VIRULENCE 2016, VOL. 7, NO. 8, 939–949 http://dx.doi.org/10.1080/21505594.2016.1207038

REVIEW

Immunotherapy for opportunistic infections: Current status and future perspectives €fflerb, Hermann Einseleb, and Markus Kappb €rgen Lo Shigeo Fujia,b, Ju a Department of Haematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan; bDepartment of Internal Medicine II, Division of Hematology/Oncology, University Hospital of W€ urzburg, W€ urzburg, Germany

ABSTRACT

ARTICLE HISTORY

The outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) has significantly improved during the last decades. However, opportunistic infections such as viral and mold infections are still a major obstacle for cure. Within this field, adoptive T cell therapy against pathogens is a promising treatment approach. Recently, the techniques to develop T cell products including pathogen-specific T cells have been sophisticated and are now available in accordance to good manufacturing practice (GMP). Here, we aim to summarize current knowledge about adoptive T cell therapy against viral and mold infections.

Received 6 April 2016 Revised 19 June 2016 Accepted 23 June 2016

Introduction Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is one of the standard treatment modalities for patients with hematological diseases. The clinical outcomes after allo-HSCT have been significantly improved, and the number of allo-HSCT recipients is increasing all over the world because the development of lower intensity conditioning regimen enables allo-HSCT for older patients or patients with pre-existing comorbidities.1 However, treatment-related morbidity and mortality related to infectious diseases such as viral infections, invasive fungal infections, acute/chronic graft-versushost disease (GVHD) and organ failure are still major obstacles.2-4 In the era of allo-HSCT from an alternative donor including unrelated donor, haploidentical related donor and cord blood transplant, management of infectious diseases is still a highly important topic.5,6 Regarding viral and invasive fungal infections, various drugs have been developed.7-9 However, the clinical outcome is still unsatisfactory once overt infections occur after allo-HSCT.8,10,11 In addition, drugs against viral and fungal infections are rather expensive and often associated with significant toxicity. Although primary prophylaxis using drugs might be efficient while drugs are used, it cannot efficiently reduce the risk of late-onset diseases.12,13 Furthermore, resistance against anti-viral or anti-fungal drugs is an emerging problem and could be associated with

CONTACT Shigeo Fuji, M.D. [email protected] Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan. © 2016 Taylor & Francis

KEYWORDS

adoptive immunotherapy; aspergillus; mold infection; viral infection

a high probability of treatment failure.14-20 Therefore, it is attractive if we could be able to induce specific anti-pathogen specific immunity to control the infections after allo-HSCT. In terms of viral infections, it is well established that T cells play an important role.21-30 In terms of mold infections, innate immunity alone was considered important historically in the control of mold infections. However, recent studies found that adaptive immunity, in particular Th1 cells, was relevant in the control of aspergillus infections.31 Thus, adoptive immunotherapy of Th1 cells has a potential to play a major role to prevent/treat them, although clinical development of adoptive immunotherapy against aspergillus infections is still underway in contrast to the remarkable progress in adoptive immunotherapy against viral infections. Here, we aim to summarize current knowledge about adoptive immunotherapy against viral and invasive aspergillus infections.

Immunotherapy against viral infections Importance of T cells against viral infections The reconstitution of functional virus-specific T cells and the importance of these T cells in the control of viral diseases following allo-HSCT has been extensively investigated.32 This led to a successful transfer into the clinical setting within adoptive immunotherapeutic approaches.33

Department of Haematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1,

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In terms of T cell immunity against viruses, most studies were related to cytomegalovirus (CMV), EB virus (EBV) and adenovirus (ADV). In these viruses, CMV is the most intensively studied pathogen.34-36 Lack of T cell immunity against CMV is associated with an increased risk of late onset/recurrent CMV antigenemia and CMV disease.21,23-29 In EBV and ADV infections, importance of T cell immunity against was also reported.37-39 Therefore, if T cell immunity is found to be insufficient in patients with viral reactivation, adoptive immunotherapy to enhance T cell reconstitution could be an option to consider in order to treat or prevent the development of endorgan disease (Fig. 1). Adoptive immunotherapy against viral infections Adoptive T cell immunotherapy against viral infections has been already extensively studied, and now several

methods which are fully adapted to good manufacturing practice (GMP) conditions are available. First, multimers such as tetramer and pentamer can be used to detect and isolate virus-specific T cells. However, they bind to T cells irreversibly, which makes it difficult to dissociate from T cells. On the other hand, streptamer can be easily dissociated from the isolated T cells.40,41 Streptamer was reported to detect as accurate as other multimers.42,43 The purity of CMV-specific T cells using streptamer was reported to be high. Odendahl et al. reported that the median purity of CMV-specific T cells was 90.2% in 22 processes.44 High purity is the strength of this technique considering the risk of GVHD in adoptive T cell therapy. Schmitt et al. reported 2 cases who received streptamer-isolated CMV-specific T cells.45 It was striking that patient 1 received only 2.2 £ 105 cells/kg and the frequency of CMV-specific T cells increased from 0% to a maximum of 27.1% of all

Figure 1. Possible strategy to reduce the risk of recurrent/late-onset viral disease using adoptive T cell therapy. (A) Patients with sufficient immune reconstitution are at low risk of recurrent/late-onset viral disease. (B) Patients with insufficient immune reconstitution are at high risk of recurrent/late-onset viral disease. (C) In patients with insufficient immune reconstitution, adoptive T cell therapy might reduce the risk of recurrent/late-onset viral disease.

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T cells. Patient 2 received much less dose of cells (0.37 £ 105/kg CMV-specific cells) and experienced less expansion of CMV-specific T cells, but successfully achieved the persistent clearance of CMV antigenemia. Another report also showed that streptamer-isolated CMV-specific T cells successfully controlled CMV antigenemia without the development of severe GVHD. The limitation of this technique is that it can be applied to only common HLA types with appropriate virus-derived peptide. Therefore, this technique cannot be useful in patients with rare HLA types. In terms of other virusspecific T cells, it is still under development.46 We need more data about the virus-derived peptides with high avidity for each HLA type which is essential to produce streptamer with high efficacy. Second, IFN-g capture uses the system that enrichment of IFN-g-secreting cells after the stimulation using virus-derived antigens was performed by using the Cytokine Secretion System and the CliniMACS device for immunomagnetic separation (both Miltenyi Biotec, Bergisch Gladbach, Germany). The strength of this method is that it is possible to isolate both CD4C and CD8C T cells, and a detailed information about HLA restriction of peptides is not necessary.47,48 Peggs et al. reported their experiences using IFN-g secretion assay to isolate CMV-specific T cells.49 The isolated products contained a median of 2840 CMV-specific CD4C T cells/kg and 630 CMV-specific CD8C T cells/kg. A median purity of CMV-specific T cells was 43.9%. Expansions of both CD4C and CD8C CMV-specific T cells were observed in vivo within days of adoptive transfer. The expansion of CD8C T cells was more robust than that of CD4C T cells. Feuchtinger et al. also reported the efficacy of CMV-specific T cells which were isolated using IFN-g secretion assay.50 In this study, adoptive T cell therapy was used in patients with CMV disease or viremia refractory to antiviral chemotherapy or both. A mean dose of CMV-specific T cell was 2.1 £ 104/kg. In 83% of cases, CMV infection was improved after adoptive T cell therapy. The purity of the product was around 10%, containing more CD4 T cells. As shown in these 2 reports, the limitation of this method is low purity compared with that using multimer, which might be associated with an increased risk of GVHD after adoptive T cell therapy. The efficacy and safety using this method has been already reported in CMV, ADV and EBV.49-56 As reported using streptamer-isolated T cells, even low-dose of virus-specific T cells isolated by IFN-g capture worked efficiently to eradicate viral infections in these reports. These findings suggest that virus-specific T cells have a high potential to expand in vivo. It can be because these T cell products contain T memory stem cell subset, although the proportion was not necessarily high.57

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Third, of short-term culture, GMP-compliant technique using G-Rex device reported promising results.58,59 The technique used clinical grade peptide mixes for the stimulation and culture for around 10 d.60 Although the purity of virus-specific T cells is expected to be low in this technique, multi-virus specific-T cells can be expanded using various combinations of peptide mix. Fourth, there is also a possibility to use genetically introduced T cell receptor technique. We are able to prepare for variety of TCRs with high avidity against respective HLA molecules with virus-derived peptide.61 Techniques to isolate each peptide-specific T cells might be useful to facilitate the identification and isolation of antigen-specific T cells.62 T cells with genetically engineered TCR would contribute to break a major obstacle in a patient or donor with low frequency of specific T cells. In summary, now fully GMP-compliant techniques to obtain virus-specific T cells are available. Further clinical studies to confirm the safety and efficacy of adoptive T cell therapy against viral infection are warranted.

Immunotherapy against aspergillus infections Importance of immunity against aspergillus infections Although it is well-established that innate immunity plays an important role to prevent and to treat aspergillus infections, recent research showed the importance of adaptive immune responses against aspergillus infections.63 Dendritic cells (DCs) bridge innate and adaptive immunity with DCs having a primary role in surveillance for pathogens. Once DCs acquire Aspergillus antigen and mature, DCs present fungal peptides to CD4C T cells. There is a paucity of data about presentation to CD8C T cells. Adaptive immunity against Aspergillus is mainly mediated by Th1 response. Th1 cells augment the effector functions of innate immune cells via secretion of inflammatory cytokines such as IFN-g and GMCSF. The importance of immune response to Aspergillus is also supported by the strong association of genetic polymorphisms with the risk of invasive aspergillus infection.64 For instance, patients with genetic variants of Dectin-1 or DC-SIGN were reported to have a significantly increased risk of invasive fungal infections.65,66 Several studies using mouse models support the idea that Th1 cells play an important role in the control of Aspergillus. Censi et al. reported that treatment of immunocompetent mice with Aspergillus crude culture filtrate antigens resulted in the development of protective Th1 memory responses, mediated by antigen-specific CD4C T cells producing IFN-g and IL-2.67 Protective

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Th1 responses were not observed in mice deficient of IFN-g or IL-12, suggesting the importance of these cytokines. Ito et al. also reported that prior infection or Aspergillus fumigatus sonicate vaccine protected mice against subsequent lethal invasive pulmonary aspergillosis using a model of invasive pulmonary aspergillosis in corticosteroid-treated mice.68 The group subsequently reported that sera from the vaccinated animals contained antibodies against Asp f3.69 The vaccination of Asp f3 was effective to prevent the subsequent Aspergillus infection in corticosteroid-treated mice. CD4C T cell depletion abrogated the protective effects of vaccination to levels comparable to non-vaccinated mice, which supports the idea that CD4C T cell is critical for the effectiveness of vaccination to prevent Aspergillus infection.70 Bozza et al. reported that vaccination with DCs pulsed with Asp f16 (Crf1) in combination with adjuvant CpG oligodeoxynucleotides for Toll-like receptor priming induced Th1 priming and resistance to Aspergillus infection.71 Later on, the group reported that other proteins such as Pep1, Gel1, Crf1 induced protection against the subsequent Aspergillus infection in similar to the protection by conidia.72 They found that these antigens can activate human Th1 cells. In summary, Th1 cells in the orchestration of other immune cells play critical roles in the prevention of Aspergillus infection in mice models. Presence of T-cell responses against Aspergillus in humans Reports which assessed the importance of T cell responses against Aspergillus in human beings are still limited. One reason is that the frequencies of fungus-specific T cells were significantly lower than those of virus-specific T cells.73 However, in patients with clinical evidence of invasive Aspergillus infections and the regression of invasive aspergillosis (IA), Aspergillus-specific T cells could be detected. Chaudhary et al. also found that Aspergillus antigen could induce T cell responses.74 In their study, Asp f3, Asp f9/16 (Crf1), Asp f11 and Asp f22 elicited relatively high IFN-g production. Hebart et al. reported that water-soluble cellular extract of Aspergillus fumigatus induced a positive lymphoproliferative response using PBMCs from healthy individuals.75 IFN-g was released after the stimulation with Aspergillus fumigatus antigens, indicating a Th1 response. Ramadan et al. found that peptides derived from Crf1 could induce Th1 cell responses in healthy donors.76 Jolink et al. analyzed the T-cell immune responses against Aspergillus fumigatus proteins Crf1 and Catalase 1 in healthy individuals.77 They identified

novel peptides derived from Crf1 and Catalase 1, although the frequency of specific T cells was low in Elispot or flow cytometric analysis. In their study, they used CD137 to isolate T cells which were demonstrated to be IFN-g-producing T cells. Stuehler et al. also demonstrated that the Aspergillus fumigatus proteins Crf1, Gel1, and Pmp20 induced Th1 responses in healthy individuals, and interestingly generated T-cell lines against Aspergillus fumigatus cross-reacted to other Aspergillus species, Mucorales species and Candida albicans.78 In patients with a hematological malignancy who developed invasive Aspergillus infection, there was a favorable response to anti-fungal therapy in patients with a higher IFN-g/interleukin-10 ratio in culture supernatants which suggested the significance of Th1 cells.75 In addition, steroid treatment suppressed the lymphoproliferation and IFN-g secretion after the stimulation with aspergillus antigen. Stuehler et al. also found that a patient with well-controlled IA experienced expansion of Crf1-specific T cells analyzed HLA-DRB104 tetramer.78 Jolink et al. also found that Crf1 and Catalase1-specific T cells were induced after Aspergillus infection improved, but no such specific T cells were detected in patients who died of Aspergillus infection.79 Potenza et al. also demonstrated that the presence of Aspergillus-specific T cells in patients who suffered from IA and the increase of such protective T cells might be associated with a better clinical outcome.80 In summary, aspergillus-specific T cells can be detected in healthy individuals, and in patients with a hematological malignancy, the presence of aspergillusspecific T cells seems to be associated with a favorable clinical outcome. These data supports the idea that adoptive immunotherapy using aspergillus-specific T cells could be a promising option in patients with IA as described below. Adoptive immunotherapy against aspergillus infections In comparison to adoptive T cell therapy against viral infections, there is still a paucity of clinical experiences of adoptive T cell therapy against mold infections. As described above, Th1 cells play an important role in the control of mold infections, although the data is still limited in non-Aspergillus mold infections. Therefore, it would be reasonable to try adoptive T cell therapy against mold infections. To introduce the adoptive immunotherapy against mold infections, it is important to develop technique of clinical-scale generation of human anti-Aspergillus T cells. Such technique should be non-labor intensive and quickly prepared. Beck et al. reported the generation of anti-Aspergillus Th1 cells using the combination of interferon-g secretion assay

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and short term culture (14 days). PBMCs from healthy donors were isolated and coincubated with Aspergillus antigens for 12 hours and Aspergillus-specific T cells were enriched using IFN-g secretion assay. Isolated cells were cultured for up to 14 d. Using this method, it was possible to obtain the enriched T cells with purity around 15% of Aspergillus-specific T cells. Tramsen et al. also reported that the similar technique incorporating IFN-g secretion assay was able to generate Aspergillus-specific T cells according to GMP conditions, although the purity with a median of 5.1% of IFN-g producing cells after the restimulation with Aspergillus antigen could be still unsatisfactory, considering the possible risk of GVHD.81 The low purity reflects the difficulty to use IFN-g secretion assay to isolate T cells with low precursor frequency in healthy donors like Aspergillus-specific T cells. Their group also reported that they isolated multi-specific T cells against Aspergillus fumigatus, Candida albicans and Rhozpus oryzae.82 Such multi-specific T cells are practically attractive as, in many cases, it is difficult to determine the fungal pathogen which caused the infectious diseases. In particular, it is often difficult to distinguish between aspergillus infection and mucor infection. Another method to isolate fungus-specific Th1 cells is the isolation based on activation-dependent expression of CD154.73 CD154 is transiently expressed on CD4 T cells after activation but much less on CD8 T cells. Khanna et al. reported the generation and expansion of Aspergillus Crf1 peptide-specific T cells using this method.73 PBMCs from healthy donors were stimulated with Aspergillus fumigatus Crf1 peptide p41, and antigen-specific T cells were enriched by the selection of CD154C cells via magnetic cell separation. Isolated CD154C cells were cultured for 14 d. Tetramer-staining showed 40% (range, 25-63) of Aspergillus fumigatus p41 peptide-specific CD4C T cells. If DCs can be used in accordance to GMP, it might help to further expand specific T cells.83 Perrucio et al. conducted a study using expanded Aspergillus-specific T cells after haploidentical transplantation in patients with a history of IA.84 In this study, control transplant recipients who did not receive such adoptive transfer tended to suffer from IA and had no detectable reconstitution of Aspergillus-specific T cells after transplantation. On the other hand, patients who received adoptive T cell therapy had significantly higher number of specific T cells against Aspergillus. A recent topic in the field of adoptive T cell therapy is genetically modified T cells expressing chimeric antigen receptors (CAR). To further enhance the effectiveness of adoptive T cell therapy against Aspergillus infection, a study group in the United States developed a system of adoptive transfer of CAR T cells that possess the pattern-

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recognition properties of Dectin-1.85 T cells are electroporated with DNA plasmids from the Sleeping Beauty transposon/transposase system to express this CAR, and expanded with artificial antigen presenting cells in the presence of cytokines.86 Dectin-1 specifically recognizes b-glucans which are expressed on the cell wall of fungi. Their approach is clinically attractive, as T cells can be long-lived as they contained central memory T cells, and can be expanded ex vivo in compliance with GMP for clinical trials. Targeting of other antigens by CAR modified T cells can be applicable to any antigens on the cell surface of fungus for which monoclonal antibody can be generated. The potential benefits of CAR modified T cells could be the high efficiency as demonstrated in the treatment of acute lymphoblastic leukemia. The potential drawbacks could be the life-threatening complications. In clinical trials of CAR modified T cells, on target/off target toxicity have to be carefully monitored.87 It is well known that CAR T cells targeting CD19 caused cytokine release syndrome (CRS).88 Higher disease burden before CAR T therapy was reported to be a risk factor for CRS.89,90 Therefore, when this technique is applied in the treatment of infectious disease, we also have to pay much attention to the disease burden. In the setting of allo-HSCT, if CAR T cells work efficiently, accompanying spread of pathogen-associated molecular patterns (PAMPs) from fungus could aggravate GVHD through the interaction between PAMPs and pathogen recognition receptors [PRRs] such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs).91 The more infection progressed, the more severe the toxicity associated with CAR T would be. In order to prevent the lethal toxicity, the introduction of an inducible “suicide gene” that can be electively activated in the event of severe toxicity is ideal. Techniques used in the setting of adoptive T cell therapy such as herpes simplex virus thymidine kinase (HSV-TK) and human inducible caspase 9 (iCasp9) might be combined in the system of CAR modified T cells.92 We need to investigate the way with which we can improve safety without compromising the potential efficacy of CAR modified T cells.93 If the safety issue is solved, adoptive T cell therapy as prevention of fungal infections might become a realistic treatment strategy in patients at very high risk of fungal infections.94 We could expect that non-modified donor lymphocyte infusion would disappear in the near future, considering the low specificity against the target and substantial risk of GVHD. As adjunctive therapy to target fungal infections as well as augment the effectiveness of adoptive T cell therapy, selection of anti-fungal drugs might be important as these drugs were reported to have impact on the host immune response in vitro.95 For instance, caspofungin

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Figure 2. Possible clinical trial design incorporating adoptive T cell therapy as preemptive therapy or prophylaxis of infectious diseases at high risk of them

can unmask b-glucan residues in the cell wall of fungi which might enhance the effectiveness of administered T cells.96 Fluconazole was reported to induce a protective Th1 response against candidiasis in mice model.97 Such immunomodulatory effects of anti-fungal drugs should be assessed in humans. Drugs which can enhance the effects of administered T cells are to be chosen as a combinatory therapy of adoptive T cell therapy against fungal diseases. In summary, now it is possible to purify and expand Aspergillus-specific T cells according to GMP conditions. The safety and effectiveness of Aspergillus-specific T cells should be tested in clinical trials. Unfortunately, currently there is a paucity of clinical data about adoptive T cell therapy using Aspergillus-specific T cells. Therefore, at first, we need trials of adoptive T cell therapy against refractory fungal infections. If the efficacy and safety are confirmed in the setting, there is a possibility to apply such cell therapy in the setting of prophylaxis of fungal infections.

Conclusion In terms of adoptive T cell therapy against viral infections, promising clinical results have been already reported from various teams. Confirmatory studies to establish the benefit of adoptive T cell therapy are warranted. In terms of adoptive T cell therapy against

invasive aspergillus infections, basic information relating to T cell immunity against Aspergillus has been clarified over the last decades. The safety and effectiveness of adoptive T cell therapy against Aspergillus should be assessed in future clinical trials. If the safety and efficacy of adoptive T cell therapy are demonstrated in the study for patients with refractory infectious diseases, there is a possibility that we could apply such adoptive T cell therapy for prophylaxis of infectious diseases in patients with high risk at infectious diseases (Fig. 2).

Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.

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Immunotherapy for opportunistic infections: Current status and future perspectives.

The outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) has significantly improved during the last decades. However, opportu...
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