Basic Concepts in Bladder Cancer Immunotherapy

Leonard G. Gomella, MD Chairman, Department of Urology Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia, PA

BCG  Intravesical  Immunotherapy  •   BCG  immunotherapy  standard  of  care  NMIBC  •   Mechanism  is  s:ll  under  inves:ga:on,is  recognized  as  immunotherapy    

•   BCG  is  internalized  by  both  urothelial  cancer  cells  and  immune  cells  –   Causes  secre:on  of  cytokines  and  chemokines,  and  presenta:on  of  BCG  and/or  cancer  cell  an:gens  to  ac:vate  T  cells  

•   Safety:  <  5%  serious  complica:ons  –   Common  SE:  fever,  hematuria,  granulomatous  prosta::s  

Redelman-Sidi, G et al. Nature Reviews Urology 2014; 11: 153–162 Lamm DL. Clin Infect Dis. 2000;31 Suppl 3:S86

Intravesical BCG Immunotherapy

BCG

Bladder cancer cells

CD8+ T cell HLA class I DC

Processing and antigen presentation

HLA class II

apoptosis BCG or cancer antigen

phagocytosis

CD4+ T cell

inflammation side effects

Macrophage

NK cell

Th-1 response IL-2, IL-12, IFN-γ, TNF-β

Cell-mediated immune response

DC CD8+

T cell Processing and antigen presentation

phagocytosis

Cytokine production

Overview  of  Cancer  Immunology  and  Immunotherapy  

Hallmarks  of  Cancer    

Hanahan D, Weinberg RA. Cell. 2011;144:646-674. Hanahan D, Weinberg RA. Cell. 2000;100:57-70.

Sustaining  prolifera:ve  signaling  

Deregula:ng  cellular  

energe:cs  

Avoiding  immune  

destruc0on  

Enabling  replica:ve  immortality  

Inducing  angiogenesis  

Resis:ng    cell  death  

Evading  growth  

suppressors   Ac:va:ng  invasion  and  metastasis  

Hallmarks    of  Cancer  

Pathogenesis  

The  immune  system  has  a  major  role  in  cancer  pathogenesis  

Increased  Incidence  of  Cancer  in    Immunocompromised  Individuals  

•   Malignant  tumors  develop  in  individuals  with  compromised  immune  systems1-­‐3  

1.   Kasiske  BL,  Wang  C,  et  al.  Am  J  Transplant.  2004;4(6):905-­‐913.  2.   Le  Mire  L,  Wojnarowska  F,  et  al.  Br  J  Dermatol.  2006;154(3):472-­‐477.  3.   Abbas  AK,  Lichtman  AH.  Basic  Immunology.  3rd  ed.  2011.  

Tes:cular  cancer  

Breast  cancer  

Prostate  cancer  

Colon  cancer  

Bladder  cancer  

Hepatobiliary  cancer  

Melanoma  

Kidney  cancer  

Non-­‐Hodgkin’s  lymphoma  

Non-­‐melanoma  skin  cancer  

Tumor  /  cancer  risk  in  transplant  pa0ents  compared  with  general  popula0on1-­‐3  

 

0   5   10   15   20  Fold-­‐increase  in  tumor  /  cancer  risk  

20-­‐fold  and  beyond  

15-­‐fold  

8-­‐fold  

3-­‐fold  

5-­‐fold  

2-­‐fold  

 Basics:  Immune  system  and  cancer  

interac:ons      •   Immune  system  and  cancer  interact  in  a  

dynamic  process  known  as  “Immunoedi:ng”  or  “the  3  E’s”  –  Elimina:on:  ini:al  tumor  development,  low  tumor  volume  immune  system  can  eradicate  cancer  cells  

–  Equilibrium:  immune  system  controls  cancer  growth    

–  Escape:  con:nued  growth;  gene:c  instability  tumor  heterogeneity  takes  place  and  overwhelms  the  immune  system  

Dunn GP, et al. Nat Rev Immunol. 2006;6(11):836-848. Mittal D, et al. Curr Opin Immunol. 2014;27:16-25

Immune  Evasion  of  Cancer  Progressive  metasta:c  cancer  represents  a  failure    of  immune  surveillance    

 

Kalbasi A, et al. J Clin Invest. 2013;123(7):2756

An:cancer  Immunity  is  Mediated  Through  a  Mul:-­‐step  Process  

Chen DS, et al. Immunity. 2013;39(1):1-10.

1.   An:gens  released  by  cancer  cells  

2.   An:gens  presented  to  T  cells  3.   T  cell  priming  and  ac:va:on  4.   T  cell  trafficking  to  tumors  5.   T  cell  infiltra:on  into  tumors  6.   T  cell  recogni:on  of  cancer  cells  7.   Killing  of  cancer  cells  

Immune  Checkpoints  Lead  to  Promo:on  or  Inhibi:on  of  Immune  Response  

Chen DS, et al. Immunity. 2013;39(1):1-10.

Ac:va:ng:      

CD28;  CD137;  OX40;  GITR;IL-­‐2  

 Inhibitory:  

 CTLA-­‐4;  PD-­‐L1/PD-­‐1;  

PD-­‐L1/B7.1  

Principles  of  Cancer  Immunotherapy    •   Immune  response  to  cancer  both  s:mulatory  and  inhibitory  

factors  •   Inhibitory  immune  checkpoints  include  CTLA-­‐4,  PD-­‐1,  PDL-­‐1  

–   Limit  immune  response  to  protect  self  –   Oien  upregulated  in  tumors  and  in  immune  cells  invading  tumors  –   Results  in  inhibi:on  of  the  T  cell  immune  response  –   Allows  tumors  to  more  easily  “hide”  from  the  immune  system  

•   Checkpoint  inhibitors  –   An:bodies  block  the  immune  checkpoint  to  enhance  T-­‐cell  and  other  immune  cell  func:ons  

–   Allow  the  immune  response  to  expand  –   Examples  of  FDA-­‐approved  inhibitors  include:  

•   CTLA-­‐4:  Ipilimumab  •   PD-­‐1:  Nivolumab,  Pembrolizumab  •   PD-­‐L1:  Atezolizumab  

 Sharma P, et al. Nat Rev Cancer. 2011;11:805-812 Pardoll D. Nat Rev Cancer. 2012;12:252-264

Clinical  Cancer  Immunotherapy    •   Passive  Immunotherapy:    

o   Monoclonal  an:bodies  directed  against  growth  factors  such  as  bevacizumab  (VGEF),  cetuximab  (EGFR)  

o   Chronically  administered,  no  sustainable  an:-­‐tumor  response  •   Ac:ve  Immunotherapy:  induce  host  response  to  tumor  by  T-­‐cell  cascade  -­‐>  CTL  

o   Need  T-­‐cell  for  solid  tumor  kill  (cytotoxic  T  lymphocyte  or  CTL)  o   T  cell  cannot  respond  to  naked  or  circula:ng  an:gens  o   Require  an:gens  to  be  “presented”  to  T  cells  on  APC  (an:gen  presen:ng  

cells)  o   Dendri:c  cells,  Langerhans  cells,  monocytes,  macrophages  are  APC  o   APC  internalize  an:gens,  couple  to  HLA  molecules  to  “present”  on  the  

surface  to  ac:vate  T-­‐cell  o   Immune  response  depends  on  s:mulatory  signals  and  inhibitory  

“checkpoints”  to  avoid  excessive  produc:on  of  immune  cells  such  s  T  cells  that  could  be  detrimental  to  normal  :ssue  

Selected  Immunotherapies  in  Oncology  •   Vaccine  based  therapies:    T  cell  ac:va:on  to  seek  out  tumor  cells  

–   Eg,  Sipuleucel-­‐T,  BCG  •   Cytokines:  naturally  occurring,  modulate  immune  response  

–   Eg,  IL-­‐2,  interferon-­‐alpha  •   Monoclonal  an0bodies:  block  specific  growth  factors,  etc  causing  cell  

death  cascade  –   Eg,  bevacizumab  targe:ng  VGEF    

NEWEST  THERAPIES  •   Checkpoint  inhibitors:    monoclonal  an:bodies  block  the  immune  

checkpoint  response;  “take  the  brakes  off”  immune  system    –   Eg,  CTLA-­‐4,  PD-­‐1,  PD-­‐L1  inhibitors  

•   Chimeric  An0gen  Receptor  (Car)  T-­‐cell  Therapy  –   Pa:ent’s  T  cells  are  reengineered  to  recognize  cancer  (experimental)  

Dinarello CA Eur J Immunol. 2007 Nov; 37(Suppl 1): S34–S45. Weiner LM, et al. Nat Rev Immunol. 2010;10:317-327. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. Pardoll D. Nat Rev Cancer. 2012;12:252-264.

hnp://www.ny:mes.com/2016/12/03/health/immunotherapy-­‐cancer.html  

Immune  Checkpoint  Inhibi:on      

•   Pembrolizumab:  PD-­‐1  monoclonal  an:body  •   Nivolumab:  PD-­‐1  monoclonal  an:body  •   Atezolizumab:  monoclonal  an:body  to  programmed  death  ligand  1  (PD-­‐L1)  

•   Avelumab:  an:-­‐PD-­‐L1  monoclonal  •   Durvalumab:  an:-­‐PD-­‐L1  monoclonal  Homet Moreno B, et al. Br J Cancer. 2015 Apr 28;112(9):1421-7 Markham A. Drugs. 2016 Aug;76(12):1227-32

PD-­‐1  T  cell  receptor              PDL-­‐1  tumor  ligand  PD-­‐1/PD-­‐L1  inhibitors  result  in  higher  response  rates  across  a  wide  range  of  tumors  than  most  other  immunotherapies  

PD-­‐1/PD-­‐L1  Ac:vity  

Suppression  of  T-­‐cell  response…..  “Taking  the  brakes  off”  

http://www.pharmaceutical-journal.com/news-and-analysis/feature/immune-checkpoint-inhibitors-bring-new-hope-to-cancer-patients/20067127.article Accessed October 24, 2016

Why  is  Bladder  Cancer  A  Good  Target  for  Immunotherapy?  

Urothelial  bladder  cancer  (UBC)  as  an  target  for  immunotherapy    

•   Pa:ents  with  UBC  have  a  high  rate  of  soma:c  muta:ons  similar  to  tumors  associated  with  tobacco  use  or  environmental  carcinogen  exposure  

•   Host  immune  system  can  recognize  tumor  an:gens.  An:gens  detected  seen  as  foreign,  s:mula:ng  an  immune  an:  tumor  response  

Lawrence MS, et al. Nature Jul 11;499(7457):214-8, 2013; Bellmunt. Ann Oncol. 2013; Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014)

Basis  of  Urothelial  Cancer  Immunotherapy  

•   High  rates  of  soma:c  muta:ons    –  May  enhance  immune  response  

•   Urothelial  cancers  may  express  compounds  that  suppress  the  immune  system  such  as  programmed  death-­‐ligand  1  (PD-­‐L1)  

•   CD4+  and  CD8+  T  cells  express  inhibitory  PD-­‐1  to  prevent  overs:mula:on  of  the  immune  response  

•   PD-­‐L1/and  PD-­‐1  are  the  immune  checkpoints  •   Check  point  inhibitors  enhance  an:-­‐tumor  effects  by  allowing  a  more  robust  immune  response  

Powles, T, et al. Nature 2014; 515: 558–562. Hafez N, Petrylak DP. Immunotherapy. 2015;7(1):1-2

Immune  Cells  Within  Tumors  Predict  Overall  Survival:  MIBC  Example  

•   Higher  immune  cell  density  (T  cells)  predic:ve  of  survival  of  pa:ents  with  MIBC  •   Suggests  importance  of  immune  response  in  MIBC  

1.   Sharma P, et al. Proc Natl Acad Sci U S A. 2007;104(10):3967-3972. 2.   Galon J, Pagès F, et al. Science. 2006;313(5795):1960-1964.

Prop

.  Surviving  W

ithou

t  Disease  

Time  in  Months  40  20  0   60   80  

0.0  

0.2  

0.4  

0.6  

0.8  

1.0  

P<0.001  

T  cells  (CD8)  <8  (median  survival=13  months)  T  cells  (CD8)  ≥8  (median  survival  >80  months)  

Checkpoint  Inhibitors  and  Biomarkers  •   FDA  approved  complementary  diagnos:c,  the  PD-­‐L1  (SP142)  assay  with  atezolizumab  –   detects  PD-­‐L1  expression  on  tumor-­‐infiltra:ng  immune  cells  

•   Phase  1  study  of  atezolizumab:  higher  response  rates  were  with  higher  tumor  levels  of  PD-­‐L1  expression  in  tumor-­‐infiltra:ng  lymphocytes,  not  tumor  cells.  

•   While  promising,  many  other  PD-­‐L1  an:bodies  exist  limi:ng  generalizability  

•   Genomic  and  other  tes:ng  being  u:lized  to  determine  best  response  to  a  given  checkpoint  inhibitor  

Petrylak DP, et al. J Clin Oncol. 2015;33(suppl): abstract 4501 Tsiatas M, et al. Ann Transl Med. 2016 Jul;4(14):270

mRNA  expression  levels  of  PD1/PDL1  and  CTLA4  genes  in  a  series  of  155  bladder  tumors.  

Pignot, et al. J Clin Oncol 34, 2016 (suppl; abstr 4523)

PD-­‐L1  Diagnos0c  Tes0ng  Clinical  Experience  at    the  Thomas  Jefferson  University  Hospital    

23  

Urothelial  Carcinoma    Tumor  Cells  

Urothelial  Carcinoma    Tumor-­‐infiltra0ng  Immune  Cells  

PD-­‐L1  IHC  Staining  Using  Ventana  SP142  

Magnifica0on  x10   Magnifica0on  x10  

Courtesy of Charalambos C. Solomides, MD, Director of Cytopathology

Generic/Dosing     Brand     Manufacturer   Target   Comp.  Biomarker  

Urothelial  Carcinoma  Approval  

Date(s)  of  UC  Approval  

Approval  in  Other  Malignancies  

Atezolizumab  3wk   TECENTRIQ   Genentech   PD-­‐L1   VENTANA  PD-­‐L1  (SP142)*  

1,  2,  3   5/18/20161,2  4/17/20173  

NSLC  

Avelumab  2wk   BAVENCIO   Pfizer   PD-­‐L1   DAKO  73-­‐10  

1,  2   5/9/2017   Merckel  Cell  

Durvalumab  2wk   IMFINZI   AstraZeneca   PD-­‐L1   VETANA  PD-­‐L1  (SP263)*  

1,  2   5/1/2017   -­‐-­‐  

Nivolumab  2wk   OPDIVO   Bristol-­‐Myers  Squibb  

PD-­‐1   DAKO  28-­‐8$   1,  2   2/2/2017   Melanoma,  NSLC,RCC,  others  

Pembrolizumab  3wk   KEYTRUDA   Merck   PD-­‐1   DAKO  22C3$    

1,  2,  3   5/18/2017   Melanoma,  NSCLC,  Microsatellite  Instability-­‐High  Cancer,  others  

Checkpoint  inhibitors  for  systemic  use  in  advanced  UC  (7/2017)

(Mark  R  et  al  In  press  American  J  Hematology  Onc)

1.  Locally  advanced  or  metasta:c  UC  with  progression  during  or  aier  treatment  w/pla:num  chemo.  2.  Locally  advanced  or  metasta:c  UC  progressing  within  12  mo  of  neoadjuvant/  adjuvant  pla:num  chemo.  3.  Locally  advanced  or  metasta:c  UC  if  pla:num  ineligible.  *  Indicates  FDA  approved  companion  biomarker  

$  FDA  approved  biomarker  in  other  malignancies    

Why did early BCG studies use 6 weeks of therapy?

n  Because BCG was packaged in 6 packs.

Why does beer come in 6 packs?