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Cancer Immunotherapy
Presented by
Md. Farhadur Rahman
Phase A Student
Department of Microbiology
BSMMU
Cancer immunotherapy is the use of the
immune system to treat cancer.
This can be done in a couple of ways:
• Stimulating patient’s own immune
system to work harder or smarter to
attack cancer cells
• Giving immune system components, such
as antibody, from outside
Forms of Cancer Immunotherapy
• Non-Specific: Generalized, non-antigenspecific immune activation
• Specific: Antigen-specific response
induced in the patient or passively
transferred from outside
Non-Specific Cancer Immunotherapy
1. Cytokines: (Can be actively induced or
passively transferred)
• Interleukins (IL-2, IL-4, IL-6, IL-12)
• Colony stimulating factor (GM-CSF)
• Interferons (e.g. IFN-α, IFN-β, IFN-ϒ)
• Tumor Necrosis Factors (TNF-α, TNF-β)
2. Immune Checkpoint Inhibitors
• Monoclonal antibodies (mAbs) against
CTLA-4
• mAbs against PD-1 or PDL-1
3. Non-Specific Immune Adjuvants
• BCG: Bacillus Calmette-Guerin
• Membrane Extracts of BCG
• Corynebacterium parvum
• Bacterial Endotoxins: Muramyl Dipeptide
4. Vaccination against neovascularization
e.g. mAbs against VEGF & VEGFR-2
Specific Cancer Immunotherapy
1. mAbs against cancer antigen
a. Naked monoclonal antibodies
b. Conjugated monoclonal antibodies
c. Bispecific monoclonal antibodies
2. Prophylactic vaccines
(e.g. HBV, HPV vaccine)
3. Theraputic vaccines
– Immunization with whole tumor cells
or tumor specific antigen
– Dendritic cell vaccine
4. Adoptive T-cell therapy
–Tumor infiltrating lymphocytes (TILs)
– Engineered T cells e.g. CAR T cell
Non-Specific Cancer Immunotherapy
Interleukins: Interleukins are a group of
cytokines that act as chemical signals
between white blood cells.
IL-2 helps ThCs & TCCs grow and divide
more quickly. A man-made version of IL-2
alone or in combination with TNF-α is
approved to treat advanced kidney
cancer and metastatic melanoma.
GM-CSF: Transfected tumor cells with the
gene for GM-CSF, creating a local source
near the tumor cells. These engineered
tumor cells, when reinfused into the
patient, will secrete GM-CSF, enhancing
the differentiation and activation of host
APCs, especially DCs.
IFN-α can be used to treat these cancers:
• Hairy cell leukemia
• Chronic myelogenous leukemia (CML)
• Follicular non-Hodgkin lymphoma
• Cutaneous (skin) T-cell lymphoma
• Kidney cancer
• Melanoma
• Kaposi sarcoma
Cytokines are difficult to administer locally,
and systemic administration of high
levels of a given cytokine can lead to
serious or even life threatening
consequences.
Immune Checkpoint Inhibitors
Monoclonal antibodies (mAbs) against CTLA-4:
Engagement of CTLA-4 on T cells with the
CD80/86 molecule on APCs results in T-cell
inhibition. mAbs against CTLA-4 can induce
tumor rejection. Unfortunately, a significant
number of patients experienced autoimmune
side effects.
mAbs against PD-1 or PDL-1:
Interaction between PD-1 on T cell &
PDL-1 on other cells (e.g. APCs) inhibit
TCR mediated proliferation & cytokine
production. Some cancer cells produce
large amounts of PDL-1, which helps
them evade immune attack.
mAb treatments that target either PD-1
or PD-L1 can boost the immune response
against cancer cells and have shown a
great deal of promise in treating certain
cancers, such as melanoma of the skin &
non-small cell lung cancer.
Non-Specific Immune Adjuvants
BCG (Bacillus Calmette-Guerin):
BCG is used to treat early stage bladder
cancer. It is a liquid put into the bladder
through a catheter. BCG attracts the
body’s immune system cells to the
bladder, where they can attack the
bladder cancer cells.
Vaccination against neovascularization
e.g. mAbs against VEGF & VEGFR-2:
Antibodies directed against VEGFR-2, or
VEGF itself, can block tumor angiogenesis
in murine tumor models.
Specific Cancer Immunotherapy
mAbs against cancer antigen:
a. Naked monoclonal antibodies:
Naked mAbs are antibodies that work by
themselves. There is no drug or
radioactive material attached to them.
These are the most common type of
mAbs used to treat cancer.
Naked mAbs can work in different ways:
• Some boost a person’s immune response
against cancer cells by attaching to them
and acting as a marker for the body’s
immune system to destroy them.
• Other naked mAbs work mainly by
attaching to and blocking antigens on
cancer cells (or other nearby cells) that
help cancer cells grow or spread.
For example, trastuzumab is an antibody
against the HER2 protein. Breast and
stomach cancer cells sometimes have
large amounts of this protein on their
surface. When HER2 is activated, it helps
these cells grow. Trastuzumab binds to
these proteins and stops them from
becoming active.
b. Conjugated monoclonal antibodies:
mAbs in clinical use can be coupled with
radioactive isotopes, chemotherapy
drugs, or potent toxins of biological
origin.
In such “guided missile” therapies, the
toxic agents are delivered specifically to
tumor cells. This ideally focuses the toxic
effects on the tumor and spares normal
tissues.
c. Bispecific monoclonal antibodies:
These drugs are made up of parts of 2
different mAbs, meaning they can attach
to 2 different proteins at the same time.
An example is blinatumomab, which is
used to treat some types of acute
lymphocytic leukemia (ALL).
One part of blinatumomab attaches to the
CD19 protein, which is found on some
leukemia and lymphoma cells. Another
part attaches to CD3, a protein found on
T cells. By binding to both of these
proteins, this drug brings the cancer cells
and immune cells together, which is
thought to cause the immune system to
attack the cancer cells.
Theraputic vaccines:
• Immunization with whole tumor cells or
tumor specific antigen: This has the
advantage that we do not necessarily
have to know the identity of the antigen
concerned. The disadvantage is that the
majority of tumors are weakly
immunogenic, and do not present
antigen effectively.
• Dendritic cell vaccine:
DCs cultured in GM-CSF and incubated
with tumor fragments, then re-infused
into the mice, have been shown to
activate both TH cells and CTLs specific
for the tumor antigens. When the mice
were subsequently challenged with live
tumor cells, they displayed tumor
immunity.
Employing this strategy, sipuleucel-T
became the first approved therapeutic
cancer vaccine against metastatic
prostate cancer.
Adoptive T-cell therapy
Tumor infiltrating lymphocytes (TILs):
Basic steps:
1. Collection of T cells from fresh patient
biopsy specimens
2. Proliferation of T cells in vitro
3. Transfusion of T cells
TIL
Tumor-infiltrating
Lymphocytes
TIL enrichment
IL-2
• Engineered T cells: T cells engineered to
express tumor antigen-specific receptors
1. Bispecific T cells are created by the
introduction of genes that encode proteins
that recognize antigens expressed by target
tumor cells.
2. Chimeric Antigen Receptor (CAR) T cells:
Here genes can encode chimeric tumor
antigen-specific receptors, or T bodies, that
target surface antigens in an MHCindependent fashion.
It is constructed by linking the variable
regions of the antibody heavy and light
chains to intracellular signaling chains
such as CD3-zeta, potentially including
costimulatory domains encoding CD28 or
CD137.
• T cells engineered for enhanced survival:
A limitation to adoptive transfer of CTLs
is that they have short-term persistence
in the host in the absence of antigenspecific Th cells and/or cytokine
infusions. CTLs with chimeric GM-CSF–IL2 receptors that deliver an IL-2 signal
when they bind GM-CSF.
Stimulation of the CTLs with antigen
causes GM-CSF secretion and resulted in
an autocrine growth loop such that the
CTL clones proliferated in the absence of
exogenous cytokines.
Augmentation of Efficacy of Adoptive
Cell Therapy
• Strategies to augment the efficacy of
adoptively transferred T cells
1. Lymphodepletion by chemothrapy
before transfusion
2. Antibody infusion to prevent CTLA-4
inhibitory effect
3. Antibody infusion to block PD L-1 – PD-1
interaction
4. Cytokines administration e.g. IL-2, IL-7,
IL-12, IL-15, or IL-21