Prepared and Presented by:

Fatuma Felix (B.pharm, M.Sc.)

China Pharmaceutical
university
15-06-2016
 INTRODUCTION
• According to the National Cancer Institute, Immunotherapy is
defined as a treatment to boost or restore the ability of the immune
system to fight cancer, infections, and other diseases.
 RATIONALE FOR IMMUNOTHERAPY
• It has long been recognized that the immune system and malignant cells often coexist
in a dynamic equilibrium, and the complex interaction between growing tumors and
the immune system may determine the course of disease. Tumors must develop the
ability to evade the immune system in order to proliferate and metastasize.

• The theory of immune surveillance suggests that the immune system is proactively
able to eliminate abnormal cells and prevent cancer formation in the body. Studies
have shown that patients with compromised or suppressed immune function are at
increased risk of developing cancer. Additionally, although controversial, use of
immunosuppressive agents has been associated with an increased incidence of certain
cancers.

• Clearly the adaptive immune response is able to control the growth of some tumors, as
evidenced by the observation that the presence of tumor-infiltrating lymphocytes
(TILs) often is associated with improved overall survival (OS). However, the immune
system is rendered ineffective as tumors progress. The dynamic process of cancer
immuno-editing can be conceptualized by a seesaw that balances immune protection
with immune evasion
 Cancer immuno-editing
• Cancer immuno-editing involves three stages:
 Elimination - Cancer cells are identified and effectively destroyed by
the immune system.
 Equilibrium - The immune system is unable to completely eliminate
all cancer cells but is able to control or prevent further outgrowth.
 Escape - The immune system is unable to eliminate and control the
outgrowth of the tumor because the cancer cells have evolved
under the selective pressure of the immune system, and those cells
that have acquired the ability to suppress or evade the immune
response continue to proliferate and spread.

• The goal of cancer immunotherapy is to boost or restore the ability of

the immune system to detect and destroy cancer cells by over coming
the mechanisms by which tumors evade and suppress the immune
response, in essence to shift the equilibrium back in favor of immune
protection.
 Dynamic equilibrium between cancer and immune system

The immune system The cancer cells evade

Tumor cells are
control and prevent the immune system and
destroyed by the
further outgrowth of the continue to proliferate
immune system
tumor cells and spread
 IMMUNOTHERAPY CATEGORIES

• Immunotherapy for cancer can be categorized as:

a. PASSIVE IMMUNOTHERAPY
• Passive immunotherapy enhances pre-existing immune
response and has a short life. Examples include monoclonal
antibodies, lymphocytes and cytokines.

b. ACTIVE IMMUNOTHERAPY
• Active immunotherapy engages the immune system and is
potentially durable. One example is therapeutic cancer
vaccines.
• directs the immune system to attack tumor cells by
targeting Tumor Associated Antigens (TAAs).
 TYPES OF CANCER IMMUNOTHERAPY
1. THERAPEUTIC CANCER VACCINE
• Therapeutic cancer vaccines are designed to stimulate the patient’s own
immune system against tumor antigens.
• By triggering the immune system, therapeutic vaccines can initiate a
durable anti-tumor response that can attack tumor cells and lead to
improved survival.
• It is important to recognize, however, that therapeutic cancer vaccines
differ from traditional preventative vaccines, such as those for various
infectious diseases.
• Notably, the primary goal of a therapeutic cancer vaccine is NOT to
prevent disease, but to generate an active immune response against an
existing cancer.
• Some therapeutic cancer vaccines have contained a recombinant protein
comprised of a tumor antigen and an immune cell activator. Once injected
or infused, APCs process the antigen and then express antigenic fragments
on their surface for presentation to the patient’s T cells.
• These activated APCs are able to interact with naïve T cells in the initiation
of a T-cell driven immune response.
 CLASSIFICATION OF CANCER VACCINES
• Cancer vaccines can be classified into several major
categories :
 cell-based vaccines
 protein/peptide vaccines
 genetic vaccines (DNA-based, RNA-based, and
viral-based)

• Tumor cell vaccines can be

 Autologous (derived from patient-specific tumor
cells)
 Allogeneic (produced from established human
tumor cell lines).
 How It Works

DNA from
Normal thefrom
cells patient’s Cancer Cells
an unrelated is Transferred
healthy individual into
thatNormal
take upCells
DNA
Normal
Normal CellsCells
fromfrom Unrelated
Unrelated
express Healthy
cancer Healthy
Cancer Individual
Individual.
antigens. Cells
 How It Works

Dendritic
Foreign
cells
cells
incorporate
expressingDNA
cancer
fromantigens
the foreign
are taken
cells expressing
up by
cancer antigens. patient’s
They activate
dendritic
killercells.
T cells in the patient.
 How It Works

Activated T cells seek out cancer cells in the patient

Leaving normal patient cells intact
and destroy them.
 2. MONOCLONAL ANTIBODIES

• Tumor-specific monoclonal antibodies can elicit a direct or indirect

immune response that leads to cell death. There are a variety of
monoclonal antibodies and these work via different mechanisms of
action to cause cell death.

• Some of these mechanisms include blocking signaling pathways needed

for tumor cell growth, triggering an immune-mediated cytotoxic
response (e.g., antigen-dependent cellular cytotoxicity), or blocking
angiogenesis.
 Cont……..

• Tumor-specific monoclonal antibodies have become part of the

therapeutic repertoire in treating leukemia, breast, colorectal,
and head and neck cancers after improving Overall Survival (OS)
and progression-free survival in randomized, Phase 3 clinical
trials.

• Response rates of 8%-10% have been observed when these are

used as a single agent in advanced stage, heavily pretreated, and
recurrent disease. These rates increase to 30% when combined
with traditional chemotherapy and/or radiotherapy.
CANCER IMMUNOTHERAPY: MONOCLONAL ANTIBODIES
 3. CHECKPOINT INHIBITORS
• The immune system depends on multiple checkpoints or
“immunological brakes” to avoid over activation of the
immune system on healthy cells.
• Tumor cells often take advantage of these checkpoints to
escape detection by the immune system. CTLA-4 and PD-1
are checkpoints that have been studied as targets for cancer
therapy.
• CTLA-4 has been shown to be aberrantly up regulated and present
on the surface of T cells in certain cancers, dampening T-cell
activation in response to tumor cells.

• PD-1 is another immunologic checkpoint that has been found to be

up regulated in certain tumors; it inhibits T-cell function contributing
to the tumor’s ability to evade the immune system.

• Inhibiting a checkpoint (i.e., “releasing the brakes”) on the immune

system may enhance the anti-tumor T-cell response. This class of
therapy has shown efficacy in cancer and clinical trials are ongoing.

• Another regulator of the immune response that functions in the

tumor micro-environment is the (indoleamine-2,3-dioxygenase) IDO
pathway.IDO normally functions to prevent damage from excessive
immune activation by breaking down tryptophan, which is required
for T-cell activity. Tumor cells often exploit this pathway by over-
expressing IDO in the presence of effector cell stimuli. Thus, IDO
inhibitors have the potential to alter the tumor microenvironment
and boost the T-cell–mediated immune response.
Immune Checkpoint Modulators in Clinical Development
 4. CYTOKINES
• Cytokines, such as interleukin-2 (IL-2) and interferon-α (IFN-α),
stimulate a broad-based immune response as opposed to
generating a targeted response to a specific antigen. As an example,
IL-2 has numerous effects on the immune system and acts as a
general T-cell growth factor. It does this by binding to receptors on
the surface of T cells.

• This binding stimulates the proliferation of T cells, continued

cytokine production, and activation of multiple types of immune
cells. It is interesting to note that high-dose IL-2 therapy has been
shown to lead to a complete response in a subset of patients (4%-
6%) in renal cell carcinoma and melanoma. This suggests that for
this subset of patients, IL-2 therapy is able to successfully
manipulate the endogenous anti-tumor immune response.
IL2 Stimulation of T-Cell proliferation
5. Adoptive T-cell therapy
• Involves infusion of ex-vivo activated and expanded tumor
specific T-cells into the patient to give their immune system
the ability to overwhelm remaining tumor via T-cells which
can attack and kill cancer.

• The T-cells are taken directly from the patients blood after
they have received an active cancer vaccine then expanded
and engineered to recognize and attack tumors.

• Various sources and types of T-cells have been used including

Tumor infiltrating lymphocytes and engineered T-cells(
express cancer specific T-cells receptors such as a chimeric
antigen receptor-CAR).
 STATE OF CANCER IMMUNOTHERAPY
Immunotherapy has a long history
• Immunotherapy has been under evaluation for more than a
century, but only recently has it entered a renaissance phase
with approval of multiple agents for the treatment of cancer.
 The future of immunotherapy

• Clinical research in immunotherapy is rapidly

increasing: The number of abstracts at the major
conferences has doubled.

• There are approximately 800 ongoing clinical trials in

various phases for cancers such as breast, colon,
head and neck, and kidney.
 CONCLUSIONS

• Cancer immunotherapy has been studied and tested for several

decades, but only recently have immune-based therapies been
shown to provide an OS benefit in patients with advanced
cancer.

• The complex interactions between tumors and the immune

system has advanced and a range of new therapeutic strategies
has been developed.

• These new agents exploit a wide array of mechanisms to

enhance the anti-tumor immune response and are beginning to
have a clinical impact on the treatment of many different tumor
types.
 REFERENCES
• Mary L. Disis, Mechanism of Action of Immunotherapy:
Seminars in Oncology, Vol 41, No5, Supp5, October2014,
ppS3-S13