Tumour Immunotherapy: Harnessing Immune Responses to Cancer

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Tumour ImmunotherapyHarnessing Immune Responses
to Cancer
Dr Alasdair Fraser Sylvia Aitken Research Fellow
Section
of Experimental Haematology,
Glasgow Royal Infirmary
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Tumour Immunotherapy possible?
It would be as difficult to reject the right ear
and leave the left ear intact, as it is to
immunize against cancer.
W.H.Woglom, Cancer Research (1929)
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Tumour Immunotherapy questions

• Can immune stimulators combat cancer?
• Which forms of immunotherapy can be used?
• Is vaccination effective against established
  tumours?
• Can anti-tumour responses be generated in
  vitro?
• Can in vitro responses translate into in vivo
  effects?
• What barriers are there to development of
  effective IT?

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How can we harness the immune response?
Ab / ADCC / cytokine attack
Th
B
Th cells educate other T/B cells
APC recruits T cells able to recognise tumour
antigens
CTL recognise and destroy other tumour cells
T
T
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Passive immunotherapy

• Adminstration of monoclonal antibodies which
  target either tumour-specific or over-expressed
  antigens.
• Kill tumour cells in a variety of ways

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Antibody-based immunotherapy
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Effects of antibody therapy

• Rituxan and Campath often used to control disease
  with fewer side-effects than chemotherapy.
• Herceptin is the only monoclonal which is
  effective against solid tumours.
• Immunotoxins still not commonly used due to
  problems with penetration and specificity.
• Bexxar trial in 2005 reported 59 of BCL
  disease-free 5 years after a single treatment.

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Active immunotherapies

• Cytokines- IL-2 / IFNs / TNFa
• Vaccination strategies- single peptide multi
  ple peptides HSP complexes
  whole tumour cells
• Cell-based therapies - tumour-specific
  CTL tumour-derived APC DC priming

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Effective therapies
Complete regression of a large liver metastasis
from kidney cancer in a patient treated with
IL-2. Regression is ongoing seven years later
Rosenberg (2001) Nature, 411381-4
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Other Immunostimulants

• BCG (bacterial preparation) injected
  intra-tumour- Can be effective for early-stage
  bladder cancer.
• IFNa was gold standard for CML until recent
  introduction of Gleevec (imatinib)
  affects MHC Class I expression and cell division.
• TNFa effective in vitro, but too toxic to use in
  patients (pyrexia / -algias).

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Peptide vaccines

• Single peptides
• Melanoma most thoroughly covered (Phase III).
• bcr-abl fusion peptide trial underway.
• Naked DNA prime-boost also trialled.
• Tumour escape through selection of non- antigen
  variants selected.
• Multiple peptide vaccines
• Microarray data identified new candidate Ags.
• Breadth of IR correlates with improved survival.

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Peptide vaccination

• Improved effects of vaccination when given with
  adjuvants (eg CpG).
• Immunostimulators also accentuate response
  (GM-CSF, IL-2, IL-12).
• Alternatively, can target inhibitory receptors to
  increase anti-tumour responses (aCTLA4).

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Effectiveness of multiple antigen vaccines
Patient with multiple metastatic melanomas
treated with tyrosinase / gp100 / MART vaccine
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Heat Shock Proteins for Therapy
HSPs protect the delicate functions of the cell.
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Heat Shock Proteins(HSP70)
ATPase
peptide-binding domain
tumour peptide sequence
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How is the anti-tumour effect produced?
CD91
endocytosis
receptor
APC
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Survival rates in a model of lymphoma
Immunized with PBS (?) 40 µg HSP70 from liver
(?) 20 µg HSP70 A20 cells (?) 40 µg HSP70 A20
cells (?)
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Vaccination using HSP complexes
Peripheral blood from CML patient
Isolate HSP complexes from tumour cells
Develop DC
Load mdDC with HSP complexes in vitro
Co-culture with patient T cells and expand
effectors for infusion into patient
Immunize patient directly with tumour
antigen-primed mdDC
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Using whole cells for immunization

• Killed tumour cells effective vaccinating agents
  in mouse models- not effective in humans.
• Novel methods can enhance immunogenicity of
  tumour cells.

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Allogeneic Transplant-The Original Immunotherapy.

• Allogeneic bone marrow or stem cells
  repopulate patient with entirely new immune
  system (matched to donor closely)
• Relatively crude- associated with significant
  morbidity / mortality
• Modification using T cell depletion or RISCT

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relapse
Quiescent tumour stem cell
Development of resistance to therapy
Proliferating tumour cells
Tumour therapy
MRD established
Diagnosis
No Donor Available
Matched allodonor
peptide vaccine (single Ag) HSP
vaccine (multiple Ag)
Ag-specific CTL
leukaemic DCs ex-vivo Ag-primed
DC IFNa/ IL-2
Myeloablative alloSCT or RISCT DLI
?
Lasting remission / cure
Copland et al (2005) Cancer Immunol. Immunother.
54297
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Dendritic cell therapy

• Dendritic cells are key components of the
  adaptive immune response
• APC function with ability to direct IR
  (activation/tolerance)
• Present in peripheral blood as circulating
  subtypes (lt0.4 TWC)

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Dendritic cell sources for therapy
Copland et al (2005) Cancer Immunol. Immunother.
54297
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DC-based therapy
Currently in Phase II and Phase III trials for
melanoma, prostatic carcinoma and lymphoma.
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Results of current clinical trials

• Wide variation in markers of response
• Evidence of IR through dth, CD4 prolifn.,
  isolation of tumour-specific CTL in periphery and
  detection of TIL.
• How do these reflect true responses to therapy?

Peptide vaccine trials 175 patients total 7
patients responded (4.0)
Tumour vaccine trials 142 patients total 6
patients responded (4.2)
DC vaccine trials 257 patients total 16 patients
responded (6.2)
Total for all cancer vaccine studies 3.8
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Immunotherapy of cancer in action

• PTLD- Post-transplant lymphoproliferative disease
• Caused by EBV recrudescence during
  immuno-suppression.
• Current chemotherapy toxic.
• Novel immunotherapy approach applied-
• Bank of EBV-specific T cell clones collected from
  dozens of blood donors, expanded and stored
  (currently covers 95 of all UK MHC haplotypes)

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Effects of matched EBV-specific CTL therapy
Haque et al. J Immunol (1998). 160, 6204-6209
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EBV load after allogeneic CTL infusions
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Defining whether malignancies are suitable for
Immunotherapy

• Chronic Myeloid Leukaemia
• High tumour burden
• Effective therapy (IM)
• Intact immune response
• Several candidate antigens identified
• Strong potential for IT approaches
  

• Multiple Myeloma
• Low tumour burden
• Adequate therapies
• Impaired immune response
• Few candidate antigens identified
• Many factors (eg. age) reduce effectiveness of
  IT.