ImmunoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update This article was published in the following Dove Press journal: ImmunoTargets and Therapy Sandra Guallar-Garrido Abstract: Physicians treating patients affected by nonmuscle-invasive bladder cancer Esther Julián (NMIBC) have been in shock during the last six years since manufacturing restrictions on the production of the first-option medicine, Mycobacterium bovis Bacillus Calmette-Guérin Departament de Genètica i de Microbiologia, Facultat de Biociències, (BCG), have resulted in worldwide shortages. This shortage of BCG has led to a rethinking Universitat Autònoma de Barcelona, of the established treatment guidelines for the rationing of the administration of BCG. Some Bellaterra (Barcelona), Spain possible schedule modifications consist of a decrease in the length of maintenance treatment, a reduction in the dose of BCG in intravesical instillations or the use of different BCG substrains. All these strategies have been considered valuable in times of BCG shortage. In addition, the lack of availability of BCG has also led to the general recognition of the need to find new treatment options for these patients so that they are not dependent on a single treatment. Few alternatives are committed to definitively replacing BCG intravesical instilla- tions, but several options are being evaluated to improve its efficacy or to combine it with other chemotherapeutic or immunotherapeutic options that can also improve its effect. In this article, we review the current state of the treatment with BCG in terms of all of the aforementioned aspects. Keywords: mycobacteria, nonmuscle invasive, immunotherapy, alternative treatment BCG History Origin of BCG and Its Relationship with Bladder Cancer Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a species originated after 230 recultures of the pathogen M. bovis. Over a period of thirteen years, Albert Calmette and Camille Guérin recultured isolated colonies from the originally pathogenic M. bovis. In 1921, they demonstrated that the obtained bacillus was not only non-pathogenic in animal models but also protected against tuberculosis challenge in vaccinated animals. Afterwards, the massive production of BCG was initiated for use in tuberculosis prevention in humans, and it is still the only commercially available vaccine against tuberculosis. At that time, the use of a mixture of two bacteria, Serratia marcescens and Streptococcus pyogenes, was investigated for cancer treatment, and the possibility to use the newly developed and safe BCG offered a novel therapeutic option for some cancer patients. Although Correspondence: Esther Julián Departament de Genètica i de some studies demonstrated the potential efficacy of the new BCG as a treatment for Microbiologia, Facultat de Biociències, diverse types of cancer, it was not until the 1970s that BCG was approved as an Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain immunotherapeutic treatment for bladder cancer (BC) patients.1 Tel +34 93 5814870 Since then, BCG has been the standard therapy for treating high-risk nonmus- Fax +34 93 5812387 Email esther.julian@uab.cat cle-invasive bladder cancer (NMIBC) patients to avoid the recurrence and submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 1–11 1 DovePress © 2020 Guallar-Garrido and Julián. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www. http://doi.org/10.2147/ITT.S202006 dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Guallar-Garrido and Julián Dovepress progression of the disease. Intravesical instillations of the presence of the mentioned lipids is the differing ability hundreds of millions of bacilli are applied weekly in to induce the activation of the immune system through those patients over the course of six weeks (“induction distinct lipid immune receptors.5 Similarly, relevant pro- treatment”) after the transurethral resection of tumors teinaceous antigens such as MPT64 or MBP70 are differ- (TURBT) visible at the lumen surface of the bladder. If entially expressed among BCG substrains. How those the patient responds appropriately to the therapy, differences influence the immunogenic effect and safety a “maintenance treatment” consisting of six-week periods of the different BCG substrains in NMIBC therapy is an of instillation every three months for one to three years is issue that is still being researched. then undertaken to reach the optimum effect for avoiding recurrence and progression episodes. Safety and Efficacy As a therapeutic medicine in NMIBC patients, BCG is BCG Substrain Characteristics considered safe, although several adverse events have When BCG was developed, seed lots were sent to different been described in BCG-treated NMIBC patients.8 Flu- countries around the world. For over forty years, each like symptoms and/or burning discomfort in the bladder laboratory recultured this mycobacterium with their own occur in the majority of patients. In the EORTC trial, the protocol for its maintenance and production; thus, BCG overall rate of adverse events in BCG-treated patients was evolved differently in each laboratory, generating several as high as 70%, with 8% of patients discontinuing the substrains. The genetic comparison of the different BCG treatment due to toxicity.9 Despite not being frequent, substrains has demonstrated the deletion of some regions infections due to BCG, both local and, in rare cases, of their genomes, the inclusion of single-nucleotide poly- disseminated infections,10−13 have also been reported. In morphisms or insertion sequences, or the appearance of the case of BCG infection, antituberculosis drug treatment tandem duplications. The first elimination of the Region of is prescribed, which consists of four daily antimicrobials Differentiation (RD) 1 and point mutations in the for four months and two antimicrobials for two more original M. bovis strain generated the earliest BCG sub- months. When serious adverse events appear, intravesical strains, formed by the parent BCG and the first daughter instillations of BCG are stopped, and these patients are strains: BCG Russia, Moreau, Japan, Sweden and deprived of this efficacious treatment. Birkhaug. Later, the deletion of RD2 led to the “late” Regarding differences in safety and toxicity between group of strains, which included BCG Prague, Glaxo, the different BCG substrains, few studies have tried to Danish, Tice, Frappier, Connaught, Phipps and Pasteur.2–4 address this issue. Recently, a comparison of the toxicity Changes in the genetic background led in some cases triggered by BCG Tice, Moreau and RIVM in 844 patients to different mycobacterial phenotypes. One of the main demonstrated that BCG Tice caused more local and mild characteristics of mycobacteria is their cell wall, which systemic adverse effects than other tested BCG strains, contains long chains of mycolic acids, producing while patients receiving BCG RIVM suffered more severe a highly hydrophobic and impermeable wall, as well as complications.14 Noticeably, those patients who received glycolipids, lipoproteins, glycans and proteins.5 Some of two different strains developed severe complications just these lipids, such as mycolic acids, phthiocerol dimycocer- after the treatment switch. In contrast, in another study in osates (PDIM) or phenolic glycolipids (PGL), which have which BCG Connaught and BCG Japan were compared, been related to the interaction with host cells, are not the switch of substrains during the treatment reduced the equally present on the surface of the different BCG adverse events found at the beginning of the treatment.15 substrains.6 For instance, BCG Moreau and Japan do not All these data demonstrate the necessity of further studies have PDIM and PGL, and both lipids have been related to to elucidate the safety of BCG strains in NMIBC patients. the virulence and reactogenicity of mycobacteria. Another relevant issue regarding BCG therapy is the Otherwise, the substrains Moscow, Sweden, Birkhaug, efficacy of the different substrains. Some studies support the Frappier, Pasteur, Phipps, Tice, Copenhagen, Prague and idea that no substrain seems to be clearly superior to the Connaught contain PDIM and PGL.7 Moreover, only early others. A recent meta-analysis comparing 10 BCG substrains BCG strains contain three types of mycolic acids (alpha-, was unable to find the best substrain,16 and a previously methoxy- and keto-mycolate), while the later strains con- published retrospective study performed by Guerrero-Ramos tain only alpha- and keto-mycolates. The importance of et al found similar recurrence-free survival rates between submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 2 DovePress Dovepress Guallar-Garrido and Julián patients who had received BCG Connaught and those who previous natural floods. The forced closure of the factory had received BCG Tice.17 Similar conclusions were reached to decontaminate the area stopped BCG production. At by Unda-Urzaiz et al, who compared BCG Tokyo, Russian, that time, the BCG Connaught produced and distributed Tice, Connaught and RIVM;18 Krajewski et al, who compared by Sanofi was one of the main sources for BC treatment in BCG Tice, Moreau and RIVM;14 and a recent study that North America and Europe, which are the regions with the compared the BCG Moreau and Tice substrains.19 However, highest incidence of BC around the world.21 Afterwards, Rentsh et al demonstrated that BCG Connaught was signifi- Sanofi decided to stop the production of BCG and in mid- cantly more effective in terms of recurrence-free survival than 2017 confirmed that they were exiting the market. BCG Tice.20 Hence, these results were not conclusive, and Moreover, during the last five years, problems in BCG more research is required to determine whether shared fea- production in other companies resulted in supply con- tures among all BCGs are the clue for the appropriate therapy straints from the main suppliers.22 Hence, the severity of or whether key components(s) exist in some strains that the problem was dramatically increased due to both the determine immunotherapeutic activity. increasing global demand for BC treatment and the announced anticipated shortages because suppliers depleted their stocks. Even the increased production of Current Situation for BC Treatment BCG by Merck of more than one hundred percent23 is BCG Shortages still not enough to solve the enormous scarcity problem. The Beginning of the Problem As explained above, different substrains spread during the Clinical and Social Impact of BCG Shortages last century when worldwide laboratories were mass pro- BCG constraints have had an obvious clinical impact on BC ducing BCG for tuberculosis vaccines in their own coun- treatment. Because of this situation, NMIBC patients might tries. When BCG was established for NMIBC therapy, the have received fewer doses of BCG than those recom- manufacturers modified the vial concentration (one dose of mended, might have received instillations of different BCG substrains depending on the BCG availability in BCG for bladder cancer is similar to over 4000 doses of each region, might have received a reduced length of stan- BCG for vaccination) and the formulation to be delivered dard maintenance therapy, and so forth. Moreover, there into the bladder. Overall, few companies produce BCG for was an increased number of patients who had to be treated oncotherapy (Table 1) and export it worldwide. At the end by cystectomy. Ourfali and coworkers estimated the clinical of 2012, an unexpected event led to the collapse of the effect of BCG shortages between 2013 and 2016 in their Sanofi factory producing BCG Connaught in Canada. In unit of treatment.24 They found a significantly higher rate of a routine Food and Drug Administration (FDA) inspection, recurrence at 24 months after TURBT for current intermedi- mold was found in the area of BCG production due to ate- and high-risk NMIBC patients than for their patients diagnosed and treated during the three years before the Table 1 BCG Production Worldwide for Bladder Cancer Treatment BCG shortage. Apart from patient care, clinical trials have Strain Name Supplier been affected, and BCG shortages have even partially Connaugh TheraCys/ Sanofi Pasteur (Canada)* affected the immunization programs for TB prevention in ImmuCyst children around the world.25–27 From an economic point of view, Ourfali et al also Danish Urovac/BCG- Green Signal Bio Pharma Private Onco Limited GSBPL (India) found an increased cost due to the decrease in BCG production estimated at approximately €783 per patient Japan Immunobladder Japan BCG Laboratory (Japan) with a new diagnosis of NMIBC during the period of TICE OncoTice Organon-Merck (USA) restricted supply.24 Moreover, the prices of chemothera- RIVM BCG-Medac Medac GmbH (Germany) pies used for BC therapy spiked dramatically during /Vejicur a 2014 BCG shortage. In fact, that year, the price of mitomycin jumped by almost 100%. Data recorded in the Russian SII-Onco BCG Serum Institute of India Pvt Ltd (India) USA demonstrated that the amount spent for mitomycin in the USA between 2012 and 2015 increased from Note: *Production was definitely stopped and Connaugh strain is not available in the market $4.3 million to $15.8 million.28 submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 3 DovePress Guallar-Garrido and Julián Dovepress Optimization of the Use of the Scarce Comprehensive Cancer Network (NCCN),36 and the National Institute for Health and Care Excellence Vials of BCG (NICE)37,38 are constantly updated, taking advantage of pub- As soon as BCG shortages began, different strategies were lished results addressing an improved NMIBC treatment to adopted at different levels, from improvements in BCG overcome BCG adverse events.39,40 Furthermore, all updated production to modifications of the recommended treatment. recommendations were collected and compared in a new Improving BCG Production guideline.41 Recently, the Bladder Cancer Advocacy The production of BCG is not an easy matter. Due to the Network (BCAN) released a joint statement with representa- slow growth of the mycobacteria, any inaccuracy during tives of different urological societies to also help physicians the manufacturing process can lead to a large loss of time in the current framework. The consensus of general recom- and money, as the BCG shortages have proven.22 For this mendations to address BCG shortages is described below. reason, some researchers proposed optimizing BCG bulk For intermediate-risk NMIBC patients (multicurrent- production by modifying the growth in pellicles to the use multifocal low-grade disease) of bioreactors29 or evaluating the possibility of extending the shelf life of the already manufactured BCG vials.30 ● Intravesical chemotherapy (mitomycin, gemcitabine or epirubicin) must be used as a first-option treatment Regulatory Issues/Favorable Policies instead of BCG. Induction once a week for six to The effect of the decreased availability of BCG stocks is eight weeks plus a monthly maintenance schedule for exacerbated in some countries where a particular BCG is the one year. only source authorized for the treatment of BC patients. In ● For second-line treatment, a one-third dose of BCG the USA and Canada, for instance, OncoTICE from Merck is instead of full-dose BCG can be used. In that case, the only BCG available. A reasonable option would be different patients can be treated the same day clus- importing BCG from other countries, but regulatory issues tered in groups of three to avoid BCG wastage. hinder a rapid supply, and clinical trials have to be conducted ● Maintenance BCG can be omitted. in some cases to introduce new substrains. In this sense, the SWOG Cancer Research Network is conducting For high-risk NMIBC a randomized control trial, S1602, that compares the Tokyo and TICE substrains, aiming to approve the use of other ● Maintenance BCG therapy can be shortened to options for the treatment of US patients.31 Moreover, BC one year (instead of 3 years) for “low-tier” high- therapy becomes a serious issue in low- and middle-income risk tumors (TaHG tumors). countries where there are also limitations related to the higher ● One-third of the BCG dose can be considered for cost of import taxes and shipment, as well as the longer time both induction and maintenance. needed, for importing BCG.32 Thus, favorable policies ● Other alternatives to BCG include mitomycin should be implemented to facilitate access to alternative C (induction and maintenance up to one year) or drugs in countries that cannot afford their current cost. electromotive mitomycin (EMDA-MMC). Other options, such as gemcitabine, epirubicin or sequential Variations in Clinical Guidelines Recommendations gemcitabine/docetaxel, may also be considered. There are multiple organizational guidelines that assist phy- ● Mandatory cystectomy is recommended in patients sicians in finding the most favorable intravesical BCG ther- with very high-risk disease (T1HG tumors) asso- apy. Since the first shortage of BCG and throughout the ciated with carcinoma in situ (CIS). subsequent years when the shortage of BCG has persisted, international medical advisory boards have elaborated and The uniform application of guideline recommendations in adapted guideline recommendations to address the problem, daily practice to guarantee drug availability is critically although each strategy depends specifically on the BCG important. A recent study comparing daily practice with availability for each setting. For instance, guidelines such physicians’ knowledge of guidelines has found nonadher- as those from the European Association of Urology ence by physicians to the recommendations. In this regard, (EAU),33,34 the American Urological Association (AUA)/ an overtreatment with BCG instillations compared to the Society of Urologic Oncology (SUO),35 the National guideline recommendations has been found in both low-risk submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 4 DovePress Dovepress Guallar-Garrido and Julián and intermediate-risk patients.42 Although an underuse of mechanism that could explain BCG nonresponsivity in guideline-recommended intravesical treatments was pre- some individuals.50 viously reported,43,44 in the context of BCG shortage, it is On the other hand, optimum maintenance schedule has especially relevant to understand why routine practice dif- not been clarified.51 Differences among the studies in the fers in some cases from the recommended guidelines to tumor stage of patients, treatment schedules, dose, BCG improve patient care. It is worth noting that the BCG short- substrain and other parameters complicate the aim of age has resulted in an unusual increase in the prescription of achieving the best BCG maintenance schedule, and conse- BCG for CIS, which, although always recommended in the quently, further research is needed to maximize the effect guidelines,33 was not applied properly by physicians.45 of the current treatment. Recombinant BCGs Future of Noninvasive BC To maximize the antitumor effect of BCG as well as reduce the Treatment side effects, modifying BCG genetically to express additional To rationalize the use of BCG, several valid strategies are immunomodulators such as cytokines or chemokines is widely performed, from designing different schedules of adminis- explored.52 Notably, none of the constructs are currently con- tration to manipulating BCG to improve its immunother- sidered in clinical trials. The most recently published studies apeutic effect. focus on the use of bacterial antigens. Kanno et al improved the antitumor effect of BCG Moreau transformed with the detoxifed S1 subunit of pertussis toxin, which increased the Improving BCG Treatment Th1 immune response.53,54 Another approach consists of the Modification of Schedules. Priming–Boosting Strategy use of recombinant BCG with the insertion of listeriolysin On the one hand, an optimized immune effect triggered by from Listeria monocytogenes, which modifies the phagosomal intravesical BCG could lead to a reduction in the length of membrane in acidic conditions, and the deletion of urease C, the treatment, saving BCG doses and potential adverse which neutralizes the phagosome. These modifications lead to events, and could lead to the recovery of some nonrespon- decreased pathogenicity and an increased release of antigens sive BCG patients, who represent one of the main concerns into the cytosol of infected macrophages and dendritic cells for physicians due to the lack of treatment alternatives. An (DC), thus enhancing antigen presentation and T cell induction-boosting strategy could drive this increased responses. After good toleration was shown in Phase immune effect. In 1976, Morales et al discarded the parallel I clinical trials, Phase II is currently ongoing.55,56 Finally, intradermal vaccination with BCG and the intravesical BCG BCG effectiveness can be affected by antimicrobial peptides treatment in NMIBC patients, since no improvement was (AMPs) produced by mammalian cells to eliminate pathogens observed compared to BCG intravesical treatment alone.1 from the urinary tract. Cho et al produced recombinant BCG- This was later confirmed in other studies.46–48 However, expressing proteins that inhibit AMPs and lead to low survival a recent study in a mice model showed that priming with of BC cells in vitro due to increased BCG internalization and BCG improved the triggered immune response of later cytokine secretion.57 intravesical treatments. In the same study, the authors per- formed a retrospective study in patients, showing that pre- Current Alternatives to BCG vious BCG vaccination had a significantly improved Research on improving NMIBC therapy has mainly outcome compared with no previous BCG vaccination. focused on rescue patients who do not respond to BCG Two clinical trials are in progress in which NMIBC patients therapy, since BCG is truly efficacious in the majority of are first intradermally vaccinated with mycobacteria and patients for avoiding recurrence and progression episodes. then further treated with intravesical BCG. Priming is per- The alternative treatment options include virus and other formed in each trial with Tokyo BCG31 or RUTI (a ther- bacteria different from BCG as vehicles for specific tumor apeutic vaccine for tuberculosis).41,49 It is worth noting that growth inhibition agents or immunostimulatory compo- Ji et al (2019) recently demonstrated the safety of BCG nents, chemotherapeutic agents, new delivery options for priming in NMIBC patients as well as the different current therapies, and systemic immunotherapies that have responses of enhanced innate effector cells against some to be demonstrated to be efficacious in other types of specific BC cell lines, suggesting a potential BCG resistance cancers (Figure 1). submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 5 DovePress Guallar-Garrido and Julián Dovepress New chemotherapeutic instillations such as live or nonviable mycobacteria, bac- drugs teria other than mycobacteria or bacteria-derived compo- nents (reviewed in 62). For instance, the use of Salmonella has been proposed as a good alternative to treat the tumor Viral-based Bacteria-based agents agents because it is able to induce a massive infiltration of CD8+ cells, which correlates with better mouse survival rates.63 BCG Salmonella enterica Choleraesuis or S. enterica Ty21a alternatives induced the infiltration of natural killer T cells with only Checkpoint Improved one dose while BCG required multiple doses.64 A phase inhibitors delivered I clinical trial is currently assessing the safety of Ty21a systems (NCT03421236). In addition, Lactobacillus used as a food supplement is a safe microorganism that is able to induce NK cells, DCs and neutrophils, helping in the removal of Combined therapies the tumor.65 Another new immunotherapeutic agent is Figure 1 Current alternative research for nonmuscle invasive bladder cancer a vaccine using Pseudomonas aeruginosa mannose- treatment. sensitive hemagglutinin that increases antigen presenting function by activating the proliferation and differentiation Virus-Based Treatments of dendritic cells and further inhibits the proliferation New approaches to improve the treatment of NMIBC also of BC cell lines. This vaccine is available in China, include the use of virus as a vehicle to specifically intro- although its efficacy and safety have not yet been duce genetic material into tumor cells. This approach is verified.66,67 Moreover, because some mycobacterial com- a hopeful technique for several reasons. Virus can be ponents are ubiquitous in all mycobacterial species, the easily delivered into the bladder through the current pro- use of mycobacteria other than BCG has been studied cedure but has higher effectivity than BCG. In addition, for BC treatment. A M. phlei-derived complex called due to its specificity and the use of a guided virus to MCNA is being studied in clinical setting and is a good a specific type of cells, the reported adverse events should option for nonresponding BCG patients.68,69 Among non- decrease.58 Currently, there are several clinical trials tuberculous mycobacteria, M. brumae has recently shown ongoing. For instance, the enterovirus Coxsackievirus in preclinical studies a potential role in NMIBC since it A21, which is in a phase I clinical trial, is an effective inhibits tumor proliferation and triggers a proper antitumor oncolytic virus targeting specifically intracellular adhesion immune response.70–72 One important issue of mycobac- molecule-1, enhancing cell lysis.59 Serotype 5 adenovirus terial delivery remains their hydrophobicity and, conse- (CG0070) with conditional replication that controls the quently, clump formations. Hence, an optimized emulsion expression of GM-CSF cytokine, important in durable has been recently published to decrease clump formation, antitumor activity, is in a phase II clinical trial in patients which leads to increased antitumor activity triggered by who failed BCG therapy. GM-CSF is also expressed in BCG and M. brumae.73 fowlpox virus, which is able to induce an immune response in unresponsive BCG patients after four intrave- Chemotherapeutic Treatments and Improved sical doses.60 Moreover, a Phase III trial is currently eval- Delivery uating the antitumor activity of a recombinant adenovirus Different strategies can improve the use of chemotherapy that is able to transduce IFN-α into cancer cells with for treating NMIBC. The appearance of new agents, the a polyamide surfactant to facilitate adherence.61 Due to combination of different chemotherapeutic agents, the use the initial results in some studies demonstrating good of hyperthermia for improving intravesical instillation, or response, we are waiting with high enthusiasm the coming other strategies have been considered for improving the results. treatment of intermediate- and high-risk NMIBC patients. Mitomycin C is a chemotherapeutic agent widely used in Bacteria-Based Treatments cases of BCG failure, but other options are also available, One alternative to diminish the adverse events of BCG such as epirubicin, pirarubicin, and gemcitabine. In a recent consists on using safer alternatives to intravesical study, intravesical gemcitabine induced a lower rate of submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 6 DovePress Dovepress Guallar-Garrido and Julián recurrence, progression and treatment failure than epirubicin and slowly releases dissolving gemcitabine tablets.87 or pirarubicin.74 Furthermore, new multiagent intravesical Pharmacokinetically, 60–70% of the drug load is delivered chemotherapy regimens have been studied to improve the over 2 weeks, compared to the 2-h conventional dwell time efficacy and tolerability of BCG (reviewed in 75). For for intravesical drugs. In the following years, it is highly instance, excellent responses have been found when admin- expected that new device-assisted therapies will be improved istering gemcitabine with docetaxel, which seems to be an and more offerings will be available due to the promising effective alternative to treat CIS when BCG cannot be results after increasing the time of exposure together with administered, but further studies are needed.76 BCG supply issues. To decrease side effects, important for those patients who poorly tolerate BCG instillations while improving the Checkpoint Inhibitors in Nonmuscle-Invasive BC efficacy of BCG, the combination of BCG with che- Many efforts have been focused on checkpoint inhibition motherapeutic agents has also been studied. A recent therapies to block precise molecules, such as programmed meta-analysis concluded that the combination of both death receptor 1 (PD-1), programmed death-ligand 1 (PD- treatments appeared to be effective for intermediate- to L1), T-cell immunoglobulin and mucin domain-containing high-risk NMIBC patients but not for other cases. -3 (TIM-3), or cytotoxic T-lymphocyte-associated protein 4 Moreover, side effects were significantly decreased in (CTLA-4), to rescue the suppressed antitumoral immune patients who received BCG plus chemotherapy.77 response. Success in preclinical and clinical studies for the The efficacy of intravesical therapies can also be treatment of muscle-invasive bladder cancer patients, for improved through delivery adaptations such as hyperther- whom few therapeutic opportunities are available, led to mia, electromotive drug administration or new devices. FDA to approve some of these therapies. In the case of Hyperthermia is a safe and effective treatment that can NMIBC, pembrolizumab, an anti-PD-1 therapy, has been also be combined with other therapies such as mitomycin granted by FDA as a priority review for a new supplemental C. Local delivery systems are approved in Europe and Biologics License Application (sBLA).88 Merck is seeking recommended for intermediate- and high-risk NMIBC approval for high-risk BCG-unresponsive NMIBC patients patients, but further studies are required to decipher with CIS who are either ineligible for cystectomy or have whether this technique can substitute for BCG instillations, chosen not to undergo the procedure (Keynote-057 and which is the best system among all currently available; the Keynote-676trial) (Keytruda, Merck). Despite hopeful right scheme to follow; and the best temperature of the results from checkpoint inhibitors, the combination of this device.78 Recently, Zhou et al demonstrated that three therapy with chemotherapy or BCG is also being consecutive sessions, in which only the second session researched. For instance, the POTOMAC study, which ana- was combined with pirarubicin, was a safe and effective lyzes the effect of combining the anti-PD-L1, durvalumab, adjuvant treatment.79 Another possible solution to improve plus BCG versus BCG alone, both in the induction and treatment delivery is electromotive administration to pene- maintenance treatment of high-risk NMIBC patients, or trate deeper into the tissue through an electrode while the BMS-986205 study, which compares the administration transporting the drug by iontophoresis. Despite encoura- of nivolumab or nivolumab in combination with BCG in ging results demonstrating the increased penetration of the BCG-unresponsive patients. Not only are safety and effec- drug using this technique, and the confirmation of excel- tivity addressed in these studies but also the interest in lent oncologic efficacy in high-risk BCG-unresponsive obtaining a decreased cost of the treatment per patient.49,89 NMIBC patients,80–82 tolerability is still a challenge. As in other types of cancer, photodynamic therapy was also Concluding Remarks tested,83–86 but the efficacy of this treatment modality BCG remains the gold-standard treatment for high-risk should be explored further in clinical trials. NMIBC patients. Although BCG is not easy to produce, Device-assisted therapies are also an attractive solution to today there are no real alternatives to BCG, and its produc- improve the efficacy of chemotherapeutic treatments. With this tion has to be maintained by any means. Nevertheless, the aim, several devices are being developed to prolong the release situation of recent years has prompted research for the study of the drug over time, such as the GemRIS device, developed of possible therapeutic alternatives for these patients. by Taris Biomedica. The device consists of a 5-cm semiperme- Currently, most new therapeutic options are being tested in able silicone tube that functions as an osmotic pump BCG-unresponsive patients. Few trials are performed to submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 7 DovePress Guallar-Garrido and Julián Dovepress replace BCG. In view of the promising results that some of 11. Moussa M, Abou Chakra M. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instil- these new options show, new therapeutic options will be seen lation: a case report. Urol Case Reports. 2018;20:3–4. doi:10.1016/j. in the coming years. Another crucial point is to understand eucr.2018.05.012 why BCG works in a percentage of patients while in others it 12. Ziegler J, Ho J, Gibson IW, et al. Disseminated Mycobacterium bovis infection post-kidney transplant following remote intravesical BCG does not. All of this will lead us to personalized treatment therapy for bladder cancer. Transpl Infect Dis. 2018;20(5):e12931. with a combination of therapies for longer bladder preserva- doi:10.1111/tid.12931 tion times and better quality of life for patients. 13. Marques M, Vazquez D, Sousa S, Mesquita G, Duarte M, Ferreira R. Disseminated Bacillus Calmette-Guérin (BCG) infection with pul- monary and renal involvement: a rare complication of BCG immu- notherapy. A case report and narrative review. Pulmonology. 2019. Acknowledgments doi:10.1016/j.pulmoe.2019.10.001 This work was funded by the Spanish Ministry of 14. 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An update on immu- Gemcitabine and Anthracycline Antibiotics in Prevention of notherapy options for urothelial cancer. Expert Opin Biol Ther. Superficial Bladder Cancer Recurrence. 2019:1–5. 2019;19(12):1265–1274. doi:10.1080/14712598.2019.1667975 submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 10 DovePress Dovepress Guallar-Garrido and Julián ImmunoTargets and Therapy Dovepress Publish your work in this journal ImmunoTargets and Therapy is an international, peer-reviewed open programs and new therapeutic agents and protocols on patient per- access journal focusing on the immunological basis of diseases, spectives such as quality of life, adherence and satisfaction. The potential targets for immune based therapy and treatment protocols manuscript management system is completely online and includes employed to improve patient management. 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