Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies

Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.

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Is there a role for urine cytology following BCG therapy for non-muscle-invasive bladder cancer (NMIBC)?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.404 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 404-404

Author(s):

Sarah Prattley ◽

Ruth Jarvis ◽

Jon Featherstone ◽

Krishna Narahari ◽

Murali Varma ◽

...

Keyword(s):

Bladder Cancer ◽

Urine Cytology ◽

Invasive Bladder Cancer ◽

Positive Cytology ◽

Muscle Invasive Bladder Cancer ◽

Flexible Cystoscopy ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

404 Background: Voided urine cytology has been used as an adjunct in the diagnosis of non-muscle invasive bladder cancer (NMIBC), with a sensitivity and specificity ranging between 13-75% and 76-100% respectively. There is limited data on the accuracy and utility of cytology following BCG therapy. We reviewed the results of cytology in patients undergoing induction and maintenance BCG immunotherapy in our institution. Methods: Newly diagnosed patients who had received induction and maintenance intravesical BCG therapy from 2004 - 2019 were identified from a prospective database and their outcomes reviewed retrospectively. Histopathology results of biopsies / resected specimens and voided urine cytology results were examined for 273 patients. Results: A total of 2567 cytology results and 638 biopsy results were recorded. The average age was 73.2 years and median number of BCG treatments was four (induction followed by three maintenance courses). Median follow up was 38 months. 94 patients (34.4%) had recurrence following BCG therapy. Of those 33 patients (12.1%) had progression to muscle invasive disease. The number of cytology samples per patient after BCG therapy ranged from 1-23 (median 7), with several patients having repeated, potentially unnecessary negative urine cytology. Overall accuracy of cytology (n = 526) was sensitivity 44.2%, specificity 84.7%, PPV 38.9%, NPV 87.3%. Patients that had an erythematous bladder or red patch at flexible cystoscopy underwent subgroup analysis; this gave a very high NPV of 95.9%, with additional sensitivity being 65.5%, specificity 85.9% and PPV 33.3%. Number of positive cytology results (Chi2 = 44.30, P = 0.002), any positive cytology (Chi2 = 27.94, P < 0.001) and positive cytology after induction BCG therapy (Chi2 = 30.381, P < 0.001) were all strongly associated with recurrence. Conclusions: Positive urine cytology in patients undergoing intravesical BCG therapy predicts increased risk of recurrence and has good specificity. We would recommend using voided urine cytology in patients who have an erythematous bladder or red patch at flexible cystoscopy. If the cytology is positive then proceed to biopsy, however, if it is negative continue with surveillance. [Table: see text]

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Bladder preservation therapy for muscle invasive bladder cancer: the past, present and future

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa155 ◽

2020 ◽

Vol 50 (10) ◽

pp. 1097-1107

Author(s):

Tomokazu Kimura ◽

Hitoshi Ishikawa ◽

Takahiro Kojima ◽

Shuya Kandori ◽

Takashi Kawahara ◽

...

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Bladder Preservation ◽

The Past ◽

Muscle Invasive

Abstract Radical cystectomy is the gold standard treatment for muscle invasive bladder cancer, but some patients have medically inoperable disease or refuse cystectomy to preserve their bladder function. Bladder preservation therapy with transurethral resection of the bladder tumor and concurrent chemoradiotherapy, known as trimodal treatment, is regarded to be a curative-intent alternative to radical cystectomy for patients with muscle invasive bladder cancer during the past decade. After the development of immune checkpoint inhibitors, a world-changing breakthrough occurred in the field of metastatic urothelial carcinoma and many clinical trials have been conducted against non-muscle invasive bladder cancer. Interestingly, preclinical and clinical studies against other malignancies have shown that immune checkpoint inhibitors interact with the radiation-induced immune reaction. As half of the patients with muscle invasive bladder cancer are elderly, and some have renal dysfunction, not only as comorbidity but also because of hydronephrosis caused by their tumors, immune checkpoint inhibitors are expected to become part of a new therapeutic approach for combination treatment with radiotherapy. Accordingly, clinical trials testing immune checkpoint inhibitors have been initiated to preserve bladder for muscle invasive bladder cancer patients using radiation and immune checkpoint inhibitors with/without chemotherapy. The objective of this review is to summarize the evidence of trimodal therapy for muscle invasive bladder cancer during the past decade and to discuss the future directions of bladder preservation therapy in immuno-oncology era.

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COVID‐19 infection threat in patients with high‐risk non‐muscle invasive bladder cancer receiving intravesical BCG therapy

International Journal of Clinical Practice ◽

10.1111/ijcp.13752 ◽

2020 ◽

Author(s):

Serkan Akan ◽

Caner Ediz ◽

Yunus Emre Kızılkan ◽

Adem Alcin ◽

Hasan Huseyin Tavukcu ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

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Adjuvant cancer peptide vaccine treatment with intravesical BCG therapy for non-muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15587 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15587-e15587

Author(s):

Wataru Obara

Keyword(s):

Clinical Trial ◽

Bladder Cancer ◽

Peptide Vaccine ◽

Muscle Invasive Bladder Cancer ◽

Ctl Response ◽

Vaccine Treatment ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

e15587 Background: We previously reported safety and high immunogenicity of peptide vaccine treatment using two novel peptides derived from oncoantigens, M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1), for patients with advanced bladder cancer. We further conducted a multi-center phase II clinical trial using the same peptides to investigate the effectiveness to prevent recurrence after TURBt for patients with non-muscle invasive bladder cancer (NMIBC). Methods: The key eligibility criteria were patients with intermediate or high risk for NMIBC, with tumors having expression of MPHOSPH1 and/or DEPDC1, and with HLA class I expression on tumor cells. HLA-A24-restricted MPH and/or DEP derived peptide were subcutaneously administered in combination with intravesical BCG therapy after TUR-Bt. All enrolled patients had received the vaccination without knowing HLA-A status, and the HLA genotypes were used for a key-open marker. The primary endpoint was to examine effect on recurrence free survival (RFS) and secondary endpoint was induction of peptide-specific CTL response, injection site of reaction (ISR) and adverse effect. Results: A total of 133 patients were enrolled. RFS rates at 2 years in all patients were 74.4 %. Although the difference in RFS between the A24(+) and A24(-) groups (77.2% vs. 70.4%) was not statistically significant (p=0.24), that in the ISR-positive group was significantly better than that in the ISR-negative group (81.6% vs. 54.3%, p=0.0004). The peptide vaccine treatment was well-tolerated without any treatment- associated severe adverse events, while the bladder irritability caused by BCG treatment was observed in 64 cases (48.1%). The MPHOSPH1 and DEPDC1 peptide-specific CTL responses in the 24(+) group were observed in 82 % and 83 % of patients, respectively. Four (7.4%) cases in the 24(-) group revealed the peptide-specific CTL response, indicating some cross-reactivity against the vaccinated peptides on other HLA allele(s). Conclusions: Combination immunotherapy of intravesical BCG and cancer peptide vaccine demonstrated the promising clinical effect on recurrence prevention for NMIBC as well as good immunogenicity and safety. Clinical trial information: 00633204.

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Genome-wide association study on genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17000 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17000-e17000

Author(s):

Masaki Shiota ◽

Naohiro Fujimoto ◽

Yoshiaki Yamamoto ◽

Ario Takeuchi ◽

Katsunori Tatsugami ◽

...

Keyword(s):

Treatment Failure ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Muscle Invasive Bladder Cancer ◽

Genome Wide ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

e17000 Background: Bacillus Calmette–Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. Methods: This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in the distinct cohort. Results: The genome-wide association study indicated 19 candidate SNPs associated with BCG failure. Consistent results were obtained in six of these SNPs in the validation cohort. Following the combinational use of validated SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. Conclusions: This study showed that several SNPs were associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The combinational use of these SNPs may have value in clinical applications, although this should be confirmed in future studies.

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Renal Granulomatosis Post Intravesical Bacillus Calmette–Guerin Therapy for Non-muscle-invasive Bladder Cancer

Journal of Clinical Imaging Science ◽

10.4103/jcis.jcis_83_17 ◽

2018 ◽

Vol 8 ◽

pp. 18

Author(s):

Karen Tran-Harding ◽

Rashmi T Nair ◽

Halemane Ganesh

Keyword(s):

Bladder Cancer ◽

Invasive Bladder Cancer ◽

Bacillus Calmette Guerin ◽

Muscle Invasive Bladder Cancer ◽

Contrast Enhanced ◽

Bcg Therapy ◽

Muscle Invasive ◽

Intravesical Bcg Therapy ◽

Enhanced Computed Tomography ◽

Contrast Enhanced Computed Tomography

Intravesical Bacillus Calmette–Guerin (BCG) immunotherapy is a proven, effective treatment for intermediate- and high-risk non-muscle-invasive bladder cancer. Minor side effects are common and expected but systemic effects can occur in <5% of treated patients. We present a rare case of a 49-year-old male that presented with fever and chills after 3 weeks of intravesical BCG therapy post transurethral resection of bladder tumor. New renal lesions were present on contrast-enhanced computed tomography scan which was histologically proven to be necrotizing renal granulomatosis.

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