Cancer Immunotherapy Update

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Cancer Immunotherapy Update

• Gerry Linette
• 4/6/07

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Cutaneous Melanoma

• 59,940 new cases (estimated) in 2007
• Most patients are cured with surgery alone.
• 20 relapse and develop metastatic disease
  involving lymph nodes (stage III) or distant
  sites (stage IV)
• Lungs, liver, and brain are most common sites.
• Treatment is surgery (stage III) or systemic
  agents (stage IV)
• Stage IV is incurable with expected survival 9
  mo.
• Treatment options include chemotherapy and
  clinical trials evaluating new targeted agents or
  immunotherapy

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Observation and hypothesis

• Melanoma is inherently immunogenic
• Anti-melanoma antibodies (Surgery 64233, 1968)
• Endogenous T cell immunity (PNAS 813511, 1984)
• TIL are prognostic (Cancer 771303, 1996)
• Immunization will effectively increase the
  magnitude of the response leading to tumor
  regression

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Science Watch highly cited papers in melanoma
research (1970-2007)

• 1. Nestle et al. Vaccination of melanoma patients
  with peptide- or tumor lysate-pulsed dendritic
  cells (1998) Nature Medicine, 4 328-332. Cited
  1863 times.
• 2. Kamb et al. A cell cycle regulator potentially
  involved in genesis of many tumor types (1994)
  Science, 264 436. Cited 1830 times.
• 3. Morton et al. Technical details of
  intraoperative lymphatic mapping for early stage
  melanoma (1992) Archives of Surgery, 127
  392-399. Cited 1723 times.
• 4. Dranoff et al. Vaccination with irradiated
  tumor cells engineered to secrete murine
  granulocyte-macrophage colony-stimulating factor
  stimulates potent, specific, and long-lasting
  anti-tumor immunity (1993) PNAS,90 3539-3543.
  Cited 1483 times.
• 5. Van Der Bruggen et al. A gene encoding an
  antigen recognized by cytolytic T lymphocytes on
  a human melanoma (1991) Science, 2541643-1647.
  Cited 1378 times.

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T Cell Homeostasis 3 distinct phases
R. Ahmed
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Immune monitoring tetramer staining can measure
antigen-specific CD8 T cells
BAL fluid from Influenza virus infected mice
MHC class I
Avidin-PE
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The problem with therapeutic immunization
viral infection
vaccination
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Dendritic Cell Immunization

• Phase I/II vaccine trials (1998-2005)
• Phase III vaccine trial (2006)

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DC are potent stimulators of the mixed lymphocyte
reaction
Steinman and Witmer PNAS 1980
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Human DC are potent antigen presenting cells for
TT
JEM 1983
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Dendritic cells are the key initiators of immunity
Steinman and Pope 2002 Reis e Sousa 2006
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Summary of DC vaccine trials in metastatic
melanoma
Curr Opin Oncol 19121, 2007
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March 1998
16 patients with advanced melanoma given one
million autologous DC injected weekly into the
draining lymph node x4 then monthly. 12 pts
received melanoma antigen peptide pulsed DC 4
pts received autologous tumor lysate pulsed DC
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Peptide Lysate n 12
4 Responders PR(7m) CR(15m) PR(12m) PR(3m)
CR(15m)
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DTH testing KLH 16/16 positive Melanoma 5/16
positive 4 of the 5 had a clinical response
after vaccination
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Immune correlative studies
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• Randomized study of 108 patients (2000-2003) at
  6 centers
• newly diagnosed metastatic melanoma with no bone
  or brain mets
• DTIC 850 mg/m2 iv day every 28 days
• Peptide-pulsed DC immunizations given sc every 2
  wk x5 then every 4 wk
• Primary endpoint response rate by RECIST
  criteria
• Secondary endpoints Toxicity, progression-free
  survival and overall survival
• Immune monitoring data was not reported

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(No Transcript)
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Treatment Outcomes
chemo vaccine n 55 53 CRPR 5.5 3.
8 Median PFS 2.8 mo 3.2 mo Median OS 11.6
mo 9.3 mo 95 CI (9.8-14.4) (7-15.6)
Only 108 pts enrolled. Study closed at the first
interim data analysis (futility).
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Influence of HLA on survival after DC immunization

• study design issues
• sc route is sub-optimal
• semi-mature DC used and only 49 of
• DC met release criteria
• tumor antigen expression not evaluated
• ? sub-optimal peptides for non-A2 alleles
• Different schedule
• No KLH

N22
N31
A2 peptides included two validated anchor
modified peptides G209-2M (gp100) and M26-2L
(Mart-1) A1 mage-1, mage-3, tyrosinase A2
tyr, mart1, gp100, mage-3, GnTv A3 mage-1,
gp100 A24 tyr, mage-1, mage-3, gp100 B44 tyr,
mage-3
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• The only thing worse than a bad experiment is

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Vaccination improves survival in
androgen-independent prostate cancer
Prostatic acid phosphatase/GM-CSF fusion protein
loaded in autologous dendritic cells (APC8015
Provenge) given iv every 2 weeks for three doses.
Trial D9901 randomized controlled double
blind study in AIPC receiving no other therapy
all pts are asymptomatic and have no visceral
mets. vaccine control Pts 82 45 Median
survival 25.9 mo 21.4 mo 3yr survival 34 11
p0.01 p0.0046 ASCO 2005