Tumour Immunotherapy:Harnessing Immune Responses to Cancer
Dr Alasdair Fraser
Sylvia Aitken Research Fellow Section of Experimental Haematology,
Glasgow Royal Infirmary
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)
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?
How can we harness the immune response?
Tumour cell present
Broken up to release antigens
APC
APC recruits T cells able to recognise tumour antigens
T
T
Th
CTL
CTL recognise and destroy other
tumour cells
CTL
Th cells educate other T/B cells
B
Ab / ADCC / cytokine attack
‘Passive’ immunotherapy
• Adminstration of monoclonal antibodies which target either tumour-specific or over-expressed antigens.
• Kill tumour cells in a variety of ways:
Apoptosis induction
Complement-mediated
cytotoxicity
ADCC
NKMØ
Conjugated to toxin / isotope
Antibody-based immunotherapy
Name Malignancy Target
Rituxan B cell lymphoma CD20
Herceptin Breast, lymphoma Her-2/neu
Campath B-CLL CD52
Erbitux Colo-rectal EGFR
Avastin Colo-rectal VEGF
Name Malignancy Target
Mylotarg AML CD33(calicheamicin)
Bexxar B cell lymphoma CD20(131In / 90Y)
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.
‘Active’ immunotherapies
• Cytokines- IL-2 / IFNs / TNFα
• Vaccination strategies- single peptidemultiple peptides
HSP complexes whole tumour cells
• Cell-based therapies - tumour-specific CTLtumour-derived
APC DC priming
Complete regression of a large liver metastasis from kidney cancer in a patient treated with IL-2.
Regression is ongoing seven years later
Effective therapies
Rosenberg (2001) Nature, 411;381-4
Other Immunostimulants
• BCG (bacterial preparation) injected intra-tumour- Can be effective for early-stage bladder cancer.
• IFNα was ‘gold standard’ for CML until recent introduction of Gleevec (imatinib) – affects MHC Class I expression and cell division.
• TNFα effective in vitro, but too toxic to use in patients (pyrexia / -algias).
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.
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 (αCTLA4).
Effectiveness of multiple antigen vaccines
Patient with multiple metastatic melanomas treated with tyrosinase / gp100 / MART vaccine
STRESSES
HSPs protect the delicate functions of the cell.
Heat Shock Proteins for Therapy
Heat Shock Proteins(HSP70)
NH4COOH
ATPase peptide-binding domain
tumour peptide sequence
How is the anti-tumour effect produced?
APC
TAP systemTransporter Associated with Peptide processingCD91
Hsp70 or gp96 / peptide complex
endocytosisreceptor
CTL
NK
tumour peptides presented to CTL / NK cells via HLA Class I
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 ()
Vaccination using HSP complexes
Peripheral blood from CML patient
Isolate HSP complexes from
tumour cellsDevelop DC
Co-culture with patient T cells and expand effectors
for infusion into patient
Load mdDC with HSP complexes in vitro
Immunize patient directly with tumour antigen-
primed mdDC
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.
CTL
tumour
tumour
tumourtumour
CTL
tumour
CTL
tumour
CTLCTL
CTL
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
relapse
Tumourtherapy
No Donor Available
MRD established
peptide vaccine (single Ag) HSP vaccine (multiple Ag) Ag-specific CTL leukaemic DCs ex-vivo Ag-primed DC IFNα/ IL-2
Development of resistance to therapy
Lasting remission / cure
Myeloablative alloSCT or RISCT
+ DLI
Matched allodonor
Quiescent tumour ‘stem’ cell
Proliferating tumour cells
?
Diagnosis
Copland et al (2005) Cancer Immunol. Immunother. 54:297
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 (<0.4% TWC)
Dendritic cell sources for therapy
Haemopoietic Stem Cell
Common Myeloid Progenitor
Monocyte
CirculatingMyeloid DC
Immature mdDC
Ex vivo GM-CSF + IL-
4
CD34+Stem Cell
CD34+ DC
Ex vivo GM-CSF +
Flt-3 + TNF
Mature mdDC
Maturation factors
Copland et al (2005) Cancer Immunol. Immunother. 54:297
DC-based therapy
DC developed from patient monocytes
Pulsed with target antigens
Stimulated to maturation and inoculated back into
patient
Tumour-specific immune responses
measured
Currently in Phase II and Phase III trials for melanoma, prostatic carcinoma and lymphoma.
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%
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)
Effects of matched EBV-specific CTL therapy
Haque et al. J Immunol (1998). 160, 6204-6209
0200000400000600000800000
1000000120000014000001600000
Sample Timepoint
EB
V C
op
y N
um
ber
/Mill
ion
Cel
ls
EBV load after allogeneic CTL infusions
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.
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