Transcript Immunotherapy Immunotherapy Hormone therapy

Newer cancer therapies
Immunotherapy
Immunotherapy
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Non-specific
immunotherapy
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Specific immunotherapy
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Active immunotherapy
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BCG
Cytokines
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Antibody therapy
Adoptive transfer of T cells
Vaccine-based
immunotherapy
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Tumour-based vaccines
Virus-based vaccines
Peptide-based vaccines
others
Key immune cells in cancer
The main immune cells that play a role in the protection against
tumours and their rejection are
 Cytotoxic T-lymphocytes (CTLs)
 MHC restricted - recognize only small endogenously
processed protein fragments (peptides) that must be
presented in a surface protein called the major
histocompatibilty complex (MHC)
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Natural Killer (NK) cells:
 toxicity without prior sensitization and without MHC
restriction. Usually activated when T cells cannot be
activated
Macrophages:
 usually activated by bacterial / viral infections leading to
tumour cell death
 Stimulates secretion of the tumour necrosis factor (TNF)
Cytotoxic T-lymphocytes (CTLs)
Macrophage engulfing a bacillus
class I MHC antigen processing pathway
The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515
How tumour cells avoid
immunosurveillance
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Altering Their Characteristics : Generate variants lacking antigens
normally detected by CTL, NK cells and antibodies. Tumour cells may
also lack co-stimulatory molecules, which activate T cells, and signaling
molecules needed to respond to cytokines, such as gamma-interferon,
that promote tumour cell killing by immune mechanisms.
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Suppressing the Immune Response : Tumour cells inappropriate or
ineffective signals to CTL, or secreting TGF-beta etc
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Hiding from the Immune Response : Immunoprivileged sites
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Exploiting the Immune System's Ignorance: Growth without eliciting
any immune response.
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Outpacing the Immune Response: Tumour cells can simply proliferate
so quickly that the immune response is not fast enough to keep their
growth in check
Immune escape mechanisms of tumour cells
Downregulation or inactivation of any of the signalling cascade molecules leads to
tumour cell death.
However, tumour cell will not be recognised if
Peptides are not released from a protein or
Peptides not loaded onto the MHC molecule
Expression of Fas ligand on tumour cells may induce apoptosis in the specific T cell
Immunotherapy
Activating the Immune System
Non-specific approach
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1892 - WB Coley observed tumour
regression after bacterial infections
BCG vaccine to treat bladder carcinoma
1970-80’s – cytokines
includes interferons, interleukins and tumor
necrosis factor (TNF)
 Limited success
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Specific approach – The promise of
antibody-based therapy
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Search for tumour specific
antigens
Development of
monoclonal antibodies
1975 Milstein and Kohler
developed hybridoma
technology
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antibody-producing cells
could be made to survive
indefinitely if they were
fused with cancer cells
The problems of antibody-based
therapy
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virtually all these antigens are also found on
normal cells!
Ab therapy may still be used because
the antigen in normal tissues may not be
accessible to blood-borne antibodies
 the cancer cells may express more antigen than
normal cells do
 antibody-induced injury of normal cells may be
reversible.
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Clinical trials – Ab-based therapy
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A33, a 43k glycoprotein with selective expression in normal
and malignant epithelium of the (gastrointestinal tract)
G250, a glycoprotein expressed by a high percentage of renal
cancers;
LewisY (LeY), an oligosaccharide epitope expressed on
glycolipids and glycoproteins by a wide range of epithelial
cancers;
GD3, a ganglioside with high expression in melanoma and
other neuroectodermal tumors;
FAP-alpha, a 95 k glycoprotein strongly expressed in the
stromal fibroblasts of epithelial cancers;
Truncated EGF receptor, a 140 k form of the EGF receptor
(deleted in exons 2-7), which is expressed by a proportion of
brain cancers and other tumour types.
antibodies have been genetically modified to provide chimeric
(G250, GD3) or humanized (A33, LeY, F19) constructs
Adoptive immunotherapy
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stimulating T cells by exposing them to
tumour cells or antigens in the laboratory
and then injecting expanded populations of
the treated cells into patients
Patient is both donor and recepient
Adoptive immunotherapy
The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515
Generation of dendritic cell vaccines from peripheral blood monocytes:
1) Monocytes cultures with GM-CSF +IL-4 to produce DCs
2) Matured with CD40 ligand
3) Pulsed with peptide or tumour lysate
4) Re-injected as vaccine to induce T-cell immune response against tumour
Vaccine-based immunotherapy
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1940-50’s, tumour immunogeneity seen in mice
 the tumors bore antigens that could immunize
other mice of the same strain against
transplants of the tumors.
 T lymphocytes from immunized animals could
transfer immunity against tumours to healthy
animals of the same strain.
 T cells from the immunized mice could kill
tumour cells in vitro.
 Antibodies failed to transfer immunity
Vaccines
administration of some form of antigen to induce a
specific antitumour immune response.
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Tumour-based vaccines
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Virus-based vaccines
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Use of viral oncolysate e.g. Vaccinia viruses expressing
carcinoembryonic antigen (CEA)
Peptide-based vaccines
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Use whole cell/crude extracts of tumours
tumour-associated antigens (TAAs) epitopes bound directly
to MHC on the cell surface can activate CTLs
Others:
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humoral responses e.g. Her2-neu, CEA, TP53, gangliosides
Approaches to antitumor vaccination
The Journal of Clinical Investigation Vol 113 ( 11) June 2004 pp 1515
APC – antigen presenting cell
DC – dendritic cell
TAA – tumour associated antigen
MHC – major histocompatibility complex
Immunoconjugates
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RADIOACTIVE ISOTOPES: I131 or yttrium 99
TOXINS: Use of antibodies to deliver toxins to a tumor site. E.g.
ricin (made from castor beans), which inhibits protein synthesis and
thwarts tumor growth.
CHEMOTHERAPEUTIC DRUGS: Reach tumours in larger and
lethal doses when delivered by an antibody.
ENZYMES: convert "prodrugs" into cytotoxins will home to tumors
when attached to antibodies
GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies
directly or packaged into viral particles engineered to have targeting
antibody on their surface.
INFLAMMATORY MOLECULES: tumour necrosis factor (TNF)
and other messenger molecules of the immune system as well as
certain microbial products, can bring about an inflammatory reaction
that destroys tissues at the tumour site.
Immunotherapy
Immunotherapy
Hormone therapy
Hormone sensitive cancers (Breast cancer in females and
prostate cancer in males) are susceptible to deprivation of the
corresponding mitogenic hormone.
Treatment of either involves
 direct inhibition of steroid synthesis : E.g. using either LHRH
superagonists or aromatase inhibitors in breast cancer
 blocking their effects at the target cell level through the
receptors: Steroid receptor antagonists block receptor
activity. E.g. tamoxifen is an oestrogen receptor antagonist.
Problems with hormone therapy include sexual dysfunction
(e.g.ovulation), secondary cancers etc
Hormone therapy
References
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Immunotherapy for cancer by L.J Old
 Scientific American (Sept 1996) pg 102
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Tumours: Immunotherapy
 MP Rubinstein and D J Cole www.els.net
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Progress on new vaccine strategies for the
immunotherapy and prevention of cancer
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Jay A. Berzofsky, et al The Journal of Clinical
Investigation Volume 113 Number 11 June 2004
1515-1525