Cancer Immunotherapy!

Shr-Uen Lin !2014.10.20

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An-Li Cheng, NTUH2

Why immunotherapy?

Klaus&F&Rabe&et&al,&2012&Lancet.�

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Why immunotherapy?

Target'therapy'with'mul0ple1or1no'drivers??�4

Immunotherapy #  1796    Dr.  Edward  Jenner  realized  cowpox  protected  against  smallpox  

#  1850s  in  Germany:  Occasionally  tumor  shrinkage  when  tumor  was  infected    #  Crude  extracts  from  other  paHents  as  tumor  vaccine

Knowledge !&

Pain

Vaccine    Monoclonal  ABs  

Inhibitors  Cytokines  

Engineered  T  cells5

Soldano Ferrone et al. 2012 CA Cancer J Clin6

Hypothesis: !• Cancer cells express different antigens form normal cells!• These antigens are immunogenic!• Immune responses cell prevent or inhibit tumor growth !!

Tumor antigen specific:!• Tumor-specific antigens: EBV, HPV, mutated proteins!• tumor-associated antigens: abnormally expressed proteins! !Tumor antigen non-specific:!• Targeting cell-surface molecules involved in common

activation and effector pathways of the immune system!

Treatment  to  boost  or  restore  the  ability  of  the  immune  system  to  fight  cancer

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Vaccine

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Pacis® BCG, Merck.

HPV related cancer:!!

• Cervical (99%) • Anal (90%) • Vaginal (60%) • Penile (40%) • Esophageal • Oral • Lung

1. Pap smear test!2. Vaccine:!• L1 major capsid proteine • Cervarix: 16, 18 (2009)(GSK) • Gardasil: 6, 11, 16, 18 (2006)(Merck)

Cervical cancer

Cervical Cancer, NCI

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5455 women aged 16~24 from 62 study site of 16 countries

Cervical Intraepithelial Neoplasm (CIN)-Warts Efficacy Trial in Women (Gardasil)

Laura A.Koutsky et al. 2007 NEJM.

Wen-Fang Cheng, NTUH11

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Sipuleucel-T (Provenge®)(Dendreon) FDA approved on April 29, 2010.

Philip W. Kantoff et al. 2011 Nat Rev Clin Oncol.

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The “IMPACT” trail (D9902B)Inclusion: • Asymptomatic Metastatic CRPC • Gleason score ≦ 7 • Serum PSA ≧ 5 ng/ml • Serum testosterone ≦ 500 ng/L !Exclusion: • ECOG ≧ 2 • Visceral metastasis • Long-bone fractures • Spinal core compression • Glucocorticoids treatment in 28 days • External-beam radiotherapy in 28 days

OS 25.8 to 21.7 m, 3-year survival 31.7 to 23.0 %

Sipuleucel-T HR: 0.78; 95% [CI]: 0.61 to 0.98; P=0.03Paul F. Schellhammer et al. 2010 NEJM.

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Robert M. Hershberg et al. 2006 J Clin Oncol. Mark W. Frohlich et al. 2009 Cancer.

D9901

D9901 D9902A D9902B

Period Nov 1999~Sep 2004 May 2000~May 2005 Jul 2003~Jan 2009

Patient No. 127 98 512

Primary EP TTP OS OS

Result Negative Positive Positive

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Cytokines - Interferon

• Intron A: IFN-α-2b (Merck) • FDA approved for:

• AIDS-related Kaposi sarcoma • Hairy cell leukemia • Melanoma • Non-Hodgkin’s lymphoma.

• Pegintron: pegylated IFN-α-2b (Merck) !• Referon: IFN-α-2a (Roche) • Pegasys: Pegylated IFN-α-2a (Roche)

Robert D. Schreiber et al. 2006 Nat Rev Immunol.

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Cytokines - IL-2

Thomas A. Waldmann 2006 Nat Rev Immunol.

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Monoclonal antibodies

• Block necessary signaling pathways • Payload delivery • Trigger immune-mediated cytotoxic response • Effects on the tumor vasculature and/or stroma.

Lloyd J. Old et al. 2012 Nat Rev Cancer.

Rituximab (Rituxan)(Roche)• Anti-CD20 • First approved on Feb 10, 2006 for CD20+ diffused large B-cell,

non-Hodgkin’s lymphoma base on three clinical trails • Randomized, active-controlled • R-CHOP vs CHOP (cyclophosphamine, doxorubicin, vincristine

and prednisone) • Primary end point TTF • Secondary endpoint OS, DFS and…… • Now: B-cell NHL,CLL and RA

E4494 LNH 98-5/GELA M39045/MiNT

Patient No. 630 399 824

Age 60+ 60+ 18~60

Stage III/IV III/IV I/II

2-year survival 74 vs 63 69 vs 58 95 vs 86Rituximab / FDA Approval for Rituximab NCI and references on the web page.

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Trastuzumab (Herceptin)(Roche)• Anti-ERBB2 • Approved on Nov 16, 2006 for node+, HER2+ breast cancer • 3752 HER2+ (IHC and FISH) patients in two trials (NSABP B31 & NCCTG N9831) • Standard adjuvant chemotherapy + (hormone and local radiotherapy) + Trastuzumab or not • Primary end point DFS (recurrence, second primary cancer or death) • 133/1872 vs 261/1880, hazard ratio 0.48, 95 percent CI: 0.39; 0.59

Norman Wolmark et al. 2005 NEJM

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Ado-Trastuzumab Emtansine (T-DM1)(Roche)• FDA approved on Feb 22, 2013 for HER2+

metastatic breast cancer • Single agent for who previously received

trastuzumab and/or taxane  • Primary end point PFS, OS and safety

Ellie Guardino et al. 2011 Clin Cancer Res.

Kim Blackwell et al. 2012 NEJM

DM1 payload delivery

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Bevacizumab (Avastin)(Roche)

FDA approval for Bevacizumab, NCI

• Anti-VEGF • First approved on Feb 26, 2004 in mCRC

Rakesh K. Jain et al. 2011.

clinicaltrials.gov

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Cetuximab (Erbitux)(Merck)• First approved on Feb 12, 2004 for mCRC with irinotecan • Stage IV EGFR+mCRC, progressed after irinotecan in 3 months • 2:1 randomized for Cetuximab+irinotecan or Cetuximab only • Now for CRC and head and neck cancer

Eric Van Cutsem et al. 2004 NEJM.

RR: 29.1 vs 17.5; TTP: 4.1 vs 1.5; OS: 8.6 VS 6.9

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25Caroline Robert et al. 2013 Clin Cancer Res.

??

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Ipilimumab (Yervoy)(Pfizer)• Anti-CTLA-4 • FDA approved on Mar 25, 2011 for unresectable / metastatic melanoma • Phase III/IV progressed metastatic melanoma • Compare with glycoprotein 100 peptide vaccine • 676 pts, 3:1:1 randomized for Ipi + gp / Ipi / gp

Walter J. Urba et al. 2010 NEJM.Median OS: 10.0 vs 10.1 vs 6.4 Median PFS: 2.76 vs 2.86 vs 2.76

27 Walter J. Urba et al. 2010 NEJM.

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Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy James P. Allison et al. 2014 JEM

ICOS-deficient

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Pembrolizumab (Keytruda)(Merck)• FDA approved on Sep 4, 2014 base on a randomized

phase I trial (n=173) • Unrecectable / metastatic melanoma after failure of

Ipilimumab (and Vemurafenib if BRAF V600 mutated)

Adil Daud et al. 2014 Lancet.

30Adil Daud et al. 2014 Lancet.

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Chimeric Antigen Receptor - The Living Drug

32 Dan L. Longo et al. 2011 NEJM.

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Crystal Mackall et al. 2012 Clin Cancer Res.

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M. Essand & A. S. I. Loskog. 2011 J Int Med.

4th generation CAR?

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THANKS FOR YOUR ATTENTION!!!

Herceptin approval in gastric or GE junction adenocarcinoma• Approved on Oct 10, 2010 base on ToGA trial • HER2+ metastatic patients who have not received prior treatment for metastatic disease • Combination with cisplatin and a fluoropyrimidine (either capecitabine or 5-fluorouracil) • 594 locally advanced or metastatic HER2+ (by IHC or FISH) • Primary endpoint OS, closed after second interim analysis

36 Yoon-Koo Kang et al. 2010 Lancet.

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New Concepts for Clinical Trial —Basket

Benjamin Besse et al. Eur Respir Rev 2014 & NCT01804140.

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Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases

George D. Demetri, et al. 2008 Clin Cancer Res.

New Concepts for Clinical Trial —Umbrella

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Benjamin Besse et al. Eur Respir Rev 2014 & NCT02117167.

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Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial

Ignacio I. Wistuba, et al. 2011 Cancer Discov.