Cancer Immunotherapy Shr-Uen Lin 2014.10.20 1
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
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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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.
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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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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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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
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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.
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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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.