Notesale: Turn your study into money

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However, immunotherapy provides a more specific therapeutic strategy – more
efficacious and fewer side effects
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2013 was a turning point in cancer, as long-sought efforts to unleash the immune
system against tumours are paying off – even if the future remains a question mark
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These may provide targets for effective immune mediated rejection of the
tumour
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e
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- Interactions between the tumour and the immune system can result in the
immune mediated selection of the most resistant tumour cells and tumour
mediated immune suppression
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Immune modulations, including monoclonal antibody therapy and various
vaccination based strategies, can stimulate tumour rejection
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Elimination – due to the immune surveillance
b
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Escape – methods to suppress the immune system, i
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secondary mutations
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Inflammation induced tumour promotion by cytokines and hormone mediated
mechanisms:
- Low levels of continuous inflammations result in activation of downstream TFs
that lead to cancer
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- They regulate immune responses, i
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T regs, and tissue repair in healthy
individuals and the population rapidly expands during inflammation, infection
and cancer
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- However, this therapeutic strategy is costly and targeted delivery still remains a
problem for the scientific field
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Monoclonal antibodies:
- Receptor blockade
- ADCC and complement mediated tumour lysis
- Cytokine mediated responses

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Cytokine therapies (i
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interferons, IL-2 etc)
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Immune gene therapy:
- Ex vivo generation of tumour targeted effector cells
- DNA/virus based vaccination

• MONOCLONAL ANTIBODY THERAPY:

Direct, antibody mediated inhibition of hormone receptors:
Monoclonal antibodies are specific antibodies that detect one specific peptide and there are
different uses for these antibodies within cancer therapy
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Binding of ligand to a GF receptor triggers a dimerization event and activation of a
signalling cascade, leading to cellular proliferation and resistance to cytotoxic agents
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& c
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Antibody Dependent Cellular Cytotoxicity (ADCC):
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Mabs bind to antigens on the
tumour cell surface, providing the target for Fc receptors on the surface of NK cells
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b
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Cell debris is taken up by APCs (b), which present tumour antigens to B cells,
triggering the release of antibodies with specificities for numerous epitopes on the
target antigens (c) and cytotoxic T lymphocytes (CTLs) that are capable of
recognising and killing cells that express the target antigen (d)
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Antibody-directed enzyme prodrug therapy (ADEPT):
a
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b
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c
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d
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This is due to the specific targeting that overcomes the problem
of drug dilution and inappropriate targeting on non-cancer cells
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Blood vessels are an important component to cancer metastasis and induction of
angiogenesis is dependent on growth factors, i
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VEGF
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MA-bs can be used to attack a number of cancer associated targets including:
- Tumour-associated blood vessles
- VEGF
- Diffuse malignant cells (i
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leukaemia)
- Tumour cells within a solid tumour
- Tumour-associated stroma – attack stroma that supports the cells



Activation and suppression of antigen specific T cells:
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These mAbs block intrinsic immune checkpoints, allowing sustained T cell
responses, including increased cytolytic activity and production of cytokines, such as
IFN-gamma
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Blocking receptor mediated signalling for tumour cell survival and/or growth:
reduced/loss of efficacy when downstream signalling components are deregulated
(i
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mut-RAS for anti-EGFR therapy, loss of PTEN function, etc)
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Marking tumour cells for immune mediated destruction:






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Direct responses (NK cells, macrophages and complement mediated lysis)
Indirect immunological response (i
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activation of antigen specific cytotoxic T
cells)
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Unfortunately, a common side effect of HSCT is graft vs
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leukaemia (GVL) effect
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When this occurs, the graft cells attack the cancer cells because they are recognised
as “foreign” just as the host cells are
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Combination of chemotherapy with HSCT and donor leukocyte infusions (DLIs)
improve patient survival in AML, but GVHD remains a major cause of death and
morbidity
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T cells can be engineered to express conditional suicide switches so that the T cells
can be killed by administration of a drug that activates the switch
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Suicide constructs have been incorporated into allogenic T cells so that they can be
ablated in the event of GVHD, toxicity or uncontrolled T cell proliferation
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This regulation of GVHD allows the maintenance of the highest possible interval of
GVL while keeping GVHD low,


Adoptive transfer of autologous, vaccine-primed, in vitro expanded T cells:
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Manipulation of Tregs:
- Prevent immunosuppression
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Endogenous T cells express a single heterodimeric TCR
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Bispecific T cells are created by the introduction of genes that encode for TCR that
recognize antigens expressed by the target tumour cells
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Alternatively, these genes can encode chimeric tumour antigen-specific receptors, or
T bodies, that target surface antigens in an MHC-independent fashion
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CAR T cell design:





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b
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c
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