Download Molecularly defined vaccines and clinical immunotherapies

Molecularly defined vaccines!
and clinical immunotherapies!
Daniel Speiser, Ludwig Institute for Cancer Research
1. Cancer cells : they are the origin of cancer, but… 2. Hallmarks of cancer <ssue, cancer microenvironment 3. Cancer and inflamma<on: The immune contexture in tumor <ssue 4. Immunotherapy of cancer Cellular components of tumors
Cancer ºB
tissue
ºT
Stromal
cells
Cancer
cells
Endothelial
cells
*Monocytes
*DC
*NK
*Granulocytes
* innate immune cells
º specific immune cells
Melanoma microenvironment
The Hallmarks of Cancer Hanahan / Weinberg, Cell 2000 Figure 1. Acquired Capabilities
of Cancer. It is suggested that
most if not all cancers have
acquired the same set of
functional capabilities during
their development, albeit
through various mechanistic
strategies.
The Hallmarks of Cancer -­‐ the next genera<on, Cell 2011 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 T cell / tumor cell interaction
Tight interaction of the T cell (left)
with the large tumor cell (right)
Tumor cell lysis
A lethal whole in the tumor cell (bottom),
punched by the T cell (top) already detached
and on its way to other tumor cells
The three main stumbling blocks for anti-cancer T cells
Trends in Immunology, March 2012
Multiple inhibitory receptors of T cells
Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy
Peggs / Quezada / Allison, Immunol Reviews 2008 224:141
Immunotherapy for melanoma patients
Immunotherapy without or with antigen ?
Innate immune system
Specific immune system
antigen important, endogenous antigen sufficient ?
Iden<fica<on of op<mal innate immune s<mulators (adjuvants) for B-­‐cell vaccines to induce protec<on from bacteria and parasites T-­‐cell vaccines to induce protec<on from viruses and tumors T cell priming is highly selective
lymph follicule
metastasis
?
DC
T
:-)
DC
T
in vitro culture
DC
T
Efficient human CD8 T cell responses
induced by life vaccines
Human effector and memory CD8 T cell responses
to smallpox and yellow fever vaccines
Miller, Ahmed et al., Immunity 28: 710 (2008)
Complete T cell differentiation to memory and effector cells requires
strong activation (incl. strong clonotypic bursts) during priming
Yellow fever vaccine induces integrated multilineage
and polyfunctional immune
responses. JEM 2008, Vol.
205 No. 13. 3119-3131
Denis Gaucher /
Rafick-Pierre Sékaly et al.
Figure 9. Consensus transcriptional network of genes differentially
expressed on day 7 as compared with day 0. Network representation of
inferred transcription factors and predicted target genes that are
consistently modulated in at least two out of three datasets, with the third
dataset not being contradictory. Modular immune in vitro construct system
[MIMIC].
CD8 T cell differentiation
T EM -> T CM appears to be exceptional
Zanetti, Franchini, Trends Immunol Nov 2006 27:511
Fearon et al, Immunol Rev 2006
For vaccination, mimic viruses !
e.g. for vaccine size
Bachmann / Jennings, NatRevImmunol Oct 2010
T cell mediated protection
• 
• 
• 
antigen-specific CD8 and CD4 T cells
T cell differentiation stages (CM…)
T cell epitope(s)
T cell subsets defined by differential
function, avidity, and specificity (to one
epitope / to different epitopes)
Essential vaccine components
AA
Antigen
Antigen
Adjuvant
Innate
immune
stimulator
AID
Delivery
system
Choice of antigens for cancer vaccines
Targeting of multiple tumor-antigens, restricted by
different HLA-A,-B,-C (class I) alleles, and
different HLA-DR,-DQ,-DP (class II) alleles
Shared antigens, and/or mutated antigens
Model antigen(s):
to assess the immune response (biological readout)
to induce at least 1-2 strong T cell population(s),
supporting the overall immune response
with consequent bystander activation
Adjuvants for Cancer Vaccines
Dubensky & Reed, Seminars in Immunology 2010 22:155
Capacity of cancer vaccines to mobilize
human tumor antigen specific CD8 T cells
Data from validated
comparative studies
% of circulating
CD8+ T cells
•  Peptide or protein alone, tumor cells
< 0.01
•  Recombinant viruses, DNA
< 0.01
•  Peptide + adjuvants (except IFA)
< 0.1
•  Peptide + IFA (Incomplete Freund s Adjuvant)
~ 0.1
•  Dendritic cells + peptide
~ 0.1
•  Peptide + IFA + CpG oligonucleotides
~ 1
Higher peptide doses
è higher %ages
? Novel formulations / combinations
(e.g. antigens targeted to DC, triggers for other TLRs, etc.)