The Promise of Immunotherapy for Cancer Treatment

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The Promise of Immunotherapy for Cancer Treatment

• Julie R. Brahmer, M.D., M.Sc.
• Sidney Kimmel Comprehensive Cancer Center at
  Johns Hopkins

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Scott Gettinger 2012
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Tumor Cell or Antigen Presenting Cell
T cell
HLA
T Cell Receptor
antigen
Others ICOS, GITR, Tim-3
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B7.1/2 (CD80/86)
CD28
CTLA-4
HLA
T Cell Receptor
antigen
T cell
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Ipilimumab in Melanoma

• Phase III trial
• 676 patients with chemo-resistant metastatic
  melanoma
• Randomized to ipilimumab gp100, or either
  treatment alone
• Median overall survival of ipilimumab group 10
  months, vs 6.4 months for gp100
• Immune-related adverse events in 60 of patients
  (skin, GI, endocrine, liver)
• FDA decision March, 2011

Hodi et al, NEJM 2010 363711
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Role of PD-1 in Suppressing Antitumor Immunity
Activation (cytokines, lysis, prolif., migration)
APC
T cell
B7.1 CD28
() Signal 2
TCR Signal 1
Tumor
APC Antigen presenting cell TCR T-cell
receptor MHC-Ag Major Histocompatibility
Complex-Antigen
Keir ME et al, Annu Rev Immunol 2008 Pardoll DM,
Nat Rev Cancer 2012
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Role of PD-1 in Suppressing Antitumor Immunity
Activation (cytokines, lysis, prolif., migration)
APC
T cell
B7.1 CD28
() Signal 2
TCR Signal 1
(-)
(-)
(-)
PD-L1
Inhibition (anergy, exhaustion, death)
Tumor
Keir ME et al, Annu Rev Immunol 2008 Pardoll DM,
Nat Rev Cancer 2012
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Role of PD-1 in Suppressing Antitumor Immunity
Activation (cytokines, lysis, prolif., migration)
APC
T cell
B7.1 CD28
() Signal 2
TCR Signal 1
(-)
(-)
(-)
Anti-PD-1
PD-L1
Inhibition (anergy, exhaustion, death)
Tumor
Keir ME et al, Annu Rev Immunol 2008 Pardoll DM,
Nat Rev Cancer 2012
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Clinical Development of Inhibitors of PD-1 Immune
Checkpoint
Target Antibody Development stage
PD-1 Nivolumab- BMS-936558 Phase III
PembrolizumabMK-3475 Approved 9/4/14 for unresectable or metastatic melanoma
PD-L1 MedI-4736 Phase III
MPDL-3280A Phase III
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Durable Responses to Anti-PD-1 OFF THERAPY
5 yr
5 yr
PD after 2 yr re-Rx
Lipson E et al Clin Cancer Res 2012
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Pembrolizumab in Melanoma

• Phase Ib trial 24 response rate in patients
  with melanoma. Responses lasting for months
  1.5-8.4 months. 1 yr survival rate of 58.
• 6th drug for melanoma approved since 2011

Ribas A, ASCO 2014, FDA 2014
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Broad Activity of PD-1 or PD-L1 Inhibitors

• Lung Cancer- in Phase 3 trials
• Kidney Cancer in Phase 3 trials
• Bladder Cancer
• Head and Neck Cancer
• Ovarian Cancer
• Multiple cancers are being studied

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S1400 MASTER LUNG-1 Squamous Lung Cancer- 2nd
Line Therapy
PI V. Papadimitrakopoulou (SWOG) Steering
Committee Chair R. Herbst (YALE, SWOG) Lung
Committee Chair D. Gandara Translational Chair
F. Hirsch Statistical Chair M. Redman
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S1400 Master Protocol Unique Private-Public
Partnerships with the NCTN
Alliance
ECOG-Acrin
SWOG
S1400 Master Protocol
NRG
NCI-C
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Conclusions

• Immunotherapy agents have promising anti-tumor
  activity in multiple cancers
• Many key questions need to be answered.
• How best should these agents be used (by
  themselves or in combination)?
• Who will most likely benefit from these agents
  (personalize treatment)?
• Phase 3 trials are ongoing in order to make
  immunotherapy a reality for the treatment of
  cancer.