Page 7 - BladderCancerAbstracts

Posters

Prebiotics improve anti-PD1 immunotherapy efficacy in bladder normal urothelium, whereas untreated and mice injected with isotype
cancer by modulating the gut microbiota control antibodies showed reactive atypia or dysplasia. Both systemic
Jalal Laaraj 1,2,3 , Gabriel Lachance , Amenan Prisca Nadège Kone , and local immune profiling depicted sex differences, with female mice
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Yves Fradet , Alain Bergeron , Karine Robitaille , Vincent Fradet 1,2,3 having a higher number of splenic total and atypical B cells and show-
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1 Laboratoire d’Uro-Oncologie Expérimentale, Oncology Axis, Centre de ing increased density of both populations in the bladder tumor immune
recherche du CHU de Québec-Université Laval and Centre de recherche microenvironment compared to their male counterparts.
sur le Cancer de l’Université Laval, Quebec, QC, Canada; Faculty of Conclusions: These results suggest that long-term depletion of B cells in
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Medicine, Université Laval, Quebec, QC, Canada; Institut sur la nutri- aging mice leads to reduced inflammation in the bladder mucosa and
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tion et aliments fonctionnels (INAF) et centre NUTRISS, Université Laval, delays disease progression.
Quebec, QC, Canada
Introduction: The gut microbiota is a critical factor for the response Circulating tumor DNA in urothelial cancer patients, and FGFR-
to immune checkpoint blockade (ICB) immunotherapy in many can- targeted therapy eligibility and resistance
cers. Targeting gut microbiota with dietary elements is a new strategy to David C. Müller 1,2* , Elena Schönlau , Gillian Vandekerkhove ,
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improve ICB immunotherapy outcomes in cancer patients. The current Andrew Murtha , Jack V.W. Bacon , Kimia Rostin , Sunil Parimi ,
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study’s objective was to improve the efficacy of anti-PD1 in bladder Jean-Michel Lavoie , Krista Noonan , Naveen Basappa , Jennifer Ko ,
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cancer via the modulation of gut microbiota with prebiotics. Daygen Finch , Nimira Alimohamed , Tarek Bismar , Lucia Nappi ,
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Methods: C3H syngeneic mice were subcutaneously injected with MBT-2 Corinne Maurice Dror , Matti Annala 1,10 , Cecily Q. Bernales ,
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mouse bladder tumor cells. Prebiotics were administrated daily by oral gav- Christian Kollmannsberger , Kim N. Chi , Alexander W. Wyatt 1,11** ,
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age two weeks before tumor cell injection and until the end of the experi- Bernhard J. Eigl 1,3**
ment. Following tumor implantation, mice were treated with anti-PD1 1 Vancouver Prostate Centre, Department of Urologic Sciences, University
monoclonal antibody or isotype control intraperitoneally. Tumor growth of British Columbia, Vancouver, BC, Canada; Department of Urology,
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was monitored twice a week. Mice fecal samples were collected at base- University Hospital Basel, University of Basel, Switzerland; Department
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line and after two weeks of supplementation with prebiotics to perform of Medical Oncology, BC Cancer, Vancouver, BC, Canada; Department
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16S rRNA gene sequencing and profile the gut microbiota composition. of Medical Oncology, BC Cancer, Victoria, BC, Canada; Department
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At sacrifice, blood and tumors were harvested for flow cytometry analysis. of Medical Oncology, BC Cancer, Surrey, BC, Canada; Department
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Results: In comparison to control group, two prebiotic molecules sig- of Medical Oncology, Cross Cancer Institute, University of Alberta,
nificantly reduced MBT-2 tumor growth and improved overall mouse Edmonton, AB, Canada; Department of Medical Oncology, BC Cancer,
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survival. The gut microbiota profiling revealed an enrichment of the Abbotsford, BC, Canada; Department of Medical Oncology, BC Cancer,
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Bacteroides genus in mice gavaged with prebiotic A, while the prebiotic Kelowna, BC, Canada; Department of Medical Oncology, Tom Baker
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B induced enrichment of the Faecalibaculum genus and Lachnospiraceae Cancer Center, Calgary, AB, Canada; Prostate Cancer Research Center,
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family. Interestingly, prebiotic A supplementation combined with anti- Faculty of Medicine and Life Sciences and BioMediTech Institute,
PD-1 immunotherapy also enhanced the systemic antitumor effect of University of Tampere, Tampere, Finland; Michael Smith Genome
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ICB. Treatment with prebiotic A also resulted in a systemic expansion of Sciences Centre, BC Cancer, Vancouver, BC, Canada
circulating CD8 T cells, supporting a boosted immune response. */** Equal contributor
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Conclusions: Overall, our findings support that promising prebiotics can Introduction: The pan-FGFR-inhibitor erdafitinib is the first targeted agent
induce an antitumor effect alone, and in combination with anti-PD-1 approved in patients with metastatic urothelial cancer (mUC), along
treatment by modulating the gut microbiota, in a bladder cancer mouse with an archival-tissue companion diagnostic; however, longitudinal
model. These data will have a significant impact to understand and sequencing studies have shown changes in FGFR alterations over time.
improve the clinical response to ICB treatment for bladder cancer patients. Furthermore, erdafitinib resistance mechanisms in mUC are relatively
unexplored. This multicentre study evaluated the use of cell-free DNA
Investigating the role of tumor-associated B cells in bladder (cfDNA) compared to archival tumor tissue in mUC to assess a patient’s
cancer progression FGFR status, and through serial sampling, to evaluate genomic mecha-
Sadaf Rahimi, Priyanka Yolmo, Gwenaelle Conseil, Kartik Sachdeva, nisms of erdafitinib resistance.
D. Robert Siemens, Madhuri Koti Methods: Patients with progressing mUC undergoing standard tissue test-
Queen’s Cancer Research Institute, Queen’s University, Kingston, ON, ing for FGFR1-3 mutations and/or fusions and who had blood samples
Canada drawn during the management of their disease were eligible. Clinical
Introduction: Bladder cancer is mostly diagnosed in older individuals routine testing was applied for tissue testing. We assessed cfDNA using
(>65 years of age) and can be broadly categorized into non-muscle-inva- deep sequencing of UC-specific gene loci.
sive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Results: As of January 2023, 109 patients from six sites were enrolled.
Almost 75% of the incident bladder cancer cases are NMIBC and 25% Median age at diagnosis was 71, 36% had upper urinary tract primaries,
present with de novo MIBC. Progression to secondary MIBC often occurs and 78% were male. Most (73%) patients had detectable levels of circu-
in patients with high-risk NMIBC. Our recent study on whole transcrip- lating tumor DNA. Analysis of tumor tissue and cfDNA revealed a high
tome analysis of tumors from 460 patients showed increased expression concordance, with only four differing findings comprised of one negative
of B cell associated genes in high-grade tumors. Spatial immune profiling cfDNA test in a patient whose tumor tissue showed a FGFR3-TACC3
of 332 tumors demonstrated increased density of intratumoral B cells in fusion and three positive cfDNA test results in patients with FGFR altera-
patients who exhibited shorter recurrence-free survival. We hypothesized tion negative tissue tests. To date, four patients have had cfDNA samples
that specific B cell subsets expand due to carcinogen-induced chronic taken upon progression after erdafitinib treatment. In one of these, we
inflammation in the bladder mucosa, promoting tumor progression. detected several tumor subpopulations developing variations of the same
Methods: Female and male aging (12-month-old) mice were exposed to FGFR3 gatekeeper mutation V555L/M. Additionally, this patient gained
N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen with simul- another FGFR3 gatekeeper mutation, N540K, and a de novo FGFR3-
taneous B cell depletion using a panel of B cell depleting antibodies. TACC3 fusion under therapy.
Systemic immune profiling was conducted at multiple time points using Conclusions: In this preliminary analysis, cfDNA was a valuable addition
flow cytometry. Whole bladder sections were subjected to hematoxylin to tissue-based assays for determining somatic FGFR alteration status
and eosin (H&E) and multiplex immunofluorescence staining. — potentially giving additional patients a chance to benefit from FGFR-
Results: Increased recruitment of atypical B cells (ABCs) was observed targeted therapy. Our explorative analyses help to decipher erdafitinib
following continuous exposure to BBN. B cell depletion during BBN therapy resistance in mUC.
exposure resulted in reduced inflammation and delayed cancer progres-
sion. B cell depleted mice exhibited histologically benign or close to
CUAJ • MARCH 2023 • VOLUME 17, ISSUE 3(SUPPL1) S5