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Cancer and cancer immunotherapy
Lanyi Arpad [email protected], X65246
The hallmarks of cancer
Hanahan and Weinberg Cell, 2011 pp646-
A tumor is a wound that never heals
Hanahan and Weinberg Cell, 2011 pp646-
A tumor olyan mint egy szerv…Érhálózattal, különböző sejttípusokkal és őssejtekkel
Olyanná alakítja a környezetét hogy az kedvez a tumor növekedésének és
Progressziójának.
It seems that our immune system is able to
destroy tumors
If this response is specific Tumor-specific antigens must also exist!!
The immune response to tumors
Tumor-specific antigens and tumor associated antigens
Tumor-specific antigens
CT antigens
Cancer/testis antigens are expressed
almost entirely by cancerous cells,
showing little or no expression in
healthy tissue, with the exception of
normal testis, embryonic ovaries and
placenta.
No MHC expression
Many of them X-linked
Over 100 in total --- Potential targets
for immune therapy
The tumor-specific immune responseI
Induction of CD8+ T cell responses against tumors. CD8+ T cell responses to tumors may be induced by cross-priming (also called cross-presentation), in which
the tumor cells or tumor antigens (or both) are taken up by dendritic cells, processed, and presented to T cells. In some cases, B7 costimulators expressed by
these antigen-presenting cells (APCs) provide the second signals for the differentiation of the CD8+ T cells. The APCs may also stimulate CD4+ helper T cells,
which may provide signals for CTL development (see Chapter 5 , Fig. 5–7 ). Differentiated CTLs kill tumor cells without a requirement for costimulation or T cell
help. CTL, Cytotoxic T lymphocyte.
Immune Responses against Tumors and Transplants : Immunity to Noninfectious Transformed and Foreign Cells
Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 10, 189-205
Copyright © 2014 Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.
Activation of tumor-specific T-cells by DC
Cross-presentation
Main stratrgies for cancer immunotherapy
Sattwa S. Neelapu Mol. Oncol (2015 in press)
Why are then tumors NOT eliminated?
Cancer immunoediting
Immune evasion mechanisms by tumors
How tumors evade immune responses. Antitumor immunity develops when T cells recognize tumor antigens and are activated. Tumor cells may evade immune
responses by losing expression of antigens or major histocompatibility complex (MHC) molecules or by producing immunosuppressive cytokines or ligands such
as PD-L1 for inhibitory receptors on T cells.
Immune Responses against Tumors and Transplants : Immunity to Noninfectious Transformed and Foreign Cells
Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 10, 189-205
Why are then tumors NOT eliminated?
The role of the immunosupressive
stroma
Modulation of DC-function by the tumor
TSLP-induced DCs recruit Th2 and Treg cells
Antibody-based immunotherapy
Humanized monoclonal antibodies used in
the treatment of patients with cancer.
•
•
Naked antibodies
rituximab----Trastuzumab
Immunotoxins
• Yttrium 90
• Denileukin IL2+diphteria tox.
(cutaneous T-cell lymphoma)
ADCC--- NK and Macrophage
complement
Many therapeutic anticancer monoclonal antibodies work
by delivering the tumor cells to NK cell-mediated ADCC.
Antibodies bind to a cell-surface antigen of the
tumor cells, for example CD20. The Fc regions
of the antibodies engage FcγRIII on an NK cell,
which then becomes activated to kill the tumor
cell.
Néhány a rák-terápiában engedélyezett monoklonális ellenanyag
Brentuximab
Anti CD30 (Hodhkin lymphoma)
Anti-CD52
monoclonal
Alemtuzumab (marketed as Campath),
Used in chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma
(CTCL) and T-cell lymphoma.
Adoptive T-cell transfer
T-cell responses to tumors can be improved with chimeric
antigen receptors (CARs)
• Low affinity of TCR (compared to virus spec. T cells)
• MHC restriction prevents use in the entire population
• problem solved by Fv
• Variable fragment of the heavy and light chains of a
Tumor-specific antibody made a single chain
• Fusion of FV to an intra cell. domain cont. CD28, CD137
and zeta-chain sequences
• Generates strong signal in the absence of costimulation
B cell tumors can be targeted by CARs specific to CD19
As CD19 is present on normal B cells the CAR T-cell needs an inducible
Suicide gene (i.e. caspase 9 etc)
Treatment of B-cell tumors using anti-CD19 CAR T
cells.
Activaton of the immune system
used in the treatment of patients
with cancer.
• Therapeutic cancer vaccines
• Sipuleucel_T autologous CD54+ leukocytes activated by a fusion
protein GM-CSF some clinical benefit in advanced
prostatecancer patients
• Therapeutic vaccination: peptide vaccines , melanoma
Vaccination of melanoma patients may cause
their tumor to regress
Rec. virus
Synthetic peptide vaccine
It is not yet clear when the vaccine would work. Spectrum from remission
to no response.
AZ AKTÍV TUMOR-SPECIFIKUS
IMMUNTERÁPIA LEHETŐSÉGEI
Anti-tumor immunotherapy
A tumor antigének beviteli módja
Tumor proteinderived peptide
Anti-idiotipe Ab
Tumor protein
Vírus-tumor genome
Modified tumor cell
Irradiated tumor cell
Tumor cell lysate
Heat shock protein
Plasmid DNA
Modified DC
Loaded DC
Mocellin S et al. Lancet
Oncology 2004
Oncolitic viruses in cancer therapy
Alternative immunne adjuvant therapies
almond mushroom, edible, imune
stimulator. Because Agaricus subrufescens contains a high level of beta
glucans, compounds known for
stimulating the immune system, the
fungus is used in oncological therapy
in Japan and Brazil.
Checkpoint therapies
• Blocking negative receptors used by Tregs
• Targeting stimulatory co-receptors with
agonistic antibodies
Blocking the inhibitory effects of CTLA4 with a
human monoclonal antibody.
(Ipilimumab etc)
2 year survival is over 24% but quite some complications.
Blocking the PD1/PDL1 interaction with a human monoclonal
antibody also works.
Blocking PD-1/PD-L1 interaction with a human
monoclonal antibodies significantly improves
therapy.
Works well for melanoma, but it is in trial for many less immunogenic tumors
Padmanee Sharma1,2 and James P. Allison SCIENCE 2015 Vol. 348 pp56
Combinational therapies may help when tumors
are not immunogenic
PDL1/PD1 interakciógátló szignálokat indukál T-sejtekben.
Konstitutív vagy indukált PDL1 expresszió tumor sejteken
Dendritic cell-based therapy
TARGETING DENDRITIC CELLS
CTLA-4
CTLA-4 promotes nuclear localization of
Foxo3
transcription
factor,
which
suppresses expression of genes encoding
IL-6 and TNF.
IDO (indoleamine-2,3-dioxygenase)
induction is also CTLA-4 dependent.
 IDO catalyses the degradation of the
essential amino acid L-triptophan to Nformylkynurenine, the initial, rate-limiting
step of tryptophan catabolism.
Blocking
Downregulation
 Effector T-cells starved of tryptophan are
Transendocytosis
unable to proliferate and go into G1 cell cycle
arrest.
 Metabolites
of
tryptophan
including
kynurenine, quinolinic acid, and picolinic acid
TNF
TNF
IDO inhibitors move center stage in immuno-oncology
Terápiás ellenanyagok (2012)