Conferences

AIBCCR 2022: Cell-free DNA, Circulating Tumor Cells, Exosomes and Bladder Cancer

Session Title: Cell-free DNA, Circulating Tumor Cells, Exosomes, and Bladder Cancer

(UroToday.com) Day 2 of the 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium was chaired by Dr Bishoy Faltas (Weill Cornell Medicine) who started the session with his talk on serial cell tumor DNA (ctDNA) analysis for evolution-directed therapy in patients with urothelial carcinoma. ctDNA represents a subset of cell-free DNA (sfDNA), where tumor DNA from cancer cells are shed in the blood stream. Given that urothelial cancer has a high tumor mutational burden (TMB), this allows for identification of ctDNA in the blood which provides a ‘window’ to mutations present in the primary tumor. The advantage of ctDNA allows for serial liquid biopsies to map evolutionally trajectories in patients with advanced bladder cancer.

Dr Faltas presented published data from his group based on 183 serial ctNDA samples from 53 patients with advanced urothelial carcinoma analyzed with the GUARDANT360 targeted sequencing panel.   1  He reported that p53 and PIK3CA mutations were identified in 50% and 19% of patients respectively with FGFR3 mutations found in 10 patients. ctDNA improved clinical prognostic models (c-statistic from 0.65 to 0.84) with serial sampling further improving these models compared to baseline ctDNA alone. The key benefit of cfDNA is the ability to dynamically track clonal cell evolution. Analysis of this patient cohort suggested that cfDNA has prognostic value and can predict oncological outcomes. Patients who were ctDNA positive prior to treatment and subsequently became ctDNA negative post treatment had a significantly lower risk of death independent to confounding factors suggesting that molecular remission predicts durable response to treatment. ctDNA was also showed to be highly correlated with radiological progression of disease. He concluded this talk with his vision of evolution-directed therapy, where tumor biopsy and liquid biopsies will undergo molecular profiling to allow for treatment selection and serial analysis of liquid biopsies would allow the prediction of tumor genomic evolution with the opportunity to intervene with therapeutics.  2 

 

AIBCCR 2022 Bishoy Faltas_0 

Vision of evolution-directed therapy  2 

 

The second talk was delivered by Dr Petros Grivas (Fred Hutchinson Cancer Center) which was on the potential opportunities for screening, surveillance, monitoring and therapeutic guidance utilizing ctDNA in urothelial carcinoma. He started his talk by highlighting the relationship between cancer proliferation burden and ctDNA which can eb highly variable. Highly sensitive assays are crucial for the detection of somatic alterations in cfDNA because ctDNA only represents 0.1% of sfDNA which can limit of detection ability of assays. He highlighted important considerations in the application of ctNDA: 1) the different roles of liquid biopsies such as cancer detection (diagnostic, screening) versus genomic characterization (prognostic, predictive, therapeutic response, resistance monitoring), 2) assay characteristics (depth and breadth of sequencing, bioinformatics, large versus small panel assay and tissue specific versus agnostic assays) and 3) the different endpoints used in studies.

Dr Grivas highlighted a report which used a patient specific tumor 16-plex PCR amplicon test (Singnatera) to interrogate longitudinal ctDNA samples in patients with advanced bladder cancer.   3  Patients who were ctDNA positive prior to neoadjuvant chemotherapy and radical cystectomy as well as following radical cystectomy had a much higher risk of disease recurrence compared with patients with ctDNA negative. Similar findings were reported in patients treated with neoadjuvant immunotherapy in the single arm ABACUS trial.   4  ctDNA also had an average positive lead time of 3 months ahead of radiological identification of clinical recurrence.   3  However, it remains uncertain if earlier identification of disease recurrence would change cancer specific survival.

Translational endpoints from clinical trials may provide important data. In the INVIGOR 010, a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer, patients who were ctDNA positive had worse survival outcome (HR: 6.3, 95% CI: 4.45-8.92), but this same patient cohort had an improved disease-free survival (HR: 0.58, 95% CI: 0.43-0.79) and overall survival (HR: 0.59, 95% CI: 0.41-0.86) in the atezolizumab versus observational arm.   5  Dr Grivas concluded that ctDNA requires further validation work and well design trails with proven clinical utility is crucial before clinical adoption.

 

AIBCCR 2022 Bishoy Faltas_1 

Negative ctDNA patients have better DFS and OS. In patients with positive ctDNA, treatment with atezolizumab resulted in better DFS and OS compared to observation   5 

The next talk was on the utilization of extracellular vesicles (EV) as a diagnostic and therapeutic nanotool in bladder cancer delivered by Dr Yi-Fin Lee (University of Rochester Medical Center). She introduced the role of EV as an important regulator of intracellular communication. These lipid bilayer nanoparticles (30-250nm) are naturally released from all animal cells and transport protein, nucleic acid, lipids and metabolites. Cancer cells release more EV which is implicated in all cancer stages. EV may function in immune response modulation, biomarkers and vehicle for drug delivery. In bladder cancer, Dr Lee’s group has shown that EV can drive tumorigenesis by inducing unfolding of protein response in the endoplastic reticulum of non-cancer cells.   6 . Utilizing protein disulfide isomerase (PDI) as an example, she described how unfolded protein accumulates within the cancer cell resulting in endoplastic reticulum stress and unfolding of protein response. This results in the oxidized PDI which is packed into EV and released from the cancer cell. These EV are then endocytosed in normal cells and hydrogen peroxide is then released leading to DNA damage and malignant transformation. As a biomarker, her group has also reported that EV can modulate response to BCG therapy in bladder cancer, allowing for early identification of metastatic disease and disease recurrence.   7  She concludes that EV is an area of active research due to its physiological and pathological role in cancer and prognostic biomarkers to therapy although challenges exist in purification and characterization of EV as well as further validation studies.

The final talk was delivered by Dr Steve Soper (University of Kansas) on the opportunities and challenges on liquid biopsies for cancer. He started his talk by highlighting difference in substrate concentration in circulating tumor cells (CTC) (6-600 pg of gDNA/ml), cfDNA (2.8 molecules/ ml) and exosomes (30 molecules/ml). CTC are dynamic due to upregulation and downregulation in EMT genes. Key limitations are the ability to detect the ‘needle in the haystack’. His team developed the BioFluidica, LiquidScan, a fully automated platform with allows interrogation of CTC, cfDNA and EVs which represents an growing area of research.  


Presented by: Dr Bishoy Faltas, MD, Director, Bladder Cancer Research, Englander Institute of Precision Medicine, Weill Cornell Medicine; Dr Petros Grivas, MD, PhD, Professor of Medical Oncology, Fred Hutchinson Cancer Center; Dr Yi-Fin Lee, PhD, Professor of Urology, Pathology and Laboratory Medicine, University of Rochester Medical Center; Dr Steve Soper, PhD, Professor Chemistry and Mechanical Engineering, University of Kansas.



Written by: Wei Shen Tan MBBCh, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, Twitter: @drtanws during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022


References:
  1. Shohdy KS, Villamar DM, Cao Y, et al. Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma. Br J Cancer 2022;126(3):430-39.
  2. Vlachostergios PJ, Faltas BM. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nature Reviews Clinical Oncology 2018;15(8):495-509.
  3. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol 2019;37(18):1547-57.
  4. Szabados B, Kockx M, Assaf ZJ, et al. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. Eur Urol 2022;82(2):212-22.
  5. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595(7867):432-37.
  6. Wu CH, Silvers CR, Messing EM, Lee YF. Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells. J Biol Chem 2019;294(9):3207-18.
  7. Liu YR, Ortiz-Bonilla CJ, Lee YF. Extracellular Vesicles in Bladder Cancer: Biomarkers and Beyond. Int J Mol Sci 2018;19(9).
  8. Muller R, Purushotham S, Diaz P, et al. Detection of CTCs from whole blood of lung cancer patients using the automated Liquid Scan. Cancer Research 2019;79(13_Supplement):3984-84.

AIBCCR 2022: The Implications of Biological Sex in Bladder Cancer

Session: Sex as a Biological Variable in Bladder Cancer

The afternoon session started with Dr. Ingersoll (Institut Pasteur) discussing sex in bladder cancer. She started by explaining the difference between sex and gender. Sex is dependent on chromosome organization, sex steroids levels, reproductive organs, and sexually dimorphic characteristics. Gender is a social construct and related to behaviors. Sex differences are responsible for the difference in bladder cancer incidence while gender related differences are observed because of differences in smoking and bladder cancer occupational risk factors. Drivers of sex bias in bladder cancer are likely related to sex chromosomes in terms of genetic and epigenetic differences and sex hormones and their downstream receptors such as ERα, ERβ, GPER1, and androgen receptor (AR). In her research, she reported no difference in immune cells infiltration between sexes except for tumor specific T cells. She concluded by citing a study of 1000 healthy individuals where they evaluated the effects of sex on transcriptional responses of most immune-related genes using microbial challenges.1 They noted sex differences in gene expression of CD4+T cells and monocytes.

During the second talk, Dr. Miyamoto (University of Rochester) provided an overview of the molecular biology of sex hormone receptors in bladder cancer. Specifically, he discussed the role of AR in tumorgenicity, progression and response to conventional chemotherapy and immunotherapy. In a mice model study, 92% of the male wild-type AR mice developed bladder cancer while 50% of castrated male wild-type mice developed cancer. In comparison, 42% of the wild-type female mice developed cancer and none of the female AR knock out mice developed cancer. Overall, there was a trend of AR activity down regulating tumor suppressors such as UGT1A1 and upregulating oncogenic molecules such as NFKB in non-neoplastic urothelial cells. AR pathway targets within bladder cancer cells include EGFR, AKT, WNT, ELK, NFKB, ATF2, and FOXO1. Finally, in terms of therapeutic resistance, he noted decreased BCG therapy efficacy via modulation of Rab27b induced exocytosis in AR+ cancers. Furthermore, AR positive cells were more resistant to cisplatin chemotherapy and radiation therapy.2 In the estrogen domain, he discussed the potential outcome of having ER+ tumors depending on subunit of the estrogen receptor present; with ERα likely protective and ERβ likely oncogenic.3

The role of sex chromosomes and sex hormones were presented by Dr. Sean Li (Boston Children’s Hospital and Harvard Medical School). Utilizing four different sex genotypes in his lab including XYM, XYF, XXM and XXF, he observed that having two copies of the X chromosome was protective in bladder carcinogenesis via kdm6a gene modulation. When comparing XY versus XX, there was a 2.5-fold increase in cancer risk and when comparing testes versus ovaries, there was a 4.7-fold increase in cancer risk. Tumor infiltrating CD8+ T cells also demonstrated superior effector function in female mice. He concluded the talk by discussing decreased CD8+T cell exhaustion and suppressed tumor growth after castration in invivo studies.

In the last talk of the afternoon, Dr. Koti (Queen’s University) closed the session by addressing sex differences in responses to BCG induced B cell treatment of bladder cancer. She presented findings from her lab showing that female patients with high grade NMIBC have higher density of tumor infiltrating B cells and this was associated with shorter progression free survival and earlier recurrence. 4 Tertiary lymphoid structures (TLSs) are concentrations of immune cells that are found in the setting of chronic inflammation including cancer. In newer studies, she observed no difference in TLS from BCG responders and non-responders. However, she found that BCG induces TLS formation in the bladder microenvironment of female aging mice. Finally, she reported that decreased expansion of B-cells in male mice post BCG treatment.

 

Presented by:

  • Molly Ingersoll PhD, Research Director/Directeur de Recherche, Mucosal Inflammation and Immunity Group, Institut Pasteur & Institut Cochin
  • Hiroshi Miyamoto MD, PhD, Director of Genitourinary Pathology at the University of Rochester Medical Center.
  • Sean Li PhD, Associate Professor, Departments of Surgery and Urology, Boston Children’s Hospital and Harvard Medical School
  • Madhuri Koti DVM, MVSc, PhD Assistant Professor, Department of Biomedical and Molecular Sciences at Queen’s University

Written by: Valentina Grajales MD, MS, Urologic Oncology Fellow, Twitter: @ValGraj, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022



References: 

  1. Piasecka B, Duffy D, Urrutia A, Quach H, Patin E, Posseme C, Bergstedt J, Charbit B, Rouilly V, MacPherson CR, Hasan M, Albaud B, Gentien D, Fellay J, Albert ML, Quintana-Murci L; Milieu Intérieur Consortium. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E488-E497. doi: 10.1073/pnas.1714765115. Epub 2017 Dec 27. PMID: 29282317; PMCID: PMC5776984.
  2. Ide H, Inoue S, Mizushima T, Jiang G, Chuang KH, Oya M, Miyamoto H. Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer. Mol Cancer Ther. 2018 Jul;17(7):1566-1574. doi: 10.1158/1535-7163.MCT-17-1061. Epub 2018 May 2. PMID: 29720561.
  3. Miyamoto H, Yao JL, Chaux A, Zheng Y, Hsu I, Izumi K, Chang C, Messing EM, Netto GJ, Yeh S. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 2012 Jun;109(11):1716-26. doi: 10.1111/j.1464-410X.2011.10706.x. Epub 2012 Jan 5. PMID: 22221549.
  4. Chenard S, Jackson C, Vidotto T, Chen L, Hardy C, Jamaspishvilli T, Berman D, Siemens DR, Koti M. Sexual Dimorphism in Outcomes of Non-muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint. Eur Urol Open Sci. 2021 Jun 3;29:50-58. doi: 10.1016/j.euros.2021.05.002. PMID: 34337534; PMCID: PMC8317911.

 

 

AIBCCR 2022: T1 Bladder Cancer

Session: T1 Bladder Cancer
(UroToday.com) The second session of the 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium was chaired by Dr Trinity Bivalacqua (University of Pennsylvania), who set the scene for T1 bladder cancer, where up to 50% of patients continue to develop disease recurrence despite BCG intravesical treatment. He highlighted the importance of preclinical modelling which can help interrogate the heterogenous cell types implicated in bladder cancer to help better understand the disease.

Dr Sima Porten (University of California San Francisco) delivered the second talk on clinical outcomes and current treatment strategies for T1 bladder cancer. She highlighted the conundrum patients and physicians face regarding bladder preservation therapy, where patients receiving intravesical BCG treatment risking disease progression versus early radical cystectomy with quality of life implications. Historic reports of the natural history of high grade (HG) T1 tumors reported a 53% risk of disease progression, 36% radical cystectomy rate and cancer specific mortality of 34% at 15 years.  1  However, more contemporary series of patients treated with adequate BCG suggest a freedom of high-grade recurrence of 74% and progression-free survival of 92% at 5 years.   2  Dr Porten highlighted several studies to support early radical cystectomy for HG T1 bladder cancer. Retrospective analysis of patients with HG pT1 bladder cancer report that deferred radical cystectomy resulted in a poorer 10-year cancer specific survival compared to patients receiving early radical cystectomy (51% vs 78%, p<0.01).   3  Further, 8% of patients with HG T1 patients were found to have lymph node positive disease at radical cystectomy, with 15% of patients upstaged to muscle-invasive bladder cancer (MIBC).   4  She stressed limitations of accurate disease staging by transurethral resection of bladder tumor (TURBT), clinical parameters, imaging and the need for better biomarkers and understanding in tumor biology. Dr Porten highlighted work from UCSF on Fibroblast activation protein inhibitor (FAPI)-PET/CT which may better assist in the identification of bladder cancer patients with occult nodal disease. FAPI which is excreted in urine limits the ability for accurate local staging, but early phase studies suggest that FAPI-PET/CT is better at identifying lymph node metastasis compared to fluorodeoxyglucose (FDG) PET/CT.

In the second talk which was on molecular and genetic aberrations on T1 bladder cancer was delivered by Dr Hikmat Al-Ahmadie (Memorial Sloan Kettering Cancer Center). He highlighted significant anatomical variation in histological landmarks where the lamina propria can be multiple folds thicker in the bladder dome compared to the trigone.  5  He pointed out limitations in pathological reporting and processing. TURBT represents a piece meal resection of tumor where lamina propria might be missed by the reporting pathologist in the sea of superficial papillary tissue. Haphazard orientation of TURBT chips by the fixation during processing can also limit the depth of tumor infiltration measurement. While sub-staging of lamina propria is recommended, there remains a lack of consensus on how this should be done. Binary classification such as focal versus extensive lamina propria invasion may provide important clinically relevant information and would allow for easy clinical adoption. Dr Al-Ahmadie concluded that genomic characterization of variant histology, tumor mutational burden and DNA damage repair genes may help compliment traditional clinical and histopathological classification.

Dr Cathy Mendelsohn (Columbia University) delivered the next talk on the investigation of luminal-basal plasticity in high grade T1 urothelial carcinoma. She presented work from her group on how chronic injury and inflammation can activate basal progenitor cells leading to bladder cancer development. Genomic classification suggested that PPAR gamma may be actively suppressed in basal/ squamous tumors which suggested that a loss of signaling may promote bladder cancer formation via MEK pathway.   6  Preclinical studies suggested that PPAR gamma mutation resulted in upregulation of NFKβ signaling resulting in squamous metaplasia.   7  She hypothesized that PPAR gamma signaling and MEK inhibition can reduce tumor growth. Her group has previously shown that utilizing mouse models, treatment with rosiglitazone (PPAR gamma agonist) and trametinib (MEK inhibitor) eradicates basal tumors in a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model.   7 

Dr John Sfakianos (Mount Sinai) then discussed the immune landscape of T1 urothelial carcinoma. He emphasized the significant disease heterogeneity in T1 bladder cancer and the upregulation of inflammatory markers in HG T1 tumors. His group utilized spatial sequencing, which allows for colocalization of gene expression, and reported that BCG naive tumors have a lower HLA-E expression and T/ NK infiltration.  8  BCG treatment then resulted in a dramatic increase in HLA-E expression. This is of relevance in BCG unresponsive tumors where despite recruitment of NK and T cells via the production of CXCL9/10/11, immune exhaustion may be responsible for treatment failure. He postulated that in patients with high levels of inflammatory cellular infiltrate, chemotherapy may be more effective than BCG. Further, priming tumors with chemotherapy prior to treatment BCG may improve BCG efficacy as second line treatment.

 

AIBCCR 2022 Trinity Bivalacqua 

A) Visium spots labelled based on high expression of combination gene scores for NK, T and tumor cell markers. B) Magnified expression heatmaps within the shaded red box of combined NK, T or tumor cell markers and HLA-E. C) NK and T-cell markers by lineage showing upregulation of NK and T cell markers in the immune subtype, suggesting that along with upregulated checkpoints we see upregulated infiltration of immune markers in those tumor nests.

 

The final talk of the session was by Roger Li (Moffitt Cancer Center) on biomarkers for bladder sparing therapy in T1 bladder cancer. He highlighted the differences in predictive, prognostic and both predictive and prognostic biomarkers. Dr Li provided a comprehensive review of biomarkers in the T1 arena. He presented data on a 12-gene progression score to predict risk of NMIBC progression to MIBC which was an independent of clinical and histopathological risk factors.   9  Further work on transcriptomic profiling of T1 tumors had also identified 5 subtypes with variable response following BCG.   10  T1-Myc and T1-Early tumors had the highest risk of recurrence (58% at 24 months) with T1-TLum tumors observing the fewest recurrence (15% at 24 months) following BCG treatment.   10  Other studies he summarized include the CyPRIT cytokine urinary assay, basal versus luminal subclassification.   11, 12  He concluded that bladder cancer represents the cancer with the highest burden of copy number variation and would represent an area for future research.

Presented by: Dr Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, University of Pennsylvania; Dr Hikmat Al-Ahmadie, MD , Pathologist, Memorial Sloan Kettering Cancer Center; Dr Sima Porten, MD, MPH, Associate Professor of Urology, University of California San Francisco; Dr Cathy Mendelsohn, PhD, Professor of Urological Sciences, Pathology & Cell Biology, Columbia University; Dr John Sfakianos, MD, Assistant Professor of Urology, Mount Sinai; Roger Li, MD, Urologic oncologist, Moffitt Cancer Center,

Written by: Wei Shen Tan MBBCh, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, Twitter: @drtanws during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022

References: 
  1. Cookson MS, Herr HW, Zhang ZF, et al. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997;158(1):62-7.
  2. Matulay JT, Li R, Hensley PJ, et al. Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design. J Urol 2021;205(6):1612-21.
  3. Denzinger S, Fritsche HM, Otto W, et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53(1):146-52.
  4. Bruins HM, Skinner EC, Dorin RP, et al. Incidence and location of lymph node metastases in patients undergoing radical cystectomy for clinical non-muscle invasive bladder cancer: results from a prospective lymph node mapping study. Urol Oncol 2014;32(1):24.e13-9.
  5. Lopez-Beltran A, Cheng L. Stage T1 bladder cancer: diagnostic criteria and pitfalls. Pathology 2021;53(1):67-85.
  6. Liu C, Tate T, Batourina E, et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat Commun 2019;10(1):4589.
  7. Tate T, Xiang T, Wobker SE, et al. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat Commun 2021;12(1):6160.
  8. Ranti D, Wang Y, Daza J, et al. PD12-05 SPATIAL TRANSCRIPTOMICS PROVIDES EVIDENCE FOR ALTERNATIVE CHECKPOINT AXES IN BCG-TREATED NMIBC. Journal of Urology 2022;207(Supplement 5):e196.
  9. Dyrskjøt L, Reinert T, Algaba F, et al. Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study. Eur Urol 2017;72(3):461-69.
  10. Robertson AG, Groeneveld CS, Jordan B, et al. Identification of Differential Tumor Subtypes of T1 Bladder Cancer. Eur Urol 2020;78(4):533-37.
  11. Kamat AM, Briggman J, Urbauer DL, et al. Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin. Eur Urol 2016;69(2):197-200.
  12. Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014;25(2):152-65.

 

 

 

 

 

 

 

AIBCCR 2022: CAR-T Cells and Next Generation Immunotherapy for Bladder Cancer

Session: CAR-T and Other Novel Immunotherapeutics in Bladder Cancer  


(UroToday.com) Dr. Gao (MD Anderson) opened the first session of the 8th Annual Leo and Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium with his talk on immunotherapy and genetic alterations that affect response to treatment. He provided an overview of tumor genomic alterations highlighting IFN gamma alteration, 9p21 loss, RNA splicing errors and FGRF3 mutation. He hypothesized that MTAP deficiency in 9p21 loss in bladder cancer would result in hypersensitivity to anti-folate agents such as pemetrexed via synthetic lethality. His team observed that treating human cell lines with 9p21 with pemetrexed resulted in increased cell death. In addition, loss of 9p21 results in MTAP loss which is involved in nucleotide synthesis and cell survival. Using MTAP as a surrogate for 9p21 loss he observed a poorer response to immunotherapy. He concluded the talk by emphasizing that 9p21 loss correlates with a “cold” tumor microenvironment, poor clinical outcomes, and resistance to immunotherapy. Therapeutic strategies targeting folate metabolism, PD1/PDL-1 pathway and adenosine pathway in bladder cancer with 9p21 loss are areas of future research.

CAR-T cells are genetically engineered T cells that target tumor antigens independent of MHC presentation and can induce tumor death.1 In hematologic malignancies, CAR-T cells have had impressive therapeutic effects which have encouraged studies in solid organ tumor malignancies, especially genitourinary tumors. 1 Dr. Nausheen (University of Kansas) reviewed advances in CAR-T cell therapy, especially in hematological malignancies and how lessons learned can be applied to solid tumors. She started by reviewing the process of CAR-T cells development using viral DNA insertion to genetically modify a patient’s T cells followed by amplification before being transfused back to the patient (diagram below). As she pointed out, the first generation of CAR T cells were developed in 1993 but it was not until 2017 that it was first approved for clinical use. There are now different constructs with five generations of CAR T therapies. 2 A challenge with disease relapse is due to antigen escape but new targets are being developed using antigens such as CD22 in lymphoma and antigen multitargeting. Other strategies include modifying antigen affinity and combining antigens with other small molecules. T cell exhaustion is also being tackled by a fourth generation of CAR T cells with “self-driving” properties. In solid tumors, there are concerns relating to on-target tumor effect given that there is no exclusive antigen on tumor cells. Several strategies being studied using SynNotch receptors by identifying two antigens to activate the CAR T cell while protecting normal tissue which has only one antigen.

Dr. Horowitz (Mount Sinai) continued the session with a discussion of using both NK and CD8 T cells in bladder cancer microenvironment to target BCG unresponsive NMIBC. He started by pointing out that NK cells lack antigen receptors, and their activation is regulated by the collective strength of inhibitory and activating signals. He explained that both HLA-E and NKG2A serve as inhibitory checkpoints for CD8 T Cells. He highlighted that blocking the NKG2 A receptor enhances tumor immunity by enhancing and rescuing NK and CD8 T cells function.3 In addition, HLA-E is strongly enhanced in BCG unresponsive tumors. Lastly, he discussed that adaptive immune resistance can be seen with NK inhibitory pathways.

Expanding on NK cells, Dr. Rafei (MD Anderson) highlighted a new generation of engineered NK cells as vehicles for CAR T cell therapy in their efforts to reduce cost and increase access to treatment. These are advantageous and great candidates in that they do not cause graft versus host disease even in the allogeneic setting, there is no need for antigen priming, they can be inhibitory or activated, found primarily in the blood, part of the innate immune system and reduces the risk of disease relapse. Based on TCGA data, CD70 can be used as a pan cancer antigen including in solid organ tumors. Importantly, CD70 has low expression in normal tissues. ARGX-110, a human monoclonal antibody targeting CD70 has been tested in multiple trials with promising results. Her lab is studying Burkitt lymphoma in CD70+ mouse models and have shown impressive results with a CAR-NK construct. In addition, she reported high cytotoxicity with CAR T cell treatment in kidney cancer preclinical models without dysregulated or autonomous growth with no on target off tumor effect.

Closing the session, Dr. Akhavan (University of Kansas) introduced new opportunities to overcome obstacles in designing CAR-T cells for use within the bladder cancer space. He discussed the challenges in solid organ tumors including CAR T tumor infiltration, overcoming inhibitory molecules and cells in the tumor microenvironment and most importantly tumor antigen heterogeneity. The latter may be tackled by using CAR T cells targeting EGFR, HER2, IL13Rα2 over-expression in urothelial cancers as shown in TCGA data. Other targets currently in clinical trials include CD19, CD19+CD22, CD19 + CD20, CD22, CD20, ROR1R, CD4, CD7, CD38, CD30, and BCMA. 2 He highlighted a recent Phase I trial (NCT03089203) in metastatic castration-resistant prostate cancer using CAR T cells armored with a dominant-negative TGF-β receptor, an inhibitory factor.4 In total 13 patients received therapy; 3 patients had ≥30% PSA reduction including one patient with >98% reduction. However, there were 5 patients who developed grade ≥2 cytokine release syndrome including one patient succumbing to it. CAR T failure was seen by tumor microenvironment inhibitory molecules upregulation. Results are promising and efforts is needed to explore approaches to mitigate the inhibitory tumor microenvironment. Additionally, he reports that his lab has shown an enhanced potential for combined radiation with CAR T therapy. He reports promising results using in vivo glioma models treated with 10Gy and IL13Rα2 CAR T cells. Although CAR T cell therapy is still in infancy in solid organ tumors especially in genitourinary tumors, the future is promising.

 

 

AIBCCR 2022_CAR-T cells Gao Amir Horowitz Hind Rafei David Akhavan 

Figure 1. Flow chart of CAR T development (Zhao et al)

 

Presented By:

  • Jianjun Gao MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
  • Ahmad Nausheen MD, Medical Director BMT Survivorship Program, Medical Oncologist at The University of Kansas Cancer Center
  • Amir Horowitz PhD, Assistant Professor of Oncological Sciences and a member of the Precision Immunology Institute and the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai
  • Hind Rafei MD, Assistant Professor, Stem Cell Transplant and Cellular Therapy, The University of Texas MD Anderson Cancer Center
  • David Akhavan MD, PhD, Assistant Professor, Radiation Oncology, The University of Kansas Medical Center


Written by: Valentina Grajales MD, MS, Urologic Oncology Fellow, Twitter: @ValGraj, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022

 

References:

1. Zhang Z, Li D, Yun H, Liu W, Chai K, Tong J, Zeng T, Gao Z, Xie Y. CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future. Front Oncol. 2022 Jul 4;12:915171. doi: 10.3389/fonc.2022.915171. PMID: 35860578; PMCID: PMC9292130.

2. Zhao, Lijun and Cao J Yu. Engineered T Cell Therapy for Cancer in the Clinic. Front Immunol. 2019 Oct 11;10:2250. doi: 10.3389/fimmu.2019.02250. eCollection 2019.

3. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018 Dec 13;175(7):1731-1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29. PMID: 30503213; PMCID: PMC6292840.

4. Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, Hwang WT, Lal P, Carpenter EL, Maude SL, Plesa G, Vapiwala N, Chew A, Moniak M, Sebro RA, Farwell MD, Marshall A, Gilmore J, Lledo L, Dengel K, Church SE, Hether TD, Xu J, Gohil M, Buckingham TH, Yee SS, Gonzalez VE, Kulikovskaya I, Chen F, Tian L, Tien K, Gladney W, Nobles CL, Raymond HE; Prostate Cancer Cellular Therapy Program Investigators, Hexner EO, Siegel DL, Bushman FD, June CH, Fraietta JA, Haas NB. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022 Apr;28(4):724-734. doi: 10.1038/s41591-022-01726-1. Epub 2022 Mar 21. PMID: 35314843.

 

 

ESMO 2022: Invited Discussant: Results of COSMIC-313

(UroToday.com) Following Dr. Toni Chouieri’s presentation of the results of COSMIC-313 examining the role of triplet therapy with cabozantinib, nivolumab and ipilimumab as first-line treatment in patients with advanced renal cell carcinoma (aRCC), Dr. Sumanta Pal provided an invited discussion to contextualize these results in Presidential Symposium III at the European Society for Medical Oncology (ESMO) Annual Congress.

ESMO 2022: Invited Discussant: Results of RADICALS-HD

(UroToday.com) Following Dr. Chris Parker’s presentation of the results of RADICALS-HD examining the effect of differing durations of androgen deprivation therapy (ADT) among men receiving post-operative radiotherapy following radical prostatectomy for prostate cancer, Dr. Silke Gillessen provided an invited discussion to contextualize these results in Presidential Symposium III at the European Society for Medical Oncology (ESMO) Annual Congress.

ESMO 2022: Observations on the Biology of PSMA Implications for Targeting

(UroToday.com) On Monday, September 12, 2022, a breakout session focused on prostate-specific membrane antigen (PSMA) biology, diagnostics and treatment was held in conjunction with the European Society for Medical Oncology (ESMO) Annual Congress. Dr. Bander presented first in this session focusing on PSMA biology.

ESMO 2022: Lu-PSMA for Prostate Cancer Treatment

(UroToday.com) The 2022 ESMO annual meeting included a session focusing on PSMA biology, diagnostics and treatment and a presentation by Dr. Shahneen Sandhu discussing 177-Lutetium (Lu)-PSMA for prostate cancer treatment. Dr. Sandhu noes that the definition of PSMA theranostics is “targeted therapeutic and diagnostic companion,” specifically a 68Ga-PSMA-11 PET/CT + Lu-PSMA therapy. The first major trial utilizing Lu-PSMA in prostate cancer was the TheraP trial.1 This open label, phase II trial evaluated Lu-PSMA vs cabazitaxel for men with mCRPC after docetaxel. To screen into the study, all men had both 68Ga-PSMA-11 and 18F-FDG PET/CT and were required to have high PSMA-expression (at least one site with SUVmax ≥ 20) and no sites of FDG-positive/PSMA-negative disease. All patients had progressive disease with rising PSA ≥20 ng/mL after docetaxel and 91% had received prior enzalutamide or abiraterone. Overall, 200 patients were randomized 1:1 to Lu-PSMA 6-8 GBq every 6 weeks for up to 6 cycles of therapy or cabazitaxel 20 mg/m2 every 3 weeks for up to 10 cycles. Patients were stratified based on disease burden and prior anti-androgen therapy:

ESMO 2022: Latest Imaging Advances in PET and Beyond Translated to Bladder and Kidney Cancers

(UroToday.com) The 2022 ESMO annual meeting included a session focusing on multi-disciplinary updates in biomarkers in urinary cancers and a presentation by Dr. Elisabeth de Vries discussing the latest imaging advances in PET and beyond translated to bladder and kidney cancers. Dr. de Vries notes that molecular imaging takes advantage of tumor biology in vivo and numerous targets for ligands. With regards to PET imaging and translation to bladder and kidney cancers, the potential aim is to predict who will respond to what treatment and PET imaging. For bladder cancer, this includes HER2 (an antibody drug conjugate), immune checkpoint inhibitors, and immune response with CD8 imaging. For kidney cancer, this includes angiogenesis inhibitors, immune checkpoint inhibitors, and immune response with CD8 imaging.

ESMO 2022: PSMA Targeted T Cell Engagers

(UroToday.com) The 2022 ESMO annual meeting included a session focusing on PSMA biology, diagnostics, and treatment and a presentation by Dr. Karim Fizazi discussing PSMA Targeted T cell engagers. Dr. Fizazi started by noting that existing immunotherapies have minimally impacted outcomes of men with mCRPC, even though CTLA-4 inhibition was associated with excess in long-term survivors in a phase 3 trial. T cell engagers are “two-hands molecules” that engage cancer cells (identified by a target protein) and T cells, leading to (i) cancer cell lysis (independent of T cell receptor specificity), (ii) peptide presentation by the MHC system, and (iii) T cell co-stimulation signals. The following clinical efficacy data with PSMA-targeted T cell engagers is available:

ESMO 2022: Multidisciplinary Updates in Biomarkers in Urinary Cancers: The Microbiome

(UroToday.com) The 2022 ESMO annual meeting included a session focusing on multi-disciplinary updates in biomarkers in urinary cancers and a presentation by Dr. Lisa Derosa discussing the importance of the microbiome. Dr. Derosa notes that we have identified a number of factors that impact tumor growth and response to cancer treatment, which now include polymorphic microbiomes. However, although the impact of the gut microbiome in genitourinary cancer immunotherapy was first studied, it was done serendipitously.

ESMO 2022: Invited Discussant: The Phase III VESPER Trial & the Phase III CheckMate 274 Trial

(UroToday.com) Following presentations from Dr. Clarice Groeneveld discussing the association between underlying histology and response to neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer (MIBC) in the phase III VESPER trial and from Dr. Andrea Necchi examining tumor and immune features predictive of disease-free survival in patients receiving adjuvant nivolumab following cystectomy in the phase III CheckMate 274 trial, Dr. Michiel Van der Heijden provided an invited discussion to contextualize these results in the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.

ESMO 2022: Pure or Mixed Basal/squamous Tumours Present Decreased Outcomes After Neoadjuvant Chemotherapy in the GETUG-AFU V05 VESPER Trial

(UroToday.com) On Monday, September 12, 2022, in the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers, Dr. Groeneveld presented results of an analysis of the effect of pure or mixed basal/squamous histology on the efficacy of neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) based on the GETUG-AFU V05 VESPER trial. Previous work has suggested that molecular subtyping of urothelial carcinoma (UC) may affect the outcomes after neoadjuvant chemotherapy, though this is controversial and results have been contradictory.

ESMO 2022: PSMA for Diagnosis and Staging

(UroToday.com) During a breakout session focused on prostate-specific membrane antigen (PSMA) biology, diagnostics and treatment was held in conjunction with the European Society for Medical Oncology (ESMO) Annual Congress. Dr. Daniela Oprea-Lager presented second in this session focusing on PSMA for diagnosis and staging of prostate cancer, a “pandora’s box” as she describes it.

ESMO 2022: Phase 3 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Previously Untreated Advanced Renal Cell Carcinoma of Imdc Intermediate or Poor Risk (COSMIC-313)

(UroToday.com) On Monday, September 12, 2022, in Presidential Symposium III at the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Chouieri presented highly awaited results from the COSMIC-313 trial, examining the role of triplet therapy with cabozantinib, nivolumab, and ipilimumab as first-line treatment in patients with advanced renal cell carcinoma (aRCC).

ESMO 2022: Duration of Androgen Deprivation Therapy with Post-Operative Radiotherapy for Prostate Cancer First Results of the RADICALS-HD Trial ISRCTN40814031

(UroToday.com) On Monday, September 12, 2022, in Presidential Symposium III at the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Parker presented results of the RADICALS-HD trial examining the effect of differing durations of androgen deprivation therapy (ADT) among men receiving post-operative radiotherapy following radical prostatectomy for prostate cancer. This is a key question as, though there is substantial high-quality evidence regarding the role and durations of ADT for men receiving primary radiotherapy for the treatment of prostate cancer, there is considerable uncertainty regarding its role and duration for men who are receiving post-prostatectomy radiotherapy.

ESMO 2022: Invited Discussant: BIONIKK trial, Changes in Gut Microbiota, & LITESPARK-004 trial

(UroToday.com) Following presentations from Dr. Maxime Meylan discussing predictive biomarkers in advanced renal cell carcinoma (RCC) based on ancillary analyses of the BIONIKK trial, Dr. Carolina Alves Costa Silva examining changes in gut microbiota during standard systemic therapy for metastatic RCC, and Dr. Ramaprasad Srinivasan providing updated longer-term follow-up of the LITESPARK-004 trial assessing the HIF-2alpha inhibitor belzutifan in von-Hippel-Lindau disease associated neoplasms, Dr. Guillermo De Velasco Oria provided an invited discussion to contextualize these results in the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.

ESMO 2022: Invited Discussant: Results of the Phase 2 LITESPARK-003 Trial

(UroToday.com) Following a presentation from Dr. Jaime Merchan discussing the results of the phase 2 LITESPARK-003 trial examining the HIF inhibitor belzutifan plus cabozanitinib as first-line therapy in advanced renal cell carcinoma (RCC), Dr. Andre Fay provided an invited discussion to contextualize these results in the Proffered Paper Session 2 of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.

ESMO 2022: Longitudinal Analysis Reveals Gut Microbiota Shift During Standard Therapies in Metastatic Renal Cell Carcinoma (mRCC)

(UroToday.com) During the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers, Dr. Alves Costa Silva presented a longitudinal assessment of gut microbiota during treatment for metastatic renal cell carcinoma (mRCC). It has previously been noted that the baseline gut microbiota composition is associated with outcomes for patients receiving immune-checkpoint blockade for mRCC.

ESMO 2022: Invited Discussant: The Results of the PIVOT-09 Trial & the Role of Enfortumab Vedotin

(UroToday.com) Following presentations from Dr. Nizar Tannir discussing results of the PIVOT-09 trial examining bempegaldesleukin plus nivolumab compared to the investigator’s choice of Sunitinib or Cabozantinib in first-line treatment of advanced renal cell carcinoma (RCC) and from Dr. Jonathan Rosenberg discussing the role of enfortumab vedotin either as monotherapy or in combination with pembrolizumab in cisplatin-ineligible patients with advanced urothelial cancer (UC), Dr. Laurence Albiges provided an invited discussion to contextualize these results in the Proffered Paper Session 2 of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.

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