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Strategies for Vaccine Therapy A brief Overview

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					Strategies for Vaccine Therapy
A brief Overview

Christian Ottensmeier CRUK Senior Research Fellow University of Southampton

Key Question 1: Is there evidence for effective anti-melanoma vaccination AT THIS POINT IN TIME?

Key Question 2: How do we assess success?

Aim: Specific anti-Tumour Immunity
Active vaccination (with defined antigens)
reg T cell

Antibody

CD8+ T cell

NK Cell

Cance r Cell

Indirect attack

CD4+ T cell

Direct attack

Targets: manyfold
MHC-associated peptides

MHC Class I

Viral Antigens Translocation peptides Mutated proto-oncogene peptides Cancer-testis antigens Autoantigens: telomerase reverse transcriptase CYPIBI WT1 Idiotypic peptides Minor histocompatibility antigens Products of genomic instability Peptides from microarray analysis

Cell surface glycoproteins
Gangliosides Mucins Differentiation antigens

MHC Class II

Problems
Tumour derived antigens weakly immunogenic  Tolerance or ignorance of the host

Defective antigen presentation  Tumour escape mechanisms




Immunosuppression of the host
Systemically  Locally at the normal site of immune response (lymph nodes)




Uncertainty about the best strategy

Strategies: enormous variety - hotly contested
Two kinds of models:  “Black box” approach
– Tumour cells or lysates +/- adjuvant – Autologous or allogeneic
“easier” to do  No need to know best target  Difficulty of assessing immune responses


Strategies: enormous variety - hotly contested


Defined antigens
– Vaccine strategies
Peptide vaccination  Protein vaccination  Nucleic acids: single epitopes or poly-epitopes  Viruses  Dendritic Cells




Transfer of specfic immune cells

Tumour cell extracts


Cancer Vax “Morton vaccine”
– Allogeneic tumour cells +/- BCG


Hsueh/JCO 20, 4549; 2002



Melacine
– 2 human tumour lines/ Detox (adjuvant from Salmonella+mycobacterial cell wall)


Sondak/JCO 20, 2058; 2002



DNP-modified autologous melanoma cells

Tumour cell extracts Cancer Vax
Randomized phase III 263 pts, stage IV resected
5yr survival: 39% vaccinated 19% unvaccinated Hsueh/JCO 20, 4549; 2002

?related to IgM responses?

Tumour cell extracts Melacine
Lysate of 2 lines + adjuvant + IFNa Randomized phase III 600 pts, T3N0M0 (stg II)
5.6 yr FU no difference seen ? Impact of HLA I type A2, C3
Sondak/JCO 20, 2058; 2002

Autologous tumour cell lysates
renal cell CA, adjuvant setting

Randomized phase III Of 553 pts, 117 vaccinated 202 control pT2–3b; N0–3 M0 (1997 classification)
Jocham-Lancet 363, 594; 2004

Peptides as targets


First peptide described in 1992
– Thiery Boon’s group (MAGE-1)



Human MART-126-35 CTL kill human tumour cells


D'Souza/Romero IntJCancer 78, 699; 1998



Now many targets: MAGE, MART-1, Tyrosinase, gp100, TRP1, TERT, Ny-ESO1

Peptides as targets
 

Tools available to measure responses


In patients: induce specific T cells

T cells can mediate clinical responses
– MAGE-3 peptide:
 

7/25 responses Very low levels CTL lyse tumour cells
– Marchand/Boon Int.J.Cancer 80, 219, 1999

– MART127-35 +IL2:


13/31 pts objective responses,
– Rosenberg, Nat Med. 1998;4:321-327

– gp100209-217 210M +IFA


High levels of specific CD8+ T cells (up to 8.9%)
– Smith/JCO 21, 1562; 2003

– gp100280-288 + CD4 helper peptides+ adjuvant


Specific CTL detected
– Slingluff/ClinCaRes 7, 3012; 2001

Proteins as targets
 Protein

vaccination takes advantage of:

– Altered proteins in tumour cells – Differential levels of expression – CTL response not limited to 1 peptide – good for antibody and CD4+ Cells, not CD8+ – Phase III of adiuvant ganglioside vaccine is ongoing (EORTC 18961)

Viral delivery systems
 

Adenoviruses, Poxviruses Poxviruses widely used, safe, well tolerated
 



Modified Vaccinia Virus (MVA) Canarypox Virus Fowlpox Virus

– – – –

Adapted to encode for antigen of interest Induce specific CTL, high levels Induce CD4+ T cells BUT Immune response against viral antigens also strong


Clinical studies ongoing

Nucleic acid vaccines

DNA Fusion Vaccine Cassette
pDOM pCMV peptide



leader

polyA


ISS

ISS

 

ISS



Easy to modify Stimulate multiple effector pathways cheap Uncertainty about delivery site (sc/im/id) Dose and scheduling uncertain May need boosting strategy

 

Viral Physical methods Mini-genes

Dendritic Cells (DC)

 

Key cells in presenting antigen (APC)
> 30 DC trials published in recent years CD8 and CD4 T cell responses induced
– Responses even in bulky disease
 

Fong/Engelman, PNAS 98, 8809; 2001 -colorectal CA Heiser/Vieweg, JCI 109, 409; 2002 - prostate CA
Autologous DC loaded with peptide/tumour cell lysates Some respondses durable over years
– Nestle, Nat Med. 1998 Mar;4(3):328-32

– Example Melanoma:






To date not better than chemotherapy
– Schadendorf, ASCO 2004; abstract 7508

Heat Shock Proteins


Cellular chaperone (gp 96, hsp 70)


 
 

Chaperone for nascent and misfolded proteins Deliver peptides to APC Promotes activation and maturation of APC Stimulate pro-inflammatory cytokines Induce cross priming

 

Deliver peptides to class I molecules Phase II study promising immunological results
 

Belli-JCO 20, 4169; 2002 EORTC phase III study under discussion in stge III MM

T cellular approaches


Patient derived tumour biopsy
– Cultured Tumor infiltrating lymphocytes (TIL) – Expanded in vitro – Patient lympho-depleted with immunosuppressive chemo – TIL reinfused into patients + high dose IL2
5/13 responders, signs of autoimmunity  Dudley/Science 298, 850; 2002 adoptive T cell transfer


The Aim: to make this predictable

Rosenberg-Nature 411, 381; 2001 IL2 treatment, renal cell Ca

What have we learned?


Specific anti-tumour immune responses can be induced
 

Not only in murine models but also in patients



Results have not been spectacular so far
 

3-5% objective responses of vaccination CR rare, short duration

BUT:  Immunotherapy can be effective even against large tumour bulk

What have we learned


Immune responses can be induced


 

T cell repertoire is available CD4+ and CD8+ T cells ? Is there a role for antibodies



BUT effective immunotherapy may come at the price of toxicity Huge progress in understanding immune mechanisms



What have we learned


We can do very complex multicentre trials




Jocham, Lancet 363, 594;2004 Schadendorf, ASCO 2004 abstract 7508



We have increasingly sensitive tools
To measure immune responses  To understand the biology of the tumour




We are defining the clinical settings
Minimal disease load / adjuvant setting  “empty vessel’


What else do we need?


Better defined readouts
Immunological endpoints do not (yet) reflect clinical benefit  Assays may not be sensitive enough  Need to define the compartment of response




Clearer clinical endpoints?
Overall survival?  Time to progression?  Stabilization of disease?


Future Strategies
Combination approaches, e.g. prime boost  Combination of vaccination with


– – – –


IL2, IFNg CLTA4 blockade Anti CD25 antibodies Thalidomide and IMiDs

New delivery systems


				
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