Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis

Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis CNS Drugs (2018) 32:401–410 https://doi.org/10.1007/s40263-018-0518-4 LEADING ARTICLE Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis 1,2 2 Barbara Willekens Nathalie Cools Published online: 14 May 2018 The Author(s) 2018 Abstract Multiple sclerosis (MS) is a chronic immune- vaccination. Failures, successes and future directions are mediated disease of the central nervous system (CNS) discussed. characterized by neuroinflammation, neurodegeneration and impaired repair mechanisms that lead to neurological disability. The crux of MS is the patient’s own immune Key Points cells attacking self-antigens in the CNS, namely the myelin sheath that protects nerve cells of the brain and spinal cord. Theoretically, antigen-specific therapeutic Restoring antigen-specific tolerance via therapeutic vacci- vaccination is designed to specifically restore nation is an innovative and exciting approach in MS ther- tolerance to self. In doing so, disease-associated apy. Indeed, leveraging the body’s attempt to prevent pathways are accurately targeted without causing autoimmunity, i.e., tolerization, focuses on the underlying general immunosuppression. cause of the disease and could be the key to solving neu- Several experimental approaches have reached the roinflammation. In this perspective, antigen-specific vac- clinical development phase. Safety and feasibility cination targets only the detrimental and aberrant immune have been demonstrated in several phase I/II trials. response against the specific disease-associated anti- gen(s) involved while retaining the capacity of the immune It can be envisaged that antigen-specific therapeutic system to respond to unrelated antigens. We review the vaccination will prove to be highly relevant, experimental approaches of tolerance-inducing vaccination especially early in the disease when epitope in relapsing and progressive forms of MS that have reached spreading has not yet occurred. the clinical development phase, including vaccination with autologous T cells, autologous tolerogenic dendritic cells, T cell receptor peptide vaccination, altered peptide ligand, ATX-MS-1467, cluster of differentiation (CD)-206-tar- geted liposomal myelin basic protein peptides and DNA 1 Introduction Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) driven by immune- & Nathalie Cools mediated damage of the myelin sheath. This results in Nathalie.cools@uza.be axonal loss and neurodegeneration that lead to neurological Department of Neurology, Antwerp University Hospital, disability [1–3]. In recent years, the continuous develop- 2650 Edegem, Belgium ment of more selective disease-modifying therapies Laboratory of Experimental Hematology, Vaccine and (DMTs) to treat MS has dramatically changed the land- Infectious Disease Institute (VAXINFECTIO), Faculty of scape. In general, DMTs are therapeutic interventions that Medicine and Health Sciences, University of Antwerp, 2610 aim to modulate the underlying pathophysiology of the Wilrijk, Belgium 402 B. Willekens, N. Cools disease to improve the disease course. In MS, this can be 2 Tolerance-Inducing Therapeutics Under achieved by neuroprotective, neurorestorative and/or Investigation immunomodulatory strategies. Here, we focus on the latter. Several immunomodulatory agents have demonstrated 2.1 Peptide-Based Tolerance-Inducing Vaccination beneficial clinical effects in different forms of MS. Nev- ertheless, several issues regarding these treatments remain, To date, induction of in vivo antigen-specific tolerance by including tolerability problems, compliance and adherence subcutaneous or oral administration of peptides (i.e., pep- difficulties, and potentially severe treatment-related side tide vaccination) has proven to be a well-tolerated and effects such as opportunistic infections, secondary successful therapy for allergies [16–18]. Given the success autoimmunity and an increased risk of malignancies [4, 5]. in allergies, the possibility of treating MS with peptide While more than ten marketed drugs are currently available vaccination is being investigated. Some of the most that have shown variable efficacy in the treatment of promising results were described by Jurynczyk et al. [6] relapsing–remitting MS (RRMS), there remains a signifi- and Walczak et al. [7] in two phase I/II studies in which the cant and unmet need for safer and highly efficacious investigators transdermally applied peptides derived from treatments that are well tolerated. The need for treatments MOG, MBP and PLP. They demonstrated induction of that can stop or slow progression or improve disability in immunological tolerance by activation of Langerhans cells progressive forms of MS is even higher; to date, only one and subsequent induction of interleukin (IL)-10-secreting T drug has been approved for the treatment of primary pro- cells [7]. Moreover, the immunological effect was clini- gressive MS (PPMS). cally translated in a placebo-controlled trial that demon- Given this, more selective immunotherapies designed to strated a significant reduction in annualized relapse rate restore self-tolerance, thereby reinstating the immune bal- and magnetic resonance imaging (MRI)-defined measure- ance without causing general immune suppression, may ments of the disease [7]. Interestingly, lower peptide con- hold promise for the treatment of autoimmunity, including centrations following intramuscular [13] and transdermal MS. Since, theoretically, antigen-specific therapies com- [7] administration achieved an even better clinical out- bine maximal efficacy with minimal side effects, these come, underscoring the importance of dosage to achieve strategies are especially appealing [6, 7]. Nevertheless, for tolerance. Nevertheless, whereas peptide vaccination is many autoimmune diseases, the primary target antigen known to induce tolerance in steady-state conditions, remains to be identified. Also in MS, the target antigen(s) is unexpected adverse events can be anticipated following (are) not known, although proteins within the myelin administration in a pro-inflammatory environment. Indeed, sheath, such as myelin basic protein (MBP), myelin three patients in a phase II clinical trial investigating vac- oligodendrocyte glycoprotein (MOG) and proteolipid pro- cination with a MBP-derived APL, in which amino-acid tein (PLP), are important targets of the autoreactive substitutions were incorporated at T-cell receptor (TCR) immune response [4, 8–11]. Hence, attempts to induce contact positions, demonstrated disease exacerbations fol- antigen-specific tolerance in MS include oral administra- lowing treatment. A clear association with the vaccination tion of myelin proteins, intravenous injection of MBP [5] strategy was demonstrated in two of the patients, even after or altered peptide ligand (APL) [8], transdermal [6, 7]or the dose was lowered, and the trial was halted [8, 19]. intradermal [12] administration of myelin-derived peptides, Alternatively, soluble synthetic peptides were designed and intramuscular injection of plasmids expressing MBP to mimic the naturally processed epitopes. These so-called [13]. Cell-based vaccination strategies, such as T cells, apitopes induce antigen-specific expansion of regulatory T apoptotic lymphocytes covalently bound with multiple cells, capable of ‘‘switching-off’’ pathogenic T cells, which peptides from different myelin-derived proteins [14, 15], or produce pro-inflammatory cytokines and are responsible tolerance-inducing dendritic cells (DCs), have also been for myelin damage in the CNS. In this context, two clinical pursued and appear to reflect more selective therapies for trials have recently completed evaluation of the safety and MS. biological disease parameters of ATX-MS-1467, a mixture We review the experimental approaches of tolerance- of four short peptides derived from MBP, i.e., ATX-MS1 inducing vaccination in relapsing and progressive forms of (MBP ), ATX-MS4 (MBP ), ATX-MS6 (MBP ), 30-44 131-145 140-154 MS that have reached the clinical development phase and ATX-MS7 (MBP ). ATX-MS-1467 is administered 83-99 (Table 1) and discuss failures, successes and future intradermally every 2 weeks for 20 weeks. Patients ini- directions. tially receive a dose titration of 50 and 200 lg for 4 weeks, then a dose of 800 lg every 2 weeks for 16 weeks. A phase I open-label dose-escalating study demonstrated that ATX- MS-1467 was safe and well-tolerated in a group of six Tolerance-Inducing Vaccination in MS 403 Table 1 Overview of tolerance-inducing therapeutic approaches that entered the clinic for treatment of multiple sclerosis Vaccination strategy Developmental Administration Clinical outcomes Mode of action References progress route Peptide-based tolerance-inducing vaccination MOG, MBP, PLP Phase I/II Transdermal Reduction in ARR; reduction in Activation of Langerhans [6, 7] peptides MRI measurement of disease cells; generation of IL-10- secreting cells Altered peptide Halted Subcutaneous 62% increase in number of [8] ligand active lesions; two pts demonstrated disease exacerbations associated with vaccination strategy Apitopes (ATX-MS- Phase IIa Intradermal Safe; 79% decrease in new Gd- Expansion of Treg [20, 21] 1467) enhancing lesions Mannosylated Phase I Subcutaneous Safe Decrease of CCL2, CCL4, [22, 23] liposomes IL-7 and IL-2 at study containing MBP completion peptides TCR peptide Phase I Both Safe Generation of IL-1-secreting [25–31] vaccination intradermal TCR peptide-specific T (Neurovax) and cells; reduction of MBP- intramuscular specific T cells DNA vaccination MBP-encoding DNA Phase II Intramuscular Safe and well tolerated; Reduction of IFN-c- [13, 34] vaccine reduction in number of active producing myelin-reactive lesions; decrease in clinical T cells; decrease of myelin- relapse rate specific auto-antibody titers in the CSF Cell-based tolerance-inducing vaccination Irradiated autologous Phase I Subcutaneous Safe and feasible; 40% Generation of a cytotoxic [41] T cells reduction in relapse rate; T-cell response against stabilization of disease myelin-reactive cells; progression and lesion depletion of myelin- activity on MRI reactive T cells Mixture of Phase IIb Subcutaneous Clinical endpoints not met [45], attenuated myelin- (details not published) NCT01684761 reactive T cells (Tcelna) Autologous PBMC Phase I Intravenous Safe and feasible; stabilization Decrease in myelin-specific [49] chemically coupled of clinical and MRI T-cell reactivity in pts with a mixture of parameters of disease activity receiving highest dose of myelin-derived at study completion cells ([ 1910 ) peptides tolDC pulsed with Phase I Intradermal Ongoing Ongoing NCT02618902 myelin-derived peptides tolDC pulsed with Phase I Intranodal Ongoing Ongoing NCT02903537 myelin-derived peptides tolDC pulsed with Phase I Intravenous Ongoing Ongoing NCT02283671 myelin-derived peptides ARR annualized relapse rate, CSF cerebrospinal fluid, Gd gadolinium, IFN interferon, IL interleukin, MBP myelin basic protein, MOG myelin oligodendrocyte glycoprotein, MRI magnetic resonance imaging, PBMC peripheral blood mononuclear cells, PLP proteolipid protein, pts patients, TCR T-cell receptor, tolDC tolerogenic dendritic cells, Treg regulatory T cell 404 B. Willekens, N. Cools patients with secondary-progressive MS (SPMS), up to a investigated the administration of incremental doses of dose of 800 lg[20]. A recent multicenter, open-label, TCR Vb5.2 and Vb6.1 peptides. Intradermal injection of single-arm, baseline-controlled phase IIa clinical trial synthetic TCR Vb5.2 peptides resulted in clinical (NCT01973491) evaluated the clinical and biological improvement paralleled by beneficial immunological effects of ATX-MS-1467 in 19 patients with relapsing MS effects, such as the generation of TCR peptide-specific T (RMS). No treatment-related serious adverse events were cells and reduction of MBP-specific T cells, in a double- observed, and the adverse event profile was mild, with \ blind placebo-controlled trial in 22 patients with progres- 50% of patients experiencing local injection site reactions. sive MS [25]. Repeated intramuscular injections of Although there was no placebo group with which to TCRVb6 peptide also resulted in immunoregulatory compare results, a review of MRI data showed that treat- effects, warranting further exploration of this approach in ment with ATX-MS-1467 led to a 78% decrease in new T1 the treatment of MS [26]. Administration of both peptides Gadolinium-enhancing lesions as compared with baseline was safe and did not worsen the disease course following [21]. both administration routes [27]. Moreover, a peptide- To engage T cells specific for the naturally processed specific immune response was induced in 50–60% of antigen and to serve as a tolerogen, peptides must reach the patients with MS following intradermal injection of TCR resident antigen-presenting cells in vivo. This process can Vb5.2 peptides, whereas 90% of patients with MS be facilitated by targeting specific markers expressed on demonstrated measurable T-cell immunity towards the the surface of antigen-presenting cells. For instance, the Vb6 peptides upon intramuscular injection in inactivated mannose receptor cluster of differentiation (CD)-206 is a Freund’s adjuvant (IFA). For this, it was hypothesized that C-type lectin primarily present on the membrane of mac- a vaccine consisting of three TCR peptides (BV5S2, rophages and immature DCs. In this context, encapsulation BV6S5, and BV13S1) emulsified in IFA would be more of selected immunodominant MBP peptides into manno- immunogenic than the three peptides in saline alone. The sylated liposomes significantly enhanced the uptake of the trivalent peptide TCR vaccine, now called Neurovax (Im- peptides by DCs via the CD206 receptor. This resulted in mune Response BioPharma, Atlantic City, NJ, USA), was immune tolerance towards the myelin-derived antigens. investigated in several clinical trials and found to be safe CD206-targeted liposomal delivery of co-encapsulated and to induce a surge of proliferating IL-1-secreting TCR immunodominant MBP sequences MBP , MBP peptide-specific T cells [28–31]. A phase IIb study in 46–62 124–139 TM and MBP (Xemys , JSC Pharmsynthez, Moscow, patients with SPMS (clinical trials.gov identifier 147–170 Russia) was investigated in a phase I, multicenter, open- NCT02057159) to investigate the efficacy and safety of the label, dose-escalating safety and proof-of-concept study in vaccine is yet to start. patients with RRMS or SPMS with relapses for whom first- line DMTs had failed. Patients received six weekly sub- 2.2 DNA Vaccination cutaneous injections with incremental doses from 50 to 900 lg. After the last injection, patients were followed-up BHT-3009 is a DNA vaccine that is made of genetically for 12 weeks. No dose-limiting toxicities were observed engineered DNA that encodes the full-length human during treatment. Local injection site reactions were the MBP [32, 33]. The plasmid backbone has been modified in most common adverse event [22]. Interestingly, a statisti- such a way that it could lead to favorable immunological cally significant decrease compared with baseline was changes in patients with MS (reduction in the number of observed in serum CCL2, CCL4, IL-7, and IL-2 levels at immunostimulatory CpG motifs and increase in the number study completion (week 18) [23]. of immunoinhibitory GpG motifs). Its purpose is to restore A completely different approach is effectuated by TCR tolerance to self, leaving protective immunity against peptide vaccination. Hereto, short amino acid sequences infectious and tumor antigens intact. BHT-3009 was first derived from the TCR of pathogenic T cell clones are investigated in a randomized placebo-controlled phase I/II administered in an attempt to induce T-cell-mediated trial in patients with RRMS or SPMS and was shown to be immunoregulation directed at T cells expressing those safe and well tolerated. Moreover, a reduction in contrast- TCRs. The repertoire of TCR peptide-reactive T cells is enhancing lesions on MRI was accompanied by reduced positively selected in the thymus after depletion of nega- proliferation of interferon-c-producing myelin-reactive T tively selected clonotypes, and it has been hypothesized cells and decreased titers of myelin-specific autoantibodies that TCR-specific T cells might represent a subset of the in the cerebrospinal fluid [34]. Next, a phase II randomized naturally induced regulatory T cells. In patients with MS, placebo-controlled trial comparing two doses of BHT-3009 the Vb repertoire of activated T cells has been reported to was conducted in 289 patients with RRMS. Remarkably, be derived predominantly from the Vb5.2 and Vb6.1 the high dose of 1.5 mg was ineffective, but the low dose families [24]. Hence, several clinical trials have of 0.5 mg showed a trend towards a 50–61% decrease in Tolerance-Inducing Vaccination in MS 405 the number of new enhancing lesions as compared with identifier: NCT01684761) following previous selection of placebo (p = 0.07). In addition, a profound reduction in the appropriate dose regimen [45]. Patients with SPMS myelin-specific auto-antibody titers was seen, indicative of (n = 183) who presented T-cell reactivity against at least induction of antigen-specific immune tolerance. Never- one of the myelin-derived peptides used received two theless, no beneficial effects on disease course were vaccination cycles of five subcutaneous injections with observed [13], and whether the vaccine will enter phase III Tcelna per year [46]. Nevertheless, Tcelna did not meet clinical trials remains to be seen. its primary or secondary endpoints, i.e. reduction in brain volume change and reduction in the rate of sustained dis- 2.3 Cell-Based Tolerance-Inducing Vaccination ease progression, respectively. However, the promising results observed in another, albeit small, placebo-con- 2.3.1 T-Cell Vaccination trolled clinical trial in 26 patients with relapsing-progres- sive MS [47] may underscore the importance of careful Autologous T-cell vaccination has been suggested to patient selection and clinical trial design. deplete or regulate the pathogenic myelin-reactive T cells that maintain autoimmune processes within the CNS of 2.3.2 Autologous Leukocytes Chemically Coupled patients with MS [35, 36]. The vaccine consists of a with Multiple Myelin-Derived Peptides patient’s own myelin-specific T cells isolated from peripheral blood that are inactivated by irradiation. Fol- To simultaneously target autoreactive T cells specific for lowing administration of the autologous T-cell vaccine, an multiple myelin epitopes, a mixture of myelin-derived immune response is elicited to eliminate other pathogenic peptides could be used. Bielekova et al. [9] previously T cells in the circulation of the patient without affecting the identified six myelin-derived peptides (MBP , 13–32 rest of the immune system [37]. Stinissen et al. [38] and MBP , MBP , PLP ,MOG , and 111–129 154–170 139–154 1–20 others [39, 40] demonstrated that, apart from local reac- MOG ) that were immunodominant for high-avidity T 35–55 tions due to injection of the product, autologous T-cell cells and could discriminate between patients with MS and vaccination was safe and feasible in patients with MS. healthy controls. A seventh immunodominant peptide, Administration of irradiated, autologous MBP-specific MBP , was identified in several other studies [10, 48], ? 83–99 T-cell clones resulted in the induction of a cytotoxic CD8 including a phase IIa clinical trial testing an APL of T-cell response directed against the MBP-reactive T cells MBP in which worsening of brain MRI activity and 83–99 used for vaccination. Consequently, circulating MBP-re- MS disease was observed [8]. Grau-Lo´pez et al. [11] active T cells were also recognized and destroyed in confirmed the relevance of this cocktail of myelin peptides patients with MS receiving the autologous T-cell vaccine in MS pathogenesis, demonstrating a positive T-cell pro- [38]. Furthermore, the depletion of MBP-reactive T cells liferative response to this peptide mix in 74% of patients following three consecutive injections at 6- to 8-week with RRMS compared with 30% of healthy controls. Lut- intervals with autologous T-cell vaccination correlated terotti et al. [49] demonstrated the feasibility and safety of with a 40% reduction in relapse rate over a period of this selected pool of peptides in an antigen-specific and 12–24 months after the first injection as compared with cell-based tolerization approach in vivo. They performed a baseline. In addition, disease progression stabilized, dose-escalation study in nine patients with MS receiving a including lesion activity on MRI [41, 42]. Nevertheless, single infusion of autologous peripheral blood mononu- acceleration in progression rate 12 months after the last clear cells pulsed with these seven myelin-derived peptides injection suggested a reduced efficacy over time of autol- and chemically fixed with the cross linker 1-ethyl-3-(3- ogous T-cell vaccination, necessitating repetitive injections dimethylaminopropyl)-carbodiimide (EDC). The authors [41]. Indeed, reappearing myelin-reactive T-cell clones concluded that the antigen-coupled cells were well toler- could be effectively depleted by additional vaccinations ated and had a favorable safety profile [49]. A multicenter [43]. phase IIa trial assessing efficacy and safety in patients with It was hypothesized that the immune potential of early RRMS is currently in preparation. autologous T-cell vaccination could be increased by using more than one myelin-derived peptide for T-cell selection 2.3.3 Tolerogenic Dendritic Cell Vaccination [44], so a T-cell vaccine consisting of attenuated myelin- reactive T cells (MRTCs) selected with multiple peptides DCs, professional antigen-presenting cells of the innate derived from MBP, PLP, and MOG was developed. This immune system, fulfil a central role in the polarization of vaccine, Tcelna (imilecleucel-T, formerly known as naive T cells into different effector T cells. In doing so, Tovaxin ), was evaluated in a randomized, double-blind, DCs are of key importance in keeping the balance between placebo-controlled phase IIb study (clinicaltrials.gov 406 B. Willekens, N. Cools immunity and tolerance, as reviewed extensively by Van 3 Discussion Brussel et al. [50]. Several mechanisms by which DCs maintain peripheral tolerance have been delineated. Indeed, To enter a new era for the development of novel MS steady-state and tolerance-inducing or tolerogenic DCs treatment strategies, specific targeting of only those path- (tolDCs) display reduced expression levels of costimula- ways that contribute to the disease pathogenesis should be tory markers, resulting in T-cell anergy or deletion. In aimed for. As outlined, much effort has been put into addition, tolDCs express so-called negative membrane- precisely silencing only those immune responses that are bound costimulatory molecules, such as immunoglobulin- deleterious in the disease. So far, results from initial trials like transcript (ILT)-3 and programmed death ligand (PD- involving the induction of antigen-specific tolerance have L)-1, and immunosuppressive soluble factors such as IL- been promising, albeit mainly in patients with RRMS. 10, that can induce and/or expand regulatory T cells, Furthermore, in MS, a wide spectrum of myelin-derived thereby initiating a process called ‘‘infectious tolerance’’ antigens is targeted by a large diversity of T and B cells. In [50–52]. These specialized features of DCs have driven the addition, the progression of MS and the occurrence of development of DC-based therapies to generate antigen- relapses are suggested to be associated with epitope specific tolerance, restoring the immunological imbalance spreading, a process characterized by loss of tolerance in autoimmune disorders, including MS. against endogenous antigens released during an inflam- To date, several biological and pharmacological agents matory or auto-immune exacerbation. Hence, although it have been evaluated to generate tolDCs in vitro. We [53] seems logical to pursue antigen-specific tolerance early in and others [54–56] have shown that in vitro treatment of the disease when epitope spreading is limited, it should be monocyte-derived DCs with anti-inflammatory biologicals, noted that tolerance-inducing vaccination strategies can including vitamin D , resulted in a maturation-resistant induce so-called infectious tolerance (Fig. 1). Indeed, fol- phenotype of DCs from both healthy controls and patients lowing treatment with BHT-3009, a DNA vaccine encod- with MS. Vitamin D -treated tolDCs induced myelin- ing full-length MBP, the induction of immune tolerance specific T-cell hyporesponsiveness, whereas the tolDC- that extended beyond MBP to other myelin-derived anti- stimulated T cells retained their capacity to respond to an gens, such as PLP, MOG, and ab-crystallin was observed unrelated antigen. This hyporesponsiveness was robust, as [34]. Several other tolerance-inducing vaccination strate- T cells were not reactivated after rechallenge with gies aim to counteract epitope spreading by including immunostimulatory DCs [53]. Furthermore, treatment of multiple myelin-derived epitopes, thereby targeting mye- experimental autoimmune encephalomyelitis (EAE), the lin-reactive T cells with multiple specificities. Nonetheless, animal model of MS, with MOG -pulsed bone marrow- numerous questions remain, including dose, route, and 40–55 derived vitamin D -treated tolDCs significantly reduced frequency of administration, before tolerance-inducing EAE incidence when administered preventively and vaccination strategies become widely available to a vast resulted in clinical improvement when applied after EAE range of patients. induction [57, 58]. Of note, repeated injections with Although the optimal dose for tolerance-inducing ther- MOG -pulsed tolDCs were necessary to maintain the apeutic vaccination has yet to be determined, it has been 40–55 favorable effect on the disease course. shown that lower peptide concentrations following intra- Four phase I studies investigating the safety and feasi- muscular [13] as well as transdermal [7] administration bility of tolDC therapy for autoimmune diseases were achieved a better clinical outcome than higher doses for the completed recently [59–64]. Overall, these clinical studies induction of tolerance. Likewise, in an animal model of revealed that tolDC therapy was well tolerated and safe in rheumatoid arthritis, it was shown that the disease score the patient populations investigated. No discernible adverse ameliorated in mice receiving lower doses of tolDCs but events or toxicities were demonstrated in these studies. worsened in mice receiving higher doses [65]. In contrast, Hence, these reassuring results open the way for larger Lutterotti et al. [49] demonstrated a reduction in myelin- studies investigating efficacy as well as for implementation specific T-cell reactivity only when the highest dose of of the use of tolDCs in other autoimmune diseases, cells chemically coupled with a mixture of myelin-derived including MS. To date, three open-label, single-center, peptides was used. However, less is known about the phase I clinical trials evaluating the safety and tolerability minimal dose necessary for a therapeutic effect. Addi- of myelin-derived peptide-pulsed tolDCs administered tionally, to ensure that the ability to regulate the autoim- intradermally, intranodally, or intravenously are ongoing mune response is permanent or at least lasts for years (clinicaltrials.gov identifiers NCT02618902, following intervention, a number of repetitive injections NCT02903537, and NCT02283671). with the tolerance-inducing agent may be required. In particular, for cell-based tolerance-inducing strategies, Tolerance-Inducing Vaccination in MS 407 Fig. 1 Possible modes of action of tolerance-inducing therapeutic antigens, such as peptides, apitopes, or encoded by a DNA vaccine, approaches in multiple sclerosis (MS). (1) Although the exact cause are engulfed, processed, and presented by antigen-presenting cells, of MS remains unknown, proteins within the axon-surrounding including Langerhans cells and DCs. (3) Presentation of myelin- myelin sheath, such as myelin oligodendrocyte protein (MOG), derived antigen by DCs in the absence of costimulatory molecules, myelin basic protein (MBP), and proteolipid protein (PLP), are may result in the deletion of myelin-reactive T cells. (4) In addition, important targets of the autoreactive immune response. Furthermore, tolerance-inducing therapeutic approaches can induce so-called the progression of MS and the occurrence of relapses are associated infectious tolerance by antigen-specific expansion of regulatory T with ‘‘epitope spreading,’’ a process characterized by loss of tolerance cells (Treg) and are capable of counteracting epitope spreading against endogenous antigens released during an inflammatory or auto- (Adapted from Neuron Hand-tuned by Quasar Jarosz/CC BY-SA 3.0) immune exacerbation. (2) Following administration, myelin-derived ready-to-use aliquots for clinical applications using cry- therapeutic agent to the draining lymph node or from opreservation is needed. We recently demonstrated that, where cell-based tolerance-inducing treatments can following a freeze–thaw cycle, tolDCs maintained their directly find a way to the draining lymph node. It has phenotypic and functional properties as compared with been shown that migration towards lymph nodes is much freshly prepared DCs [53]. These findings support and lower after subcutaneous injection than after intradermal facilitate the widely applicable clinical use of cell-based injection, whereas the migration of intravenously injected tolerance-inducing vaccination. cells has so far not been monitored in humans [66–68]. When considering the route of delivery of tolerance- Nevertheless, in vivo studies in patients with cancer have inducing therapeutic vaccination, one should consider that shown that, after intradermal injection, only 2–4% of the different routes lead to different sites of accumulation of DCs migrate to draining lymph nodes [69]. Our recent the administered product, whereas for the effective findings demonstrate that the migratory capacity of these induction of tolerance it is necessary to interact with cells could be optimized by introducing messenger RNA autoreactive T cells, which mainly takes place in the (mRNA) encoding chemokine receptors. In doing so, we lymph nodes. However, direct injection into the lymph were able to endow tolDCs with the capacity to migrate node is technically very difficult and could damage the through the blood–brain barrier by introducing de novo lymph node structure. Moreover, this tissue damage could C–C chemokine receptor (CCR)-5 protein expression. evoke an undesired pro-inflammatory microenvironment. Active shuttling of cells across the blood–brain barrier For this reason, most tolerance-inducing products are would allow for targeted in situ down-modulation of administered in the skin comprising an armamentarium of autoimmune responses in MS [70]. immune-competent cells capable of shuttling the 408 B. Willekens, N. Cools References 4 Conclusion 1. Dendrou CA, Fugger L, Friese MA. Immunopathology of mul- Although current DMTs have demonstrated clear efficacy, tiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58. they come with significant, sometimes life-threatening, 2. Grigoriadis N, van Pesch V. A basic overview of multiple scle- side effects. Furthermore, current therapies generally delay rosis immunopathology. Eur J Neurol. 2015;22(Suppl 2):3–13. but do not prevent disease progression, which means that 3. 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Therapeutic peptide vaccines for treatment of Horizon 2020 research and innovation program under grant agree- autoimmune diseases. Immunol Lett. 2009;122(2):134–6. ment. Dr. Willekens is a neurologist at the Antwerp University 13. Garren H, Robinson WH, Krasulova E, Havrdova E, Nadj C, Hospital supported by a research fellowship (2016–2018) of the Selmaj K, et al. Phase 2 trial of a DNA vaccine encoding myelin University of Antwerp to work on this project. basic protein for multiple sclerosis. Ann Neurol. 2008;63(5):611–20. Conflicts of interest Barbara Willekens and Nathalie Cools have no 14. Lutterotti A, Sospedra M, Martin R. Antigen-specific therapies in conflicts of interest. MS—current concepts and novel approaches. J Neurol Sci. 2008;274(1–2):18–22. Open Access This article is distributed under the terms of the 15. Turley DM, Miller SD. 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Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis

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Abstract

CNS Drugs (2018) 32:401–410 https://doi.org/10.1007/s40263-018-0518-4 LEADING ARTICLE Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis 1,2 2 Barbara Willekens Nathalie Cools Published online: 14 May 2018 The Author(s) 2018 Abstract Multiple sclerosis (MS) is a chronic immune- vaccination. Failures, successes and future directions are mediated disease of the central nervous system (CNS) discussed. characterized by neuroinflammation, neurodegeneration and impaired repair mechanisms that lead to neurological disability. The crux of MS is the patient’s own immune Key Points cells attacking self-antigens in the CNS, namely the myelin sheath that protects nerve cells of the brain and spinal cord. Theoretically, antigen-specific therapeutic Restoring antigen-specific tolerance via therapeutic vacci- vaccination is designed to specifically restore nation is an innovative and exciting approach in MS ther- tolerance to self. In doing so, disease-associated apy. Indeed, leveraging the body’s attempt to prevent pathways are accurately targeted without causing autoimmunity, i.e., tolerization, focuses on the underlying general immunosuppression. cause of the disease and could be the key to solving neu- Several experimental approaches have reached the roinflammation. In this perspective, antigen-specific vac- clinical development phase. Safety and feasibility cination targets only the detrimental and aberrant immune have been demonstrated in several phase I/II trials. response against the specific disease-associated anti- gen(s) involved while retaining the capacity of the immune It can be envisaged that antigen-specific therapeutic system to respond to unrelated antigens. We review the vaccination will prove to be highly relevant, experimental approaches of tolerance-inducing vaccination especially early in the disease when epitope in relapsing and progressive forms of MS that have reached spreading has not yet occurred. the clinical development phase, including vaccination with autologous T cells, autologous tolerogenic dendritic cells, T cell receptor peptide vaccination, altered peptide ligand, ATX-MS-1467, cluster of differentiation (CD)-206-tar- geted liposomal myelin basic protein peptides and DNA 1 Introduction Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) driven by immune- & Nathalie Cools mediated damage of the myelin sheath. This results in Nathalie.cools@uza.be axonal loss and neurodegeneration that lead to neurological Department of Neurology, Antwerp University Hospital, disability [1–3]. In recent years, the continuous develop- 2650 Edegem, Belgium ment of more selective disease-modifying therapies Laboratory of Experimental Hematology, Vaccine and (DMTs) to treat MS has dramatically changed the land- Infectious Disease Institute (VAXINFECTIO), Faculty of scape. In general, DMTs are therapeutic interventions that Medicine and Health Sciences, University of Antwerp, 2610 aim to modulate the underlying pathophysiology of the Wilrijk, Belgium 402 B. Willekens, N. Cools disease to improve the disease course. In MS, this can be 2 Tolerance-Inducing Therapeutics Under achieved by neuroprotective, neurorestorative and/or Investigation immunomodulatory strategies. Here, we focus on the latter. Several immunomodulatory agents have demonstrated 2.1 Peptide-Based Tolerance-Inducing Vaccination beneficial clinical effects in different forms of MS. Nev- ertheless, several issues regarding these treatments remain, To date, induction of in vivo antigen-specific tolerance by including tolerability problems, compliance and adherence subcutaneous or oral administration of peptides (i.e., pep- difficulties, and potentially severe treatment-related side tide vaccination) has proven to be a well-tolerated and effects such as opportunistic infections, secondary successful therapy for allergies [16–18]. Given the success autoimmunity and an increased risk of malignancies [4, 5]. in allergies, the possibility of treating MS with peptide While more than ten marketed drugs are currently available vaccination is being investigated. Some of the most that have shown variable efficacy in the treatment of promising results were described by Jurynczyk et al. [6] relapsing–remitting MS (RRMS), there remains a signifi- and Walczak et al. [7] in two phase I/II studies in which the cant and unmet need for safer and highly efficacious investigators transdermally applied peptides derived from treatments that are well tolerated. The need for treatments MOG, MBP and PLP. They demonstrated induction of that can stop or slow progression or improve disability in immunological tolerance by activation of Langerhans cells progressive forms of MS is even higher; to date, only one and subsequent induction of interleukin (IL)-10-secreting T drug has been approved for the treatment of primary pro- cells [7]. Moreover, the immunological effect was clini- gressive MS (PPMS). cally translated in a placebo-controlled trial that demon- Given this, more selective immunotherapies designed to strated a significant reduction in annualized relapse rate restore self-tolerance, thereby reinstating the immune bal- and magnetic resonance imaging (MRI)-defined measure- ance without causing general immune suppression, may ments of the disease [7]. Interestingly, lower peptide con- hold promise for the treatment of autoimmunity, including centrations following intramuscular [13] and transdermal MS. Since, theoretically, antigen-specific therapies com- [7] administration achieved an even better clinical out- bine maximal efficacy with minimal side effects, these come, underscoring the importance of dosage to achieve strategies are especially appealing [6, 7]. Nevertheless, for tolerance. Nevertheless, whereas peptide vaccination is many autoimmune diseases, the primary target antigen known to induce tolerance in steady-state conditions, remains to be identified. Also in MS, the target antigen(s) is unexpected adverse events can be anticipated following (are) not known, although proteins within the myelin administration in a pro-inflammatory environment. Indeed, sheath, such as myelin basic protein (MBP), myelin three patients in a phase II clinical trial investigating vac- oligodendrocyte glycoprotein (MOG) and proteolipid pro- cination with a MBP-derived APL, in which amino-acid tein (PLP), are important targets of the autoreactive substitutions were incorporated at T-cell receptor (TCR) immune response [4, 8–11]. Hence, attempts to induce contact positions, demonstrated disease exacerbations fol- antigen-specific tolerance in MS include oral administra- lowing treatment. A clear association with the vaccination tion of myelin proteins, intravenous injection of MBP [5] strategy was demonstrated in two of the patients, even after or altered peptide ligand (APL) [8], transdermal [6, 7]or the dose was lowered, and the trial was halted [8, 19]. intradermal [12] administration of myelin-derived peptides, Alternatively, soluble synthetic peptides were designed and intramuscular injection of plasmids expressing MBP to mimic the naturally processed epitopes. These so-called [13]. Cell-based vaccination strategies, such as T cells, apitopes induce antigen-specific expansion of regulatory T apoptotic lymphocytes covalently bound with multiple cells, capable of ‘‘switching-off’’ pathogenic T cells, which peptides from different myelin-derived proteins [14, 15], or produce pro-inflammatory cytokines and are responsible tolerance-inducing dendritic cells (DCs), have also been for myelin damage in the CNS. In this context, two clinical pursued and appear to reflect more selective therapies for trials have recently completed evaluation of the safety and MS. biological disease parameters of ATX-MS-1467, a mixture We review the experimental approaches of tolerance- of four short peptides derived from MBP, i.e., ATX-MS1 inducing vaccination in relapsing and progressive forms of (MBP ), ATX-MS4 (MBP ), ATX-MS6 (MBP ), 30-44 131-145 140-154 MS that have reached the clinical development phase and ATX-MS7 (MBP ). ATX-MS-1467 is administered 83-99 (Table 1) and discuss failures, successes and future intradermally every 2 weeks for 20 weeks. Patients ini- directions. tially receive a dose titration of 50 and 200 lg for 4 weeks, then a dose of 800 lg every 2 weeks for 16 weeks. A phase I open-label dose-escalating study demonstrated that ATX- MS-1467 was safe and well-tolerated in a group of six Tolerance-Inducing Vaccination in MS 403 Table 1 Overview of tolerance-inducing therapeutic approaches that entered the clinic for treatment of multiple sclerosis Vaccination strategy Developmental Administration Clinical outcomes Mode of action References progress route Peptide-based tolerance-inducing vaccination MOG, MBP, PLP Phase I/II Transdermal Reduction in ARR; reduction in Activation of Langerhans [6, 7] peptides MRI measurement of disease cells; generation of IL-10- secreting cells Altered peptide Halted Subcutaneous 62% increase in number of [8] ligand active lesions; two pts demonstrated disease exacerbations associated with vaccination strategy Apitopes (ATX-MS- Phase IIa Intradermal Safe; 79% decrease in new Gd- Expansion of Treg [20, 21] 1467) enhancing lesions Mannosylated Phase I Subcutaneous Safe Decrease of CCL2, CCL4, [22, 23] liposomes IL-7 and IL-2 at study containing MBP completion peptides TCR peptide Phase I Both Safe Generation of IL-1-secreting [25–31] vaccination intradermal TCR peptide-specific T (Neurovax) and cells; reduction of MBP- intramuscular specific T cells DNA vaccination MBP-encoding DNA Phase II Intramuscular Safe and well tolerated; Reduction of IFN-c- [13, 34] vaccine reduction in number of active producing myelin-reactive lesions; decrease in clinical T cells; decrease of myelin- relapse rate specific auto-antibody titers in the CSF Cell-based tolerance-inducing vaccination Irradiated autologous Phase I Subcutaneous Safe and feasible; 40% Generation of a cytotoxic [41] T cells reduction in relapse rate; T-cell response against stabilization of disease myelin-reactive cells; progression and lesion depletion of myelin- activity on MRI reactive T cells Mixture of Phase IIb Subcutaneous Clinical endpoints not met [45], attenuated myelin- (details not published) NCT01684761 reactive T cells (Tcelna) Autologous PBMC Phase I Intravenous Safe and feasible; stabilization Decrease in myelin-specific [49] chemically coupled of clinical and MRI T-cell reactivity in pts with a mixture of parameters of disease activity receiving highest dose of myelin-derived at study completion cells ([ 1910 ) peptides tolDC pulsed with Phase I Intradermal Ongoing Ongoing NCT02618902 myelin-derived peptides tolDC pulsed with Phase I Intranodal Ongoing Ongoing NCT02903537 myelin-derived peptides tolDC pulsed with Phase I Intravenous Ongoing Ongoing NCT02283671 myelin-derived peptides ARR annualized relapse rate, CSF cerebrospinal fluid, Gd gadolinium, IFN interferon, IL interleukin, MBP myelin basic protein, MOG myelin oligodendrocyte glycoprotein, MRI magnetic resonance imaging, PBMC peripheral blood mononuclear cells, PLP proteolipid protein, pts patients, TCR T-cell receptor, tolDC tolerogenic dendritic cells, Treg regulatory T cell 404 B. Willekens, N. Cools patients with secondary-progressive MS (SPMS), up to a investigated the administration of incremental doses of dose of 800 lg[20]. A recent multicenter, open-label, TCR Vb5.2 and Vb6.1 peptides. Intradermal injection of single-arm, baseline-controlled phase IIa clinical trial synthetic TCR Vb5.2 peptides resulted in clinical (NCT01973491) evaluated the clinical and biological improvement paralleled by beneficial immunological effects of ATX-MS-1467 in 19 patients with relapsing MS effects, such as the generation of TCR peptide-specific T (RMS). No treatment-related serious adverse events were cells and reduction of MBP-specific T cells, in a double- observed, and the adverse event profile was mild, with \ blind placebo-controlled trial in 22 patients with progres- 50% of patients experiencing local injection site reactions. sive MS [25]. Repeated intramuscular injections of Although there was no placebo group with which to TCRVb6 peptide also resulted in immunoregulatory compare results, a review of MRI data showed that treat- effects, warranting further exploration of this approach in ment with ATX-MS-1467 led to a 78% decrease in new T1 the treatment of MS [26]. Administration of both peptides Gadolinium-enhancing lesions as compared with baseline was safe and did not worsen the disease course following [21]. both administration routes [27]. Moreover, a peptide- To engage T cells specific for the naturally processed specific immune response was induced in 50–60% of antigen and to serve as a tolerogen, peptides must reach the patients with MS following intradermal injection of TCR resident antigen-presenting cells in vivo. This process can Vb5.2 peptides, whereas 90% of patients with MS be facilitated by targeting specific markers expressed on demonstrated measurable T-cell immunity towards the the surface of antigen-presenting cells. For instance, the Vb6 peptides upon intramuscular injection in inactivated mannose receptor cluster of differentiation (CD)-206 is a Freund’s adjuvant (IFA). For this, it was hypothesized that C-type lectin primarily present on the membrane of mac- a vaccine consisting of three TCR peptides (BV5S2, rophages and immature DCs. In this context, encapsulation BV6S5, and BV13S1) emulsified in IFA would be more of selected immunodominant MBP peptides into manno- immunogenic than the three peptides in saline alone. The sylated liposomes significantly enhanced the uptake of the trivalent peptide TCR vaccine, now called Neurovax (Im- peptides by DCs via the CD206 receptor. This resulted in mune Response BioPharma, Atlantic City, NJ, USA), was immune tolerance towards the myelin-derived antigens. investigated in several clinical trials and found to be safe CD206-targeted liposomal delivery of co-encapsulated and to induce a surge of proliferating IL-1-secreting TCR immunodominant MBP sequences MBP , MBP peptide-specific T cells [28–31]. A phase IIb study in 46–62 124–139 TM and MBP (Xemys , JSC Pharmsynthez, Moscow, patients with SPMS (clinical trials.gov identifier 147–170 Russia) was investigated in a phase I, multicenter, open- NCT02057159) to investigate the efficacy and safety of the label, dose-escalating safety and proof-of-concept study in vaccine is yet to start. patients with RRMS or SPMS with relapses for whom first- line DMTs had failed. Patients received six weekly sub- 2.2 DNA Vaccination cutaneous injections with incremental doses from 50 to 900 lg. After the last injection, patients were followed-up BHT-3009 is a DNA vaccine that is made of genetically for 12 weeks. No dose-limiting toxicities were observed engineered DNA that encodes the full-length human during treatment. Local injection site reactions were the MBP [32, 33]. The plasmid backbone has been modified in most common adverse event [22]. Interestingly, a statisti- such a way that it could lead to favorable immunological cally significant decrease compared with baseline was changes in patients with MS (reduction in the number of observed in serum CCL2, CCL4, IL-7, and IL-2 levels at immunostimulatory CpG motifs and increase in the number study completion (week 18) [23]. of immunoinhibitory GpG motifs). Its purpose is to restore A completely different approach is effectuated by TCR tolerance to self, leaving protective immunity against peptide vaccination. Hereto, short amino acid sequences infectious and tumor antigens intact. BHT-3009 was first derived from the TCR of pathogenic T cell clones are investigated in a randomized placebo-controlled phase I/II administered in an attempt to induce T-cell-mediated trial in patients with RRMS or SPMS and was shown to be immunoregulation directed at T cells expressing those safe and well tolerated. Moreover, a reduction in contrast- TCRs. The repertoire of TCR peptide-reactive T cells is enhancing lesions on MRI was accompanied by reduced positively selected in the thymus after depletion of nega- proliferation of interferon-c-producing myelin-reactive T tively selected clonotypes, and it has been hypothesized cells and decreased titers of myelin-specific autoantibodies that TCR-specific T cells might represent a subset of the in the cerebrospinal fluid [34]. Next, a phase II randomized naturally induced regulatory T cells. In patients with MS, placebo-controlled trial comparing two doses of BHT-3009 the Vb repertoire of activated T cells has been reported to was conducted in 289 patients with RRMS. Remarkably, be derived predominantly from the Vb5.2 and Vb6.1 the high dose of 1.5 mg was ineffective, but the low dose families [24]. Hence, several clinical trials have of 0.5 mg showed a trend towards a 50–61% decrease in Tolerance-Inducing Vaccination in MS 405 the number of new enhancing lesions as compared with identifier: NCT01684761) following previous selection of placebo (p = 0.07). In addition, a profound reduction in the appropriate dose regimen [45]. Patients with SPMS myelin-specific auto-antibody titers was seen, indicative of (n = 183) who presented T-cell reactivity against at least induction of antigen-specific immune tolerance. Never- one of the myelin-derived peptides used received two theless, no beneficial effects on disease course were vaccination cycles of five subcutaneous injections with observed [13], and whether the vaccine will enter phase III Tcelna per year [46]. Nevertheless, Tcelna did not meet clinical trials remains to be seen. its primary or secondary endpoints, i.e. reduction in brain volume change and reduction in the rate of sustained dis- 2.3 Cell-Based Tolerance-Inducing Vaccination ease progression, respectively. However, the promising results observed in another, albeit small, placebo-con- 2.3.1 T-Cell Vaccination trolled clinical trial in 26 patients with relapsing-progres- sive MS [47] may underscore the importance of careful Autologous T-cell vaccination has been suggested to patient selection and clinical trial design. deplete or regulate the pathogenic myelin-reactive T cells that maintain autoimmune processes within the CNS of 2.3.2 Autologous Leukocytes Chemically Coupled patients with MS [35, 36]. The vaccine consists of a with Multiple Myelin-Derived Peptides patient’s own myelin-specific T cells isolated from peripheral blood that are inactivated by irradiation. Fol- To simultaneously target autoreactive T cells specific for lowing administration of the autologous T-cell vaccine, an multiple myelin epitopes, a mixture of myelin-derived immune response is elicited to eliminate other pathogenic peptides could be used. Bielekova et al. [9] previously T cells in the circulation of the patient without affecting the identified six myelin-derived peptides (MBP , 13–32 rest of the immune system [37]. Stinissen et al. [38] and MBP , MBP , PLP ,MOG , and 111–129 154–170 139–154 1–20 others [39, 40] demonstrated that, apart from local reac- MOG ) that were immunodominant for high-avidity T 35–55 tions due to injection of the product, autologous T-cell cells and could discriminate between patients with MS and vaccination was safe and feasible in patients with MS. healthy controls. A seventh immunodominant peptide, Administration of irradiated, autologous MBP-specific MBP , was identified in several other studies [10, 48], ? 83–99 T-cell clones resulted in the induction of a cytotoxic CD8 including a phase IIa clinical trial testing an APL of T-cell response directed against the MBP-reactive T cells MBP in which worsening of brain MRI activity and 83–99 used for vaccination. Consequently, circulating MBP-re- MS disease was observed [8]. Grau-Lo´pez et al. [11] active T cells were also recognized and destroyed in confirmed the relevance of this cocktail of myelin peptides patients with MS receiving the autologous T-cell vaccine in MS pathogenesis, demonstrating a positive T-cell pro- [38]. Furthermore, the depletion of MBP-reactive T cells liferative response to this peptide mix in 74% of patients following three consecutive injections at 6- to 8-week with RRMS compared with 30% of healthy controls. Lut- intervals with autologous T-cell vaccination correlated terotti et al. [49] demonstrated the feasibility and safety of with a 40% reduction in relapse rate over a period of this selected pool of peptides in an antigen-specific and 12–24 months after the first injection as compared with cell-based tolerization approach in vivo. They performed a baseline. In addition, disease progression stabilized, dose-escalation study in nine patients with MS receiving a including lesion activity on MRI [41, 42]. Nevertheless, single infusion of autologous peripheral blood mononu- acceleration in progression rate 12 months after the last clear cells pulsed with these seven myelin-derived peptides injection suggested a reduced efficacy over time of autol- and chemically fixed with the cross linker 1-ethyl-3-(3- ogous T-cell vaccination, necessitating repetitive injections dimethylaminopropyl)-carbodiimide (EDC). The authors [41]. Indeed, reappearing myelin-reactive T-cell clones concluded that the antigen-coupled cells were well toler- could be effectively depleted by additional vaccinations ated and had a favorable safety profile [49]. A multicenter [43]. phase IIa trial assessing efficacy and safety in patients with It was hypothesized that the immune potential of early RRMS is currently in preparation. autologous T-cell vaccination could be increased by using more than one myelin-derived peptide for T-cell selection 2.3.3 Tolerogenic Dendritic Cell Vaccination [44], so a T-cell vaccine consisting of attenuated myelin- reactive T cells (MRTCs) selected with multiple peptides DCs, professional antigen-presenting cells of the innate derived from MBP, PLP, and MOG was developed. This immune system, fulfil a central role in the polarization of vaccine, Tcelna (imilecleucel-T, formerly known as naive T cells into different effector T cells. In doing so, Tovaxin ), was evaluated in a randomized, double-blind, DCs are of key importance in keeping the balance between placebo-controlled phase IIb study (clinicaltrials.gov 406 B. Willekens, N. Cools immunity and tolerance, as reviewed extensively by Van 3 Discussion Brussel et al. [50]. Several mechanisms by which DCs maintain peripheral tolerance have been delineated. Indeed, To enter a new era for the development of novel MS steady-state and tolerance-inducing or tolerogenic DCs treatment strategies, specific targeting of only those path- (tolDCs) display reduced expression levels of costimula- ways that contribute to the disease pathogenesis should be tory markers, resulting in T-cell anergy or deletion. In aimed for. As outlined, much effort has been put into addition, tolDCs express so-called negative membrane- precisely silencing only those immune responses that are bound costimulatory molecules, such as immunoglobulin- deleterious in the disease. So far, results from initial trials like transcript (ILT)-3 and programmed death ligand (PD- involving the induction of antigen-specific tolerance have L)-1, and immunosuppressive soluble factors such as IL- been promising, albeit mainly in patients with RRMS. 10, that can induce and/or expand regulatory T cells, Furthermore, in MS, a wide spectrum of myelin-derived thereby initiating a process called ‘‘infectious tolerance’’ antigens is targeted by a large diversity of T and B cells. In [50–52]. These specialized features of DCs have driven the addition, the progression of MS and the occurrence of development of DC-based therapies to generate antigen- relapses are suggested to be associated with epitope specific tolerance, restoring the immunological imbalance spreading, a process characterized by loss of tolerance in autoimmune disorders, including MS. against endogenous antigens released during an inflam- To date, several biological and pharmacological agents matory or auto-immune exacerbation. Hence, although it have been evaluated to generate tolDCs in vitro. We [53] seems logical to pursue antigen-specific tolerance early in and others [54–56] have shown that in vitro treatment of the disease when epitope spreading is limited, it should be monocyte-derived DCs with anti-inflammatory biologicals, noted that tolerance-inducing vaccination strategies can including vitamin D , resulted in a maturation-resistant induce so-called infectious tolerance (Fig. 1). Indeed, fol- phenotype of DCs from both healthy controls and patients lowing treatment with BHT-3009, a DNA vaccine encod- with MS. Vitamin D -treated tolDCs induced myelin- ing full-length MBP, the induction of immune tolerance specific T-cell hyporesponsiveness, whereas the tolDC- that extended beyond MBP to other myelin-derived anti- stimulated T cells retained their capacity to respond to an gens, such as PLP, MOG, and ab-crystallin was observed unrelated antigen. This hyporesponsiveness was robust, as [34]. Several other tolerance-inducing vaccination strate- T cells were not reactivated after rechallenge with gies aim to counteract epitope spreading by including immunostimulatory DCs [53]. Furthermore, treatment of multiple myelin-derived epitopes, thereby targeting mye- experimental autoimmune encephalomyelitis (EAE), the lin-reactive T cells with multiple specificities. Nonetheless, animal model of MS, with MOG -pulsed bone marrow- numerous questions remain, including dose, route, and 40–55 derived vitamin D -treated tolDCs significantly reduced frequency of administration, before tolerance-inducing EAE incidence when administered preventively and vaccination strategies become widely available to a vast resulted in clinical improvement when applied after EAE range of patients. induction [57, 58]. Of note, repeated injections with Although the optimal dose for tolerance-inducing ther- MOG -pulsed tolDCs were necessary to maintain the apeutic vaccination has yet to be determined, it has been 40–55 favorable effect on the disease course. shown that lower peptide concentrations following intra- Four phase I studies investigating the safety and feasi- muscular [13] as well as transdermal [7] administration bility of tolDC therapy for autoimmune diseases were achieved a better clinical outcome than higher doses for the completed recently [59–64]. Overall, these clinical studies induction of tolerance. Likewise, in an animal model of revealed that tolDC therapy was well tolerated and safe in rheumatoid arthritis, it was shown that the disease score the patient populations investigated. No discernible adverse ameliorated in mice receiving lower doses of tolDCs but events or toxicities were demonstrated in these studies. worsened in mice receiving higher doses [65]. In contrast, Hence, these reassuring results open the way for larger Lutterotti et al. [49] demonstrated a reduction in myelin- studies investigating efficacy as well as for implementation specific T-cell reactivity only when the highest dose of of the use of tolDCs in other autoimmune diseases, cells chemically coupled with a mixture of myelin-derived including MS. To date, three open-label, single-center, peptides was used. However, less is known about the phase I clinical trials evaluating the safety and tolerability minimal dose necessary for a therapeutic effect. Addi- of myelin-derived peptide-pulsed tolDCs administered tionally, to ensure that the ability to regulate the autoim- intradermally, intranodally, or intravenously are ongoing mune response is permanent or at least lasts for years (clinicaltrials.gov identifiers NCT02618902, following intervention, a number of repetitive injections NCT02903537, and NCT02283671). with the tolerance-inducing agent may be required. In particular, for cell-based tolerance-inducing strategies, Tolerance-Inducing Vaccination in MS 407 Fig. 1 Possible modes of action of tolerance-inducing therapeutic antigens, such as peptides, apitopes, or encoded by a DNA vaccine, approaches in multiple sclerosis (MS). (1) Although the exact cause are engulfed, processed, and presented by antigen-presenting cells, of MS remains unknown, proteins within the axon-surrounding including Langerhans cells and DCs. (3) Presentation of myelin- myelin sheath, such as myelin oligodendrocyte protein (MOG), derived antigen by DCs in the absence of costimulatory molecules, myelin basic protein (MBP), and proteolipid protein (PLP), are may result in the deletion of myelin-reactive T cells. (4) In addition, important targets of the autoreactive immune response. Furthermore, tolerance-inducing therapeutic approaches can induce so-called the progression of MS and the occurrence of relapses are associated infectious tolerance by antigen-specific expansion of regulatory T with ‘‘epitope spreading,’’ a process characterized by loss of tolerance cells (Treg) and are capable of counteracting epitope spreading against endogenous antigens released during an inflammatory or auto- (Adapted from Neuron Hand-tuned by Quasar Jarosz/CC BY-SA 3.0) immune exacerbation. (2) Following administration, myelin-derived ready-to-use aliquots for clinical applications using cry- therapeutic agent to the draining lymph node or from opreservation is needed. We recently demonstrated that, where cell-based tolerance-inducing treatments can following a freeze–thaw cycle, tolDCs maintained their directly find a way to the draining lymph node. It has phenotypic and functional properties as compared with been shown that migration towards lymph nodes is much freshly prepared DCs [53]. These findings support and lower after subcutaneous injection than after intradermal facilitate the widely applicable clinical use of cell-based injection, whereas the migration of intravenously injected tolerance-inducing vaccination. cells has so far not been monitored in humans [66–68]. When considering the route of delivery of tolerance- Nevertheless, in vivo studies in patients with cancer have inducing therapeutic vaccination, one should consider that shown that, after intradermal injection, only 2–4% of the different routes lead to different sites of accumulation of DCs migrate to draining lymph nodes [69]. Our recent the administered product, whereas for the effective findings demonstrate that the migratory capacity of these induction of tolerance it is necessary to interact with cells could be optimized by introducing messenger RNA autoreactive T cells, which mainly takes place in the (mRNA) encoding chemokine receptors. In doing so, we lymph nodes. However, direct injection into the lymph were able to endow tolDCs with the capacity to migrate node is technically very difficult and could damage the through the blood–brain barrier by introducing de novo lymph node structure. Moreover, this tissue damage could C–C chemokine receptor (CCR)-5 protein expression. evoke an undesired pro-inflammatory microenvironment. Active shuttling of cells across the blood–brain barrier For this reason, most tolerance-inducing products are would allow for targeted in situ down-modulation of administered in the skin comprising an armamentarium of autoimmune responses in MS [70]. immune-competent cells capable of shuttling the 408 B. Willekens, N. Cools References 4 Conclusion 1. Dendrou CA, Fugger L, Friese MA. Immunopathology of mul- Although current DMTs have demonstrated clear efficacy, tiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58. they come with significant, sometimes life-threatening, 2. Grigoriadis N, van Pesch V. A basic overview of multiple scle- side effects. Furthermore, current therapies generally delay rosis immunopathology. Eur J Neurol. 2015;22(Suppl 2):3–13. but do not prevent disease progression, which means that 3. 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CNS DrugsSpringer Journals

Published: May 14, 2018

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