Reviewing Immunotherapy for Bladder Carcinoma In Situ

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Dorcas Skinner
6 years ago
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with immunotherapy playing important role in the metastatic post-chemotherapy state New

1 Reviewing Immunotherapy for Bladder Carcinoma In Situ Samir Bidnur Dept of Urologic Sciences, Grand Rounds March 1 st, 2017 Checkpoint Inhibition and Bladder Cancer, an evolving story with immunotherapy playing important role in the metastatic post-chemotherapy state New opportunities for targeted immunotherapy in bladder cancer, in both metastatic and intravesical states 1

Objectives Review the pathophysiology of CIS Characteristics of CIS BCG for CIS Describe the immunogenicity of CIS Underlying genetic alterations in CIS, mechanism of action of BCG Review the role

2 Objectives Review the pathophysiology of CIS Characteristics of CIS BCG for CIS Describe the immunogenicity of CIS Underlying genetic alterations in CIS, mechanism of action of BCG Review the role checkpoint blockade for CIS Rationale for early use of PD-L1 Current study design to assess for combination BCG+ PD-L1 inhibition Pathophysiology of CIS High grade, flat lesion with no lamina propria invasion Precursor to invasive disease (high risk of progression) Loss of normal urothelial cell layers Can present with irritativeluts/hematuria/asx Treatment Both result in high cost associated with CIS (and high grade NMIBC) for surveillance cystoscopy + cystectomy 2

CIS and adjacent histologically normal urothelium with similar genetic signatures Confirms field effect stcc with CIS is different than stcc without CIS CIS Management- Options Lacking Despite BCG

3 CIS and adjacent histologically normal urothelium with similar genetic signatures Confirms field effect stcc with CIS is different than stcc without CIS CIS Management- Options Lacking Despite BCG therapy, CIS can recur up to 40% of pts, and majority of these will fail repeat BCG induction BCG therapy, induction + maintenance therapy, remains the gold standard for treatment of CIS Non-BCG intravesical salvage options - Other Immunotherapy (IFN-a, mycobacterium products) - single agent chemotherapy (Valrubicin, MMC, Docetaxel) - combination chemotherapy or device-assisted chemotherapy - radiation - Novel therapies (checkpoint inhibitors) 3

Bacillus Calmette-Guérin Live, attenuated form of slow growing bovine

bovis used to study treatment for TB in early 1900s Subcultured to

efficacious when direct contact between BCG and tumour possible 9 pts with

4 Bacillus Calmette-Guérin Live, attenuated form of slow growing bovine tuberculosis bacterium, M. bovis used to study treatment for TB in early 1900s Subcultured to non-virulent strain from , human trials beginning 1921 Believed to be efficacious when direct contact between BCG and tumour possible 9 pts with recurring superficial TCC (Ta-Tis) Simultaneous intradermal/intravesical q6wk Outcomes determined via biopsy at 6wks following last BCG (3mo post TURBT) 4

5 Included rapidly recurrent Ta/T1 and/or CIS, treated with intravesical + intradermal BCG induction (x6wks) Stratified for tuberculin skin reaction + presence of CIS N=192 per group (NED post induction) with 3 wkly BCG Recurrence free survival worsening free survival Overall survival CIS group = 278 pts (underwent induction Tx) Maintenance arm: 117 pts (55% à 84% Only 14% completed entire maintenance No Maintenance arm: 116 pts (57% à 68% Therefore response to induction BCG can only be assessed at 6mo 5

AUA, EAU, ICUD, NCCN guidelines on use of BCG are all slightly different

to obtain most benefit from BCG Over 23 000 pts from SEER database studied

BCG use associated with improved overall survival in high grade NMIBC Not in

6 AUA, EAU, ICUD, NCCN guidelines on use of BCG are all slightly different Duration of maintenance, scheduling Without doubt maintenance is necessary to obtain most benefit from BCG Over pts from SEER database studied BCG administered in only 22% of eligible pts Population level data suggests BCG use associated with improved overall survival in high grade NMIBC Not in low grade NMIBC No specific mention or subgroup analysis for maintenance therapy 6

7 Few grade A recommendations in the guidelines 1. Complete initial TUR 2. Re-resection at 6wks AND 1. BCG for high grade disease CIS highest predictor of progression HR 3.41 ( ) 78% intravesical treatment but mostly chemo No maintenance for BCG Trials recruited

8 Objectives Review the pathophysiology of CIS Characteristics of CIS BCG for CIS Describe the immunogenicity of CIS Underlying genetic alterations in CIS, mechanism of action of BCG Review the role checkpoint blockade for CIS Rationale for early use of PD-L1 Current study design to assess for combination BCG+ PD-L1 inhibition 8

9 Assessed genomic alterations in CIS vs papillary tumour based on chromosome abnormalities 9

10 Pure CIS and concomitant CIS mostly in Class 2 = worse prognosis tumors showed class shifts from class 3 to class 2 during progression Class 2 tumours with few FGFR3 mutations 10

11 Cancer Immunity Cycle Elimination à Equilibrium à Escape Escape mediated by multitude of factors that generate an immunosuppressive environment Role of checkpoint inhibitors 11

12 Activated T-cells sit inactive in immunosuppressive milieu Bladder cancer with known history of succesful immunotherapy Bladder cancer amongst highest malignancies with somatic mutations 12

13 Lowest mismatch repair seen in cell line T24 and in clinical samples from HGT1 and CIS (sampled pure CIS) 13

neutrophils, NK cells, macrophages, dendritic cells Small

14 Mechanism of action of BCG not completely understood but animal models suggest roles for: Immune system: Lymphocytes, neutrophils, NK cells, macrophages, dendritic cells Small molecule cytokine signalling Urothelial cells: malignant and background urothelium 14

15 18 of 30 pts with pure CIS Outcome: Recurrence not progression Suggests role of tumour cells in antigen presentation 15

$BCG Failure BCG relapse: Recurrence of tumour after a period of disease-free status (6 months) Early: <1yr Intermediate: 1-2yrs Late: >2yrs BCG-refractory: Persistence of disease after adequate$

16 BCG Failure BCG relapse: Recurrence of tumour after a period of disease-free status (6 months) Early: <1yr Intermediate: 1-2yrs Late: >2yrs BCG-refractory: Persistence of disease after adequate induction and one maintenance course** Includes disease progression BCG-intolerant: Inability to tolerate at least one full induction course Not true BCG failure **Definition specific to CIS i.e. BCG-refractory for HG T1 is disease at 3mo, not after maintenance BCG-unresponsive becoming favoured term Persistent high-grade disease or recurrence within 6 months of receiving at least two courses of intravesical BCG (at least five of six induction doses and at least two of three maintenance doses)** **Except for HGT1- where persistence following induction alone is sufficient 16

17 17

Rationale for early use of PD-L1 Current study design to assess for combination BCG+ PD-L1 inhibition Strongest

18 Objectives Review the pathophysiology of CIS Characteristics of CIS BCG for CIS Describe the immunogenicity of CIS Underlying genetic alterations in CIS, mechanism of action of BCG Review the role checkpoint blockade for CIS Rationale for early use of PD-L1 Current study design to assess for combination BCG+ PD-L1 inhibition Strongest staining for PD-L1 seen in CIS Similar to other cancer types where aggressive disease associated with elevated PD-L1 staining 18

Modelling PD-L1 in the lab In vitro data: Profiling PD-L1 expression amongst a cohort of well characterized bladder cancer cell lines à How does PD-L1 expression vary in a panel of

Does combination BCG + apd-l1 improve survival, tissue analysis Clinical data: Sampling of CIS tissue pre & post BCG exposure (patients that were unresponsive or failed BCG

19 Modelling PD-L1 in the lab In vitro data: Profiling PD-L1 expression amongst a cohort of well characterized bladder cancer cell lines à How does PD-L1 expression vary in a panel of bladder cell lines and can it s expression be manipulated In vivo data: Combination therapy of BCG+aPD-L1 in a mouse syngeneic orthotopic immunocompetentbladder cancer model (BBN) à Does combination BCG + apd-l1 improve survival, tissue analysis Clinical data: Sampling of CIS tissue pre & post BCG exposure (patients that were unresponsive or failed BCG treatment) n=30 à Does PD-L1 expression increase in a cohort of BCG failed patients T24 with highest EMT marker expression and PD-L1 expression T24 with highest expression of PD-L1 Negative 19

Survival proportions: Survival from Randomization start Percent survival 100 50 0 0 20 40 60 80 Time (days) Combo

Treatment Combo apd-l1 BCG No Treatment Dysplasia at 16wks followed by rapid progression to lethal invasive carcinoma

Post-BCG Tumour cell score 2/30 4/30 Tumour infiltrating immune cell score Tumour stroma cell staining Global slide

20 Survival proportions: Survival from Randomization start Percent survival Time (days) Combo apd-l1 BCG No Treatment 4wks 12wks Bladder wts between group Bladder wt (mg) Combo apd-l1 BCG No Treatment Combo apd-l1 BCG No Treatment Dysplasia at 16wks followed by rapid progression to lethal invasive carcinoma Heterogeneous uptake 16wks TMA and serum studies for immune profiling (tumour vs systemic) BCG-unresponsive CIS Pre-BCG Post-BCG Tumour cell score 2/30 4/30 Tumour infiltrating immune cell score Tumour stroma cell staining Global slide staining Staining performed by Phenopath (Seattle) using PD-L1 antibody E1L3N Core biopsies of FFPE tissue sent for RNA-seq (McConkey) 20

21 Trying to obtain consensus with regard to trial design, endpoints, definitions CAN ANTICIPATE MANY NEW TRIALS REPORTING ON NOVEL INTRAVESICAL TREATMENTS FOR BCG-UNRESPONSIVE DISEASE THANK YOU 21

Management of High Grade, T1 Bladder Cancer Douglas S. Scherr, M.D.

Management of High Grade, T1 Bladder Cancer Douglas S. Scherr, M.D. Assistant Professor of Urology Clinical Director, Urologic Oncology Weill Medical College-Cornell University Estimated new cancer cases.