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Tumour Immunotherapy: Harnessing Immune Responses to Cancer Dr Alasdair Fraser Sylvia Aitken Research Fellow Section of Experimental Haematology, Glasgow Royal Infirmary

Tumour immunotherapy

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Page 1: Tumour immunotherapy

Tumour Immunotherapy:Harnessing Immune Responses to Cancer

Dr Alasdair Fraser

Sylvia Aitken Research Fellow Section of Experimental Haematology,

Glasgow Royal Infirmary

Page 2: Tumour immunotherapy

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)

Page 3: Tumour immunotherapy

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?

Page 4: Tumour immunotherapy

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

Page 5: Tumour immunotherapy

‘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

Page 6: Tumour immunotherapy

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)

Page 7: Tumour immunotherapy

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.

Page 8: Tumour immunotherapy

‘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

Page 9: Tumour immunotherapy

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

Page 10: Tumour immunotherapy

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).

Page 11: Tumour immunotherapy

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.

Page 12: Tumour immunotherapy

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).

Page 13: Tumour immunotherapy

Effectiveness of multiple antigen vaccines

Patient with multiple metastatic melanomas treated with tyrosinase / gp100 / MART vaccine

Page 14: Tumour immunotherapy

STRESSES

HSPs protect the delicate functions of the cell.

Heat Shock Proteins for Therapy

Page 15: Tumour immunotherapy

Heat Shock Proteins(HSP70)

NH4COOH

ATPase peptide-binding domain

tumour peptide sequence

Page 16: Tumour immunotherapy

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

Page 17: Tumour immunotherapy

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 ()

Page 18: Tumour immunotherapy

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

Page 19: Tumour immunotherapy

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

Page 20: Tumour immunotherapy

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

Page 21: Tumour immunotherapy

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

Page 22: Tumour immunotherapy

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)

Page 23: Tumour immunotherapy

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

Page 24: Tumour immunotherapy

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.

Page 25: Tumour immunotherapy

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%

Page 26: Tumour immunotherapy

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)

Page 27: Tumour immunotherapy

Effects of matched EBV-specific CTL therapy

Haque et al. J Immunol (1998). 160, 6204-6209

Page 28: Tumour immunotherapy

0200000400000600000800000

1000000120000014000001600000

Sample Timepoint

EB

V C

op

y N

um

ber

/Mill

ion

Cel

ls

EBV load after allogeneic CTL infusions

Page 29: Tumour immunotherapy

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.