabhbhai Patel Chest Institute, INDIA

Published: December 21, 2023

Copyright: © 2023 Palmucci et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by NIH Public Health Service Grants AI73896 (JP) and AI93257 (JP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Fungal infections are significant public health concerns, with an estimated 1 billion cases and 1.6 million deaths per year worldwide [1]. Many life-threatening fungal infections develop in immunocompromised individuals with conditions such as HIV, solid organ transplantation, and cancer. Chemotherapy-induced immune suppression is frequently associated with opportunistic fungal infections, often through drug-induced neutropenia and mucositis [2]. Even new targeted therapeutics, such as Burton’s tyrosine kinase (BTK) inhibitors, have been found to predispose cancer patients to fungal infections. While frustrating to clinicians, researchers can use cases of targeted therapy-associated fungal infections to better understand the complex relationship between the fungal pathogen and human host. Alternately, certain anticancer agents have been found to possess inherent antifungal properties. As eukaryotic diseases, cancer and fungal infections present both challenges and opportunities for novel treatments. Even in an era of targeted and precision medicine, opportunistic fungal infections are likely to remain a major factor affecting patient outcome. There is a continued need to uncover the factors influencing treatment-associated infection susceptibility and to identify potential opportunities for drug repurposing.

How can targeted therapies be used to understand host–pathogen interactions?

Over the past 20 years, small molecule inhibitor and monoclonal antibody (mAb) therapies have revolutionized cancer treatment. Targeted therapies that act upon a specific receptor or signaling molecule were expected to lead to fewer opportunistic infections because they were considered generally less cytotoxic than broadly active chemotherapies [3]. While many early promises of targeted therapeutics have been fulfilled, opportunistic fungal infections continue to emerge among patients undergoing these treatments. In certain cases, in vitro studies and drug mechanism of action have failed to predict fungal susceptibility [4]. Consequently, in 2022, the European Haematology Association released detailed guidelines on antifungal prophylaxis in acute myeloid leukemia patients receiving novel-targeted therapies [5]. The implementation of these guidelines, despite a scarcity of robust clinical studies, indicates the pressing influence of antifungal-targeted therapeutic interactions on patient care.

Targeted therapies also present an opportunity to better understand the dynamics of pathogenesis in the context of human disease and uncover specific pathways and effectors important for pathogen survival within a human host. Here, we describe examples of small molecule inhibitors whose use has furthered our understanding of invasive fungal infections (IFIs). Additional cases are presented in Table 1.

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Table 1. Fungal infections associated with select anticancer-targeted therapeutics.

https://doi.org/10.1371/journal.ppat.1011845.t001

BTK inhibitors

BTK is an important facet in B cell receptor signaling. Upon B cell receptor activation, BTK is phosphorylated and leads to B cell proliferation and survival [39]. Inactivation of the human BTK gene causes the inherited immune disorder, X-linked agammaglobulinemia, in which neither mature B lymphocytes nor their immunoglobulins are produced [39]. BTK gained prominence as a therapeutic target after it was discovered to be expressed by many B cell malignancies and possesses an antiapoptotic function [40]. Ibrutinib is a first-in-class irreversible BTK inhibitor used in the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. While ibrutinib has been groundbreaking in treating CLL and other cancers, enthusiasm was stunted by a growing number of reports of opportunistic fungal infections, particularly of the central nervous system, including meningitis and cerebral abscesses [8,9]. Increased rates of IFIs were not anticipated as patients with X-linked agammaglobulinemia do not demonstrate increased fungal susceptibility [41]. However, several potential mechanisms of increased susceptibility to fungal infections have since been described in literature, including impairments in macrophage, neutrophil, and platelet antifungal activity [42–44].

In laboratory murine models, both BTK knockout mice and mice treated with ibrutinib showed increased susceptibility to pulmonary aspergillosis [45,46]. Study of calcineurin inhibitors highlighted the importance of BTK in innate immune response to Aspergillus fumigatus. In response to phagocytosis of A. fumigatus by macrophages, BTK activates the calcineurin-NFAT pathway and potentiates TNF-α signaling [47]. Inhibition of this pathway leads to an impaired chemokine response and insufficient neutrophil recruitment, allowing the pathogen to avoid clearance. Further work has indicated that ibrutinib specifically blocks phosphorylation of BTK that activates the host inflammatory immune response to A. fumigatus [42]. Ibrutinib has also been found to contribute to aberrant innate immune cell response via the TREM-1 (triggering receptor expressed on myeloid cells) signaling pathway. Ibrutinib inhibits the TREM-1 signal cascade and subsequently abrogates antimicrobial activities, including the respiratory burst response of TREM-1-activated neutrophils [45]. More recently, ibrutinib has highlighted the importance of relatively understudied components of fungal immunity. For instance, platelets have pathogen-detecting capabilities, form granules, and are involved in neutrophil extracellular trap formation [44]. Ibrutinib was found to inhibit platelet activation, granule secretion, and platelet-mediated cell damage against A. fumigatus.

Second-generation BTK inhibitors acalabrutinib and zanubrutinib have since been granted FDA approval and possess greater binding selectivity and fewer off-target effects compared to ibrutinib. While these drugs do not inhibit the interleukin-2-inducible kinase critical for T cell signaling, disseminated fungal infections have still been reported [10]. This suggests that IFI susceptibility is not exclusively a result of off-target effects on T cell response and indicates a greater role of B cell pathways in antifungal immunity. Acalabrutinib, like ibrutinib, was also found to impair antifungal inflammatory responses like M1 macrophage polarization, TNF-α secretion, and neutrophil activation [48,49]. Cumulatively, these inhibitors have been shown to impair the innate immune response through several mechanisms that may lead to a predisposition to IFIs. However, even precise mechanisms may have complex phenotypes. For instance, we have found an association with ibrutinib therapy and disseminated cryptococcosis in human B cell malignancy patients, but precise studies with either BTK-knockout or ibrutinib-treated mice showed no impact on cryptococcosis [50]. Nevertheless, these observations have contributed to a better understanding of complex host–pathogen dynamics and have led to the development of laboratory models for studying fungal–host interactions.

PI3K inhibitors

The phosphoinositide 3-kinase (PI3K) enzyme family is essential for a range of cellular processes and is hyperactive in a variety of cancers. Class I PI3K sits downstream of G protein–coupled receptors and is important for cellular proliferation and differentiation. Specifically, the p110δ subunit is highly expressed in many hematopoietic malignancies and has been shown to have antiapoptotic effects [51]. Idelalisib is a first-in-class inhibitor of this PI3Kδ isoform that selectively binds to the enzyme’s ATP pocket and is currently used in treatments for relapsed CLL [51,52]. Unfortunately, idelalisib causes relatively high rates of neutropenia early in treatment [53]. Clinical studies found that rates of Pneumocystis jirovecii pneumonia (PJP) were significantly higher during treatment, especially when used in combination with other therapies like anti-CD20 mAbs, and several clinical trials were halted due to PJP incidence [54]. PJP prophylaxis has since become standard for patients on idelalisib. There have also been several notable cases of other IFIs reported, including Lomentospora prolificans, disseminated cryptococcosis, pulmonary aspergillosis, and a concurrent infection of PJP and Coccidioides [18–21]. However, the mechanism underpinning fungal infection susceptibility is unknown.

Previous work has shown that PI3K activity, especially via the p110δ subunit targeted by idelalisib, is required for natural killer (NK) cell fungicidal activity against Cryptococcus neoformans by controlling perforin release [55]. The PI3K signaling cascade has also been implicated in epithelial immune response and dendritic cell reactive oxygen species production in response to Candida albicans infections [56,57]. Thus, there remains a need for more in vivo testing to pinpoint specific factors following PI3K inhibitor treatment that contribute to diminished antifungal immunity.

CD-52 monoclonal antibodies

The anti-CD52 antibody, alemtuzumab, is a common treatment for CLL, lymphoma, and autoimmune disorders. CD-52 is expressed on T cells, B cells, and some monocytes, but it is not expressed on stem cells, providing some level of treatment specificity. While the exact mechanism of action is not known, killing of target cells involves complement-induced apoptosis and/or antibody-induced cytotoxicity, leading to a profound T cell lymphopenia [29].

IFIs like PJP, aspergillosis, and cryptococcosis have been associated with alemtuzumab, likely due to the depletion of T cells involved in antifungal immune responses [29,30]. Interestingly, candidiasis is not common in alemtuzumab patients, likely due to the low risk of neutropenia or damage to epithelial cell integrity [29]. Specific research is still needed to understand the risk factors associated with IFI development during alemtuzumab treatment and after exposure, especially concerning the cellular mechanisms that increase susceptibility to non-candidal fungal infections.

Drug repurposing: Can we use cancer therapeutics to fight fungal infections?

The significant burden of IFIs on the global healthcare system is exacerbated by limited safe and rapidly effective antifungals. Current IFI treatment regimens primarily involve just 3 classes of antifungals—the azoles, echinocandins, and polyenes, in addition to the pyrimidine analog flucytosine. While azoles are frequently used, well tolerated, and exhibit broad-spectrum activity, they primarily inhibit growth rather than directly killing the pathogen. Drug resistance is also a concern due to the fungistatic nature of azoles and their widespread use in agriculture [58]. Furthermore, azoles can cause significant drug–drug interactions with anticancer therapeutics by inhibiting the drug-metabolizing enzyme CYP3A4 [59]. Echinocandins have a narrower scope of antifungal activity and are not effective against all fungal pathogens, especially molds. Polyenes, such as amphotericin B, are highly potent but cause significant side effects in the patient. While a new class of antifungals has not been approved in over 2 decades, there are currently several first-in-class antifungals in late-stage clinical trials, which present promising advances for tolerability and drug–drug interactions [60]. However, the limitations of current antifungal therapies highlight the need to explore alternate approaches to combat fungal infections, with emphasis on achieving rapid fungicidal activity.

One potential avenue of exploration that has gained traction is drug repurposing. Drug repurposing can substantially reduce research and development costs as the compounds have already undergone vigorous clinical testing to understand tolerability, off-target effects, and pharmacokinetics [61]. Fundamentally, there is a large overlap between the treatment paradigms for cancer and fungal infections. As both diseases are eukaryotic, therapeutics often target cellular machinery that is conserved between disease and patient, dramatically increasing the risk of off-target effects. Both fields have struggled with drugs that tend to slow growth of their target rather than killing it outright. However, the commonalities of eukaryotes indicate a potential opportunity for repurposing of certain drugs, especially when those targets are conserved across kingdoms. Here, we present an overview of adapted therapeutics or therapeutic strategies that show promise in treating IFIs (summarized in Table 2).

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Table 2. Select immune modulating therapies with reported clinical and laboratory antifungal efficacy.

https://doi.org/10.1371/journal.ppat.1011845.t002

The story of flucytosine (5-FC) sets a precedent for adapting antitumor compounds to treat fungal infections. 5-FC, a pyrimidine analog, was originally synthesized in 1957, as an antitumor compound [81]. Cellular metabolism of 5-FC produces a toxic nucleotide that interferes with DNA, RNA, and protein synthesis. 5-FC quickly showed potent antifungal activity, but the rapid development of resistance hindered its use as a monotherapy. Currently, it is used in conjunction with amphotericin B to treat cryptococcal meningitis and Candida infections [81]. The success of 5-FC in treating systemic yeast infections highlights the need to broaden therapeutic testing parameters so potential novel treatments in a different class are not overlooked or ignored.

Nivolumab

Nivolumab is a human immunoglobulin G4 antibody that acts as an immune checkpoint inhibitor by targeting the T cell programmed death receptor 1 (PD-1). Tumor cells produce PD-1 and PD-2 ligands, which reduce T cell functionality and promote antigen tolerance and immune evasion [82]. Nivolumab binds the PD-1 receptor to block ligand binding, which leads to a recapitulation of the T cell immune response and an increase in effector T cell proliferation [82].

In the context of infection, sepsis-induced T cell exhaustion is caused by PD-1 and PD-2 ligand up-regulation [66]. To date, nivolumab has been used to treat 1 patient with fusariosis and several patients with mucormycosis—including 3 patients with mixed or coinfections with other fungal and bacterial pathogens [63–65,68,70]. Combination therapy of nivolumab and interferon gamma (IFN-γ) has been reported to reverse immune suppression during fungal and bacterial sepsis by boosting lymphocyte count, monocyte activation, and CD8+ T cells [65,70]. This treatment approach has gathered enthusiasm following the emergence of Coronavirus Disease 2019 (COVID-19)-associated mucormycosis [64]. No case reports have described negative immune consequences in response to treatment, such as cytokine release syndrome.

Data from murine models of histoplasmosis first uncovered mechanistic interactions between the PD-1 receptor pathway and antifungal immunity and served as proof-of-concept that treatment with an anti-PD-1 antibody may lead to enhanced survival during fungal infections [69]. Further work has shown that candidemia, like bacterial sepsis, appears to suppress immune function through T cell exhaustion [83]. Treatment with anti-PD-1 or anti-PD-1-ligand antibodies lead to improved survival in mouse models of systemic C. albicans infection [66]. Similarly, anti-PD-1 monoclonal antibody treatment was found to increase survival during murine models of C. neoformans pulmonary infection, aspergillosis, and mucormycosis [62,67,71]. Taken together, this clinical and early laboratory data indicate that nivolumab, especially in concert with other immune-stimulating therapies like IFN-γ, present a promising avenue for the treatment of intractable mold infections.

Other targeted therapies

There have been other sporadic reports that some antitumor compounds have inherent antifungal activity or may enhance antifungal drug efficacy. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is an immune checkpoint expressed on NK cells and cytotoxic and regulatory T cells [84]. TIGIT-bound C. albicans can inhibit NK cell activity and immune recognition, and treatment with an anti-TIGIT antibody improved survival in a candidiasis mouse model [72]. A derivative of the cyclooxygenase 2 inhibitor celecoxib, AR-12, was found to have broad-spectrum antifungal activity. AR-12 synergized with azoles and echinocandins against Candida and potentiated the effect of fluconazole against C. neoformans in a systemic murine model [73]. The receptor tyrosine kinase inhibitor, ponatinib, has broad-spectrum antifungal activity in vitro and suppresses the development of azole resistance in Candida through targeting of the proton pump, Pma1 [74]. While these compounds are a long way from use in clinical trials, their activity highlights the discovery potential within the field of cancer therapeutics. However, it will be necessary to develop better evaluation systems beyond ad hoc testing to maximize data generation and scientific benefit.

Immunotherapy

IFN-γ limits tumor growth and may stimulate antitumor immunity [85]. It has been the topic of multiple clinical trials, both as a monotherapy and more recently as an adjunctive therapy. While there are toxicity concerns, IFN-γ has shown clinical promise for ovarian and bladder cancers [86–88]. IFN-γ has also been pursued as an infectious disease treatment because of its immune-stimulating action. Specifically, IFN-γ has been successfully used in combination with nivolumab as an adjunctive immunotherapy for intractable mold infections, and in patients with a poor prognosis due to an underlying condition such as immunosuppression or severe trauma [64,65,70,75–77]. IFN-γ in the treatment of IFIs has begun to be systematically evaluated. A case series of IFN-γ treatment in combination with standard antifungals was found to reestablish immune function in patients with systemic Candida or Aspergillus infections and potentially improve outcomes in cryptococcal meningitis [78–80].

These effects have begun to be mechanistically interrogated using animal models. An inability to increase IFN-γ expression was associated with significantly higher mortality, while higher expression of IFN-γ was shown to stimulate a Th-1 antifungal immune response and increase fungal clearance during murine models of aspergillosis, pulmonary mucormycosis, and cryptococcosis, respectively [89–91]. While the intracellular mechanisms of IFN-γ treatment for IFIs remain unclear, it is apparent that the immunotherapy presents an exciting potential as an adjunctive therapy for severe fungal infections.

Radioimmunotherapy

Targeted radioimmunotherapy (RIT) is a treatment in which lethal doses of radiation are delivered to a specific location via the binding of a radioisotope to an antibody. RIT is most frequently used for hematological malignancies like non-Hodgkin lymphoma due to the specificity of antigen presentation on target cell lines [92]. RIT presents a promising avenue for future therapeutic development for infectious diseases due to the specificity of antigen–antibody interactions and the lethal dose of radiation administered, which prevents the emergence of drug resistance [93].

RIT using a bismuth-213 antibody against C. neoformans glucuronoxylomannan was found to be superior to the standard treatment, amphotericin B, during early systemic C. neoformans infection in mice [94]. There is a concerted effort to identify antigen targets shared across fungal pathogens (“pan-antigens”) for the development of multipurpose mAbs for RIT [93]. A mAb targeting β-(1,3)-glucan has shown activity in vitro against C. neoformans, C. albicans, and Blastomyces dermatitidis [95,96]. Recently, safety studies on the bismuth-213 antibody against β-(1,3)-glucan in dogs reported no negative short- or long-term side effects, and the treatment will now move into trials for use in veterinary medicine [97].

The effect of RIT on IFIs may not result from irradiation, alone. In vitro work showed that low-dose radiation did not inhibit growth of Candida or Cryptococcus species, but fungal burden was substantially reduced in irradiated mice infected with Candida or Cryptococcus [98]. Another study found that a bismuth-213 antibody against C. neoformans glucuronoxylomannan not only promoted apoptosis-like cell death but also enhanced the fungicidal activity of macrophages in vitro [99]. More recently, it has been noted that no patients who received low-dose radiation therapy for COVID-19 developed mucormycosis [100]. While there are no modern reports of RIT against IFIs in the clinic, the increased incidence of mucormycosis during the COVID-19 pandemic has returned focus to this strategy for development moving forward.

What’s next?

As of July 2023, there are 72 protein kinase inhibitors in Phase III clinical trials [101]. As Chamilos and colleagues highlighted, there is a need to develop systemic analyses of the immunosuppressive potential of small molecule inhibitors in the preclinical research stages [7]. This work could better inform clinicians on potential negative patient outcomes and ultimately benefit the cancer, immunotherapy, and fungal research communities. While targeted therapeutic development presents tremendous opportunity for a variety of diseases including cancer and autoimmune disorders, the rapid development of this treatment strategy ensures that fungal infections will continue to be an important facet in clinical outcomes. Several novel antifungals currently in development including the novel triazole opelconazole and the echinocandin rezafungin show promise for prophylactic use in transplant patients [102]. However, further research is acutely necessary to evaluate these compounds for use in concert with targeted therapeutics. In summation, the development of fungal infections during treatment courses with targeted regimens has the potential to deepen our understanding of fungal immunity, uncover the consequences of direct or off-target effects on both host and pathogen, and provide insight into future treatment and management of fungal infections

References

  1. 1. Bongomin F, Gago S, Oladele RO, Denning DW. Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision. J Fungi. 2017;3(4). pmid:29371573
  2. 2. Bhatt V, Saleem A. Review: Drug-Induced Neutropenia-Pathophysiology, Clinical Features, and Management. Ann Clin Lab Sci. 2004;34(2):131–137. pmid:15228223
  3. 3. Sun C, Tian X, Lee YS, Gunti S, Lipsky A, Herman SEM, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015;126(19):2213–2219. pmid:26337493
  4. 4. Davis JS, Ferreira D, Paige E, Gedye C, Boyle M. Infectious complications of biological and small molecule targeted immunomodulatory therapies. Clin Microbiol Rev. 2020;33(3):e00035–19. pmid:32522746
  5. 5. Stemler J, de Jonge N, Skoetz N, Sinkó J, Brüggemann RJ, Busca A, et al. Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association. Lancet Haematol. 2022;9(5):e361–e373. pmid:35483397
  6. 6. Fang H, Harris S, Liu Z, Thakkar S, Yang J, Ingle T, et al. FDALabel for drug repurposing studies and beyond. Nat Biotechnol. 2020;38(12):1378–1379. pmid:33235392
  7. 7. Chamilos G, Lionakis MS, Kontoyiannis DP. Call for Action: Invasive Fungal Infections Associated with Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin Infect Dis. 2018;66(1):140–148. pmid:29029010
  8. 8. Ruchlemer R, Ben-Ami R, Bar-Meir M, Brown JR, Malphettes M, Mous R, et al. Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study. Mycoses. 2019;62(12):1140–1147. pmid:31520441
  9. 9. Eichenberger EM, Saullo J, Brander D, Wang SH, Perfect JR, Messina JA. A case of CNS aspergillosis in a patient with chronic lymphocytic leukemia on first-line ibrutinib therapy. Med Mycol Case Rep. 2020;27:17–21. pmid:31879587
  10. 10. Byrd JC, Wierda WG, Schuh A, Devereux S, Chaves JM, Brown JR, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: Updated phase 2 results. Blood. 2020;135(15):1204–1213. pmid:31876911
  11. 11. Alkharabsheh O, Alsayed A, Morlote DM, Mehta A. Cerebral invasive aspergillosis in a case of chronic lymphocytic leukemia with bruton tyrosine kinase inhibitor. Curr Oncol. 2021;28(1):837–841. pmid:33567487
  12. 12. Byrd JC, Woyach JA, Furman RR, Martin P, O’Brien S, Brown JR, et al. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021;137(24):3327–3338. pmid:33786588
  13. 13. Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021;39(31):3441–3452. pmid:34310172
  14. 14. Tam CS, Dimopoulos M, Garcia-Sanz R, Trotman J, Opat S, Roberts AW, et al., editors. Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies. Blood Adv. 2022;6(4):1296–1308.
  15. 15. Walsh M, Xu A, Ballas Z, Sanchez R. Disseminated fungal infection in a patient receiving zanubrutinib. Clin Case Rep. 2023;11(6):e7564. pmid:37323284
  16. 16. Gold JAW, Tolu SS, Chiller T, Benedict K, Jackson BR. Incidence of Invasive Fungal Infections in Patients Initiating Ibrutinib and Other Small Molecule Kinase Inhibitors-United States, July 2016-June 2019. Clin Infect Dis. 2022;75(2):334–337. pmid:34893821
  17. 17. Cattaneo C, Marchesi F, Terrenato I, Bonuomo V, Fracchiolla NS, Delia M, et al. High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study. J Fungi. 2022;8(6):583. pmid:35736066
  18. 18. Tey A, Mohan B, Cheah R, Dendle C, Gregory G. Disseminated Lomentospora prolificans infection in a patient on idelalisib-rituximab therapy for relapsed chronic lymphocytic leukaemia. Ann Hematol. 2020;99:2455–2456. pmid:32451706
  19. 19. Hengeveld PJ, de Jongh E, Westerweel PE, Levin MD. Disseminated cryptococcal disease during treatment with idelalisib and corticosteroids for follicular lymphoma. BMJ Case Rep. 2020;13(7). pmid:32624488
  20. 20. Lafon-Desmurs B, Monsel G, Leblond V, Papo M, Caumes E, Fekkar A, et al. Aspergillose disséminée et tuberculose pulmonaire chez une patiente traitée par idelalisib pour une leucémie lymphoïde chronique. Med Mal Infect. 2017;47(4):293–296. pmid:27818019
  21. 21. Ward LM, Peluso MJ, Budak JZ, Elicker BM, Chin-Hong PV, Lampiris H, et al. Opportunistic coinfection with Pneumocystis jirovecii and Coccidioides immitis associated with idelalisib treatment in a patient with chronic lymphocytic leukaemia. BMJ Case Rep. 2020;13(4). pmid:32354764
  22. 22. Zinzani P, Dreyling M, Patnaik A, Morschhauser F, Benson A, Genvresse I, et al. Integrated safety data with Copanlisib monotherapy from Phase I and II trials in patients with relapsed indolent Non-Hodgkin’s lymphoma. Hematol Oncol. 2017;35:269.
  23. 23. Cheson BD, O’Brien S, Ewer MS, Goncalves MD, Farooki A, Lenz G, et al. Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas. Clin Lymphoma Myeloma Leuk. 2019;19(3):135–141. pmid:30584024
  24. 24. Flinn IW, Patel M, Oki Y, Horwitz S, Foss FF, Allen K, et al. Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. Am J Hematol. 2018;93(11):1311–1317. pmid:30033575
  25. 25. Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, et al. The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446–2455. pmid:30287523
  26. 26. Jiang X, Mei X, Feng D, Wang X. Prophylaxis and treatment of Pneumocystis jiroveci pneumonia in lymphoma patients subjected to rituximab-contained therapy: A systemic review and meta-analysis. PLoS ONE. 2015;10(4):e0122171. pmid:25909634
  27. 27. Stabler S, Giovannelli J, Launay D, Cotteau-Leroy A, Heusele M, Lefèvre G, et al. Serious Infectious Events and Immunoglobulin Replacement Therapy in Patients with Autoimmune Disease Receiving Rituximab: A Retrospective Cohort Study. Clin Infect Dis. 2021;72(5):727–737. pmid:32067031
  28. 28. Tse E, Leung RYY, Kwong YL. Invasive fungal infections after obinutuzumab monotherapy for refractory chronic lymphocytic leukemia. Ann Hematol. 2015;94:165–167. pmid:24879095
  29. 29. Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol. 2006;132(1):3–12. pmid:16371014
  30. 30. Ruiz-Camps I, Aguilar-Company J. Risk of infection associated with targeted therapies for solid organ and hematological malignancies. Ther Adv Infect Dis. 2021:8. pmid:33680453
  31. 31. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood. 2002;99(10):3554–3561. pmid:11986207
  32. 32. Dilhuydy MS, Jouary T, Demeaux H, Ravaud A. Cutaneous cryptococcosis with alemtuzumab in a patient treated for chronic lymphocytic leukaemia. Br J Haematol. 2007;137(6):490. pmid:17425643
  33. 33. Haidar G, Dorritie K, Farah R, Bogdanovich T, Nguyen MH, Samanta P. Invasive mold infections after chimeric antigen receptor-modified t-cell therapy: A case series, review of the literature, and implications for prophylaxis. Clin Infect Dis. 2020;71(3):672–676. pmid:31756246
  34. 34. Bernardes M, Hohl TM. Fungal Infections Associated With the Use of Novel Immunotherapeutic Agents. Curr Clin Microbiol Rep. 2020;7:142–149. pmid:34336548
  35. 35. Maschmeyer G, De Greef J, Mellinghoff SC, Nosari A, Thiebaut-Bertrand A, Bergeron A, et al. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL). Leukemia. 2019;33:844–862. pmid:30700842
  36. 36. Arriola E, Wheater M, Krishnan R, Smart J, Foria V, Ottensmeier C. Immunosuppression for ipilimumab-related toxicity can cause pneumocystis pneumonia but spare antitumor immune control. OncoImmunology. 2015;4(10). pmid:26451305
  37. 37. Del Castillo M, Romero FA, Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63(11):1490–1493. pmid:27501841
  38. 38. Stewart AG, Henden AS. Infectious complications of CAR T-cell therapy: a clinical update. Ther Adv Infect Dis. 2021;8:20499361211036773. Epub 20210824. pmid:34457269; PubMed Central PMCID: PMC8388233.
  39. 39. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14:219–232. pmid:24658273
  40. 40. Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton’s tyrosine kinase (BTK), LFM-A13 [α-cyano-β-hydroxy-β-methyl-N- (2,5-dibromophenyl)propenamide. J Biol Chem. 1999;274(14):9587–9599. pmid:10092645
  41. 41. Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol. 2021:9. pmid:33777941
  42. 42. Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132(18):1985–1988. pmid:30021784
  43. 43. Blez D, Blaize M, Soussain C, Boissonnas A, Meghraoui-Kheddar A, Menezes N, et al. Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus. Haematologica. 2020;105(2):478–489. pmid:31171644
  44. 44. Nasillo V, Lagreca I, Vallerini D, Barozzi P, Riva G, Maccaferri M, et al. BTK Inhibitors Impair Platelet-Mediated Antifungal Activity. Cell. 2022;11(6). pmid:35326454
  45. 45. Stadler N, Hasibeder A, Lopez PA, Teschner D, Desuki A, Kriege O, et al. The bruton tyrosine kinase inhibitor ibrutinib abrogates triggering receptor on myeloid cells 1-mediated neutrophil activation. Haematologica. 2017;102(5):e191–e194. pmid:28126969
  46. 46. Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell. 2017;31(6):833–43.e5. pmid:28552327
  47. 47. Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, et al. Phagocytosis-dependent activation of a TLR 9– BTK–calcineurin–NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med. 2015;7(3):240–258. pmid:25637383
  48. 48. Colado A, Marín Franco JL, Elías EE, Amondarain M, Vergara Rubio M, Sarapura Martínez V, et al. Second generation BTK inhibitors impair the anti-fungal response of macrophages and neutrophils. Am J Hematol. 2020;95:E174–E178. pmid:32267009
  49. 49. Fiorcari S, Maffei R, Vallerini D, Scarfò L, Barozzi P, Maccaferri M, et al. BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia. Front Immunol. 2020:11. pmid:32983178
  50. 50. Messina JA, Giamberardino CD, Tenor JL, Toffaletti DL, Schell WA, Asfaw YG, et al. Susceptibility to Cryptococcus neoformans Infection with Bruton’s Tyrosine Kinase Inhibition. Infect Immun. 2023:e0004223. pmid:37404186
  51. 51. Yang Q, Modi P, Newcomb T, Quéva C, Gandhi V. Idelalisib: First-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res. 2015;21(7):1537–1542. pmid:25670221
  52. 52. Cheah CY, Fowler NH. Idelalisib in the management of lymphoma. Blood. 2016;128(3):331–336. pmid:27252232
  53. 53. De Weerdt I, Koopmans SM, Kater AP, Van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: A practical approach. Haematologica. 2017;102(10):1629–1639. pmid:28775119
  54. 54. Little JS, Weiss ZF, Hammond SP. Invasive fungal infections and targeted therapies in hematological malignancies. J Fungi. 2021:7. pmid:34947040
  55. 55. Wiseman JCD, Ma LL, Marr KJ, Jones GJ, Mody CH. Perforin-Dependent Cryptococcal Microbicidal Activity in NK Cells Requires PI3K-Dependent ERK1/2 Signaling. J Immunol. 2007;178(10):6456–6464. pmid:17475875
  56. 56. Moyes DL, Shen C, Murciano C, Runglall M, Richardson JP, Arno M, et al. Protection against epithelial damage during Candida albicans infection is mediated by PI3K/Akt and mammalian target of rapamycin signaling. J Infect Dis. 2014;209(11):1816–1826. pmid:24357630
  57. 57. Blanco-Menéndez N, del Fresno C, Fernandes S, Calvo E, Conde-Garrosa R, Kerr WG, et al. SHIP-1 Couples to the Dectin-1 hemITAM and Selectively Modulates Reactive Oxygen Species Production in Dendritic Cells in Response to Candida albicans. J Immunol. 2015;195(9):4466–4478. pmid:26416276
  58. 58. Zavrel M, Esquivel BD, White TC. The ins and outs of azole antifungal drug resistance: Molecular mechanisms of transport. Handbook of Antimicrobial Resistance. New York: Springer. 2017. p. 423–452.
    • 59. Molenaar-Kuijsten L, Van Balen DEM, Beijnen JH, Steeghs N, Huitema ADR. A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs. Front Pharmacol. 2021:12. pmid:34526892
    • 60. Hoenigl M, Sprute R, Egger M, Arastehfar A, Cornely OA, Krause R, et al. The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs. 2021;81(15):1703–1729. pmid:34626339
    • 61. Ashburn TT, Thor KB. Drug repositioning: Identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673–683. pmid:15286734
    • 62. Wurster S, Robinson P, Albert ND, Tarrand JJ, Goff M, Swamydas M, et al. Protective activity of programmed cell death protein 1 blockade and synergy with caspofungin in a murine invasive pulmonary aspergillosis model. J Infect Dis. 2020;222(6):989–994. pmid:32432714
    • 63. Banck JC, Mueller N, Mellinghoff SC, Thelen M, Fraccaroli A, Blumenberg V, et al. Immune Checkpoint Blockade for Aspergillosis and Mucormycosis Coinfection. HemaSphere. 2021;5(3). pmid:33604513
    • 64. Serris A, Ouedrani A, Uhel F, Gazzano M, Bedarida V, Rouzaud C, et al. Case Report: Immune Checkpoint Blockade Plus Interferon-Γ Add-On Antifungal Therapy in the Treatment of Refractory Covid-Associated Pulmonary Aspergillosis and Cerebral Mucormycosis. Front Immunol. 2022:13. pmid:35720319
    • 65. Lukaszewicz AC, Venet F, Boibieux A, Lherm M, Devigne B, Monneret G. Nivolumab and interferon-γ rescue therapy to control mixed mould and bacterial superinfection after necrotizing fasciitis and septic shock. Med Mycol Case Rep. 2022;37:19–22. pmid:35770129
    • 66. Chang KC, Burnham CA, Compton SM, Rasche DP, Mazuski RJ, SmcDonough J, et al. Blockade ofthe negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care. 2013;17(3). pmid:23663657
    • 67. Roussey JA, Viglianti SP, Teitz-Tennenbaum S, Olszewski MA, Osterholzer JJ. Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice. J Immunol. 2017;199(10):3535–3546. pmid:29038249
    • 68. Khatamzas E, Mellinghoff SC, Thelen M, Schlößer HA, Kunz W, Buerkle C, et al. Nivolumab induces long-term remission in a patient with fusariosis. Eur J Cancer. 2022;173:91–94. pmid:35863109
    • 69. Lázár-Molnár E, Gácser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD. The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci. 2008;105(7):2658–2663. pmid:18268348
    • 70. Grimaldi D, Pradier O, Hotchkiss RS, Vincent JL. Nivolumab plus interferon-γ in the treatment of intractable mucormycosis. Lancet Infect Dis. 2017:17. pmid:27998559
    • 71. Wurster S, Albert ND, Bharadwaj U, Kasembeli MM, Tarrand JJ, Daver N, et al. Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis. Front Immunol. 2022:13. pmid:35251033
    • 72. Charpak-Amikam Y, Lapidus T, Isaacson B, Duev-Cohen A, Levinson T, Elbaz A, et al. Candida albicans evades NK cell elimination via binding of Agglutinin-Like Sequence proteins to the checkpoint receptor TIGIT. Nat Commun. 2022;13(1). pmid:35513379
    • 73. Koselny K, Green J, DiDone L, Halterman JP, Fothergill AW, Wiederhold NP, et al. The celecoxib derivative AR-12 has broad-spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis. Antimicrob Agents Chemother. 2016;60(12):7115–7127. pmid:27645246
    • 74. Liu L, Jiang T, Zhou J, Mei Y, Li J, Tan J, et al. Repurposing the FDA-approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species. J Microbial Biotechnol. 2022;15(2):482–498. pmid:33955652
    • 75. Armstrong-James D, Teo IA, Shrivastava S, Petrou MA, Taube D, Dorling A, et al. Exogenous interferon-γ immunotherapy for invasive fungal infections in kidney transplant patients. Am J Transplant. 2010;10(8):1796–1803. pmid:20353472
    • 76. Dignani MC, Rex JH, Chan KW, Dow G, DeMagalhaes-Silverman M, Maddox AM, et al. Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia. Cancer. 2005;104(1):199–204. pmid:15929126
    • 77. Tawfik DM, Dereux C, Tremblay JA, Boibieux A, Braye F, Cazauran JB, et al. Interferon gamma as an immune modulating adjunct therapy for invasive mucormycosis after severe burn–A case report. Front Immunol. 2022;13:4603. pmid:36072605
    • 78. Delsing CE, Gresnigt MS, Leentjens J, Preijers F, Frager FA, Kox M, et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: A case series. BMC Infect Dis. 2014;14(1). pmid:24669841
    • 79. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, et al. Recombinant Interferon-γlb as Adjunctive Therapy for AIDS-Related Acute Cryptococcal Meningitis. J Infect Dis. 2004;189(12):2185–2191. pmid:15181565
    • 80. Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, Williams A, et al. Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS. 2012;26(9):1105–1113. pmid:22421244; PubMed Central PMCID: PMC3640254.
    • 81. Delma FZ, Al-Hatmi AMS, Brüggemann RJM, Melchers WJG, de Hoog S, Verweij PE, et al. Molecular mechanisms of 5-fluorocytosine resistance in yeasts and filamentous fungi. J Fungi. 2021;7(11). pmid:34829198
    • 82. Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2(9):846–856. pmid:24872026
    • 83. Spec A, Shindo Y, Burnham CAD, Wilson S, Ablordeppey EA, Beiter ER, et al. T cells from patients with Candida sepsis display a suppressive immunophenotype. Crit Care. 2016;20(1). pmid:26786705
    • 84. Rotte A, Sahasranaman S, Budha N. Targeting tigit for immunotherapy of cancer: Update on clinical development. Biomedicine. 2021;9(9). pmid:34572463
    • 85. Ni L, Lu J. Interferon gamma in cancer immunotherapy. Cancer Med. 2018;7(9):4509–4516. pmid:30039553
    • 86. Gocher AM, Workman CJ, Vignali DAA. Interferon-γ: teammate or opponent in the tumour microenvironment? Nat Rev Immunol. 2022;22:158–172. pmid:34155388
    • 87. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, Kainz C, Lahodny J, et al. Interferon-gamma in the first-line therapy of ovarian cancer: A randomized phase III trial. Br J Cancer. 2000;82(6):1138–1144. pmid:10735496
    • 88. Giannopoulos A, Constantinides C, Fokaeas E, Stravodimos C, Giannopoulou M, Kyroudi A, et al. The Immunomodulating Effect of Interferon-γ Intravesical Instillations in Preventing Bladder Cancer Recurrence. Clin Cancer Res. 2003;9(15):5550–5558.
    • 89. Armstrong-James DPH, Turnbull SA, Teo L, Stark J, Rogers NJ, Rogers TRF, et al. Impaired interferon-γ responses, increased interleukin-17 expression, and a tumor necrosis factor-α transcriptional program in invasive aspergillosis. J Infect Dis. 2009;200(8):1341–1351. pmid:19754306
    • 90. dos Santos AR, Fraga-Silva TF, de Fátima Almeida-Donamzam D, dos Santos RF, Finato AC, Soares CT, et al. IFN-γ Mediated Signaling Improves Fungal Clearance in Experimental Pulmonary Mucormycosis. Mycopathologia. 2022;187(1):15–30. pmid:34716549
    • 91. Wormley FL, Perfect JR, Steele C, Cox GM. Protection against cryptococcosis by using a murine gamma interferon-producing Cryptococcus neoformans strain. Infect Immun. 2007;75(3):1453–1462. pmid:17210668
    • 92. Larson SM, Carrasquillo JA, Cheung NKV, Press OW. Radioimmunotherapy of human tumours. Nat Rev Cancer. 2015;15:347–360. pmid:25998714
    • 93. Nosanchuk JD, Dadachova E. Radioimmunotherapy of fungal diseases: The therapeutic potential of cytocidal radiation delivered by antibody targeting fungal cell surface antigens. Front Microbiol. 2012;2(JAN). pmid:22275913
    • 94. Bryan RA, Jiang Z, Howell RC, Morgenstern A, Bruchertseifer F, Casadeval A, et al. Radioimmunotherapy is more effective than antifungal treatment in experimental Cryptococcal Infection. J Infect Dis. 2010;202(4):633–637. pmid:20594103
    • 95. Bryan RA, Guimaraes AJ, Hopcraft S, Jiang Z, Bonilla K, Morgenstern A, et al. Toward developing a universal treatment for fungal disease using radioimmunotherapy targeting common fungal antigens. Mycopathologia. 2012;173(5–6):463–471. pmid:22048869
    • 96. Helal M, Allen KJH, van Dijk B, Nosanchuk JD, Snead E, Dadachova E. Radioimmunotherapy of Blastomycosis in a Mouse Model With a (1→3)-β-Glucans Targeting Antibody. Front Microbiol. 2020:11. pmid:32117166
    • 97. Helal M, Allen KJH, Burgess H, Jiao R, Malo ME, Hutcheson M, et al. Safety evaluation of an alpha-emitter bismuth-213 labeled antibody to (1→3)-β-glucan in healthy dogs as a prelude for a trial in companion dogs with invasive fungal infections. Molecules. 2020;25(16). pmid:32784359
    • 98. Ben-Yosef R, Zeira M, Polacheck I. The effect of radiation therapy on fungal growth: Results of in vitro and in vivo studies. J Infect. 2005;50(5):450–452. pmid:15907555
    • 99. Dadachova E, Bryan RA, Apostolidis C, Morgenstern A, Zhang T, Moadel T, et al. Interaction of radiolabeled antibodies with fungal cells and components of the immune system in vitro and during radioimmunotherapy for experimental fungal infection. J Infect Dis. 2006;193(10):1427–1436. pmid:16619191
    • 100. Sharma D, Welsh J, Kumar R. Can low-dose radiation therapy reduce the risk of mucormycosis in COVID-19 patients? J Cancer Res Ther. 2021:1294–1296. pmid:34916356
    • 101. Carles F, Bourg S, Meyer C, Bonnet P. PKIDB: A curated, annotated and updated database of protein kinase inhibitors in clinical trials. Molecules. 2018;23(908). pmid:29662024
    • 102. Stemler J, Mellinghoff SC, Khodamoradi Y, Sprute R, Classen AY, Zapke SE, et al. Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). J Antimicrob Chemother. 2023;78(8):1813–1826. pmid:37311136