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IMMUNOTHERAPY

Definition

Immunotherapy is a medical term defined as treatment of

disease by inducing, enhancing, or suppressing an
immune response.

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Classifications
 Activation immunotherapies: to elicit or amplify an immune response.

 Suppression immunotherapies: to reduce, suppress or more

appropriately direct an existing immune response, as in autoimmunity or
allergy.

Activation immunotherapies can be achieved by:

 Active immunotherapy: make the patient’s immune system actively produces stronger
immune response (HI or CMI or both) by using:
 Vaccine
 Cytokines
 Adjuvants
 Passive immunotherapy: provide the patient’s body with pre-made
antibodies.

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Activation immunotherapies can be achieved by:

 Adoptive immunotherapy: provide the patient’s body with primed specific

lymphocytes.

 Cell based immunotherapies: (proven to be effective for cancers): make the

immune cells such lymphocytes, macrophages, dendritic cells, NK cell, cytotoxic T
lymphocytes (CTL), etc., that work together to defend the body against cancers and
attacks by "foreign" or "non-self" invaders such as bacteria and viruses.

CANCER IMMUNOTHERAPY
The main strategies for cancer immunotherapy currently in practice include
introduction of antitumor antibodies and autologous T cells that recognize tumor
antigens and enhancing patients’ own antitumor immune responses with antibodies
that block immune checkpoints and vaccination.

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CANCER IMMUNOTHERAPY
 Adjuvants
 BCG (Bacilus Calmette Guerin)
 Dinitrocholorobenzene (DNCB)

 Passive immunotherapy (mAbs)

 Active immunotherapy
 Cytokine

 Tumour/cancer vaccine
 Immuno Cell therapy

Adjuvant activity

• Formation of a depot of antigen primarily at the site of application from which the antigen
is released during a variable period

• Increased uptake of antigen into APCs

• Induction of synthesis and secretion of enhancing factors, such as cytokines.

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Adjuvant activity

• Facilitation of antigen transport, uptake and presentation by antigen-capturing and processing cells
• Repeated or prolonged release of antigen (depot effect)
• Signaling of receptors activating innate immune cells to release cytokines which
upregulate co-stimulatory molecule

• ‘Danger signals’ from stressed or damaged tissues activate APCs

• Signaling by recombinant cytokines or co-stimulatory molecules mimics classical adjuvant activity

Passive Immunotherapy With Monoclonal Antibodies

 A limited number of tumors for decades relies on the injection of monoclonal antibodies
which target cancer cells for immune destruction or inhibition of growth.

 Monoclonal antibodies against various tumor antigens have been used in many
cancers.

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Passive Immunotherapy With Monoclonal Antibodies

Immune serum globulin – (gamma- globulin) contains immunoglobulin
extracted from the pooled blood of at least 1,000 human donors.
 Treatment of choice for preventing measles, hepatitis A and replacing Ab in
the immune deficient.
 Lasts 2-3 months.

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Passive Immunotherapy With Monoclonal Antibodies

Specific immune globulin- prepared from convalescent patients in a hyperimmune
state
 Contains high titer of specific Ab
 Pertussis, tetanus, chickenpox, hepatitis B
 Sera produced in horses are available for diphtheria, botulism, spider and snake
bites
 Act immediately and can protect patients for whom no other useful medication exists

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Effectors functions of antibodies

 Neutralization prevent contacts with host cell

reduce the pathogen load

Cell

Inhibit bacterial toxins

 Complement mediated lyses
inhibits the pathogen penetration of the host cell

 Complement binding  pathogen destruction

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Mechanisms by which antibodies clear out antigens Basic Immunology 6th Ed © Saunders 2020
Abbas A. K, Lichtman A. H, and Pillai S.

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Antibodies neutralize microbes and toxins

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Sources of Passive Immunity

 Almost all blood or blood products

 Homologous pooled human antibody (immune globulin)
 Homologous human hyperimmune globulin
 Heterologous hyperimmune serum (antitoxin)

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Passive immunity

Mother’s antibody transferred to SAT injections for prevention

baby via placenta and milk and
treatment of tetanus

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Snake antivenom

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Classification the serum preparations

 Homogeneous serum:
serum obtained from blood
donor volunteers, have
been immunized.
 Heterogeneous serum:
serum obtained from
blood of animals
hyperimmunized.

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mAb attack cancer cells

• Use mAb specific to tumor markers

• mAb kill cancer cell by various ways

MØ NK

Induce Activate C’ ADCC Conjugate with

apoptosis leading to cell toxin or isotope
lysis

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“Active” immunotherapy

• Cytokine - IL-2 / IFNs / TNFα

• Vaccine - single peptide

mixture of peptide
with HSP
and cancer cell

• Cell therapy - Specific CTL

TIL cell
DC

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 Cytokine

 Directly administrering IL-2.

 Indirectly insert cytokine gene.

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IL-2

Before

After few years

Rosenberg (2001) Nature, 411;381-4

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 Stimulation of Host Antitumor Immune Responses by Vaccination With

Tumor Antigens

DNA vaccine

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 Tumor vaccines are meant to be therapeutic, in that they stimulate immune responses to
attack cancers that have already developed.

 Most tumor vaccines tried to date have used antigens that are shared by the same type of
cancers in different patients there has been interest in developing personalized cancer
vaccines tailored for each patient’s tumor

 Tumor-specific vaccines may be administered as a mixture of the antigen with adjuvants,

just like antimicrobial vaccines. In another approach, a tumor patient’s dendritic cells are
expanded in vitro from blood precursors, the dendritic cells are exposed to tumor cells or
tumor antigens, and these tumor-antigen–pulsed dendritic cells are used as vaccines

 Tumors caused by oncogenic viruses can be prevented by vaccinating against these

viruses.

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SOME APPROACHES AVAILABLE

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 Cell Therapy

Adoptive T Cell Therapy

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Adoptive T Cell Therapy

 CAR-T cell therapy targeting the B cell protein CD19, and more
recently CD20

 The most serious toxicity associated with CAR-T cell therapy is a

cytokine release syndrome, mediated by massive amounts of
inflammatory cytokines, including IL-6, interferon- γ

 CAR-T cell therapy may also be complicated by on-target, off-

tumor toxicities, if the CAR-T cells are specific for an antigen
present on normal cells as well as tumors

 Although CAR-T cell therapy is effective against leukemias and

tumors in the blood (to which the injected T cells have ready
access), it has so far not been successful in solid tumors

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LAK and TIL cells

 LAK: lymphokine-activated killer

 TIL: tumour infiltrating lymphocytes

Isolate from patient, activate in vitro then inject back to

patient

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DC treatment

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Immune Checkpoint Blockade

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ID patient
Re-construct the
immune system by stem
cell transplantation

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Immune Checkpoint Blockade

 Although the efficacy of checkpoint blockade therapies for many advanced tumors is superior to any
previous form of therapy, only a subset of patients (25% to 40% at most) respond to this treatment.
The reasons for this poor response are not well understood.

 One of the most reliable indictors that a tumor will respond to checkpoint blockade therapy is if it
carries a high number of mutations, which correlates with high numbers of neoantigens and host T
cells that can respond to those antigens.

 The combined use of different checkpoint inhibitors, or one inhibitor with other modes of therapy, will
likely be necessary to achieve higher rates of therapeutic success. The first approved example of this
is the combined use of anti-CTLA-4 and anti-PD-1 to treat melanomas, which was shown to be more
effective than anti-CTL-4 alone. This reflects the fact that the mechanisms by which CTLA-4 and PD-1
inhibit T cell activation are different

 The most common toxicities associated with checkpoint blockade are autoimmune damage to organs.

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CANCER IMMUNOTHERAPY

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Vaccines

Provide an antigenic stimulus that does not cause

disease but can produce long-lasting, protective
immunity

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Principles and Effects of Vaccination

Sterile protection Non sterile protection

Specific Specific
Quick
amplification
Pathogen
neutralization
Specific

Clearance of the pathogen Clearance of the pathogen

before spreading after infection

Extra cellular pathogens Intracellular pathogen with

or free intracellular cell to cell transmission
pathogens

Antibody mediated Cell mediated

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Types of Vaccines and Their Characteristics

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Vaccine technologies

•Live vaccines Examples

•Recombinant vaccines polio, yellow fever RSV

•Killed vaccines influenza, pertussis

•Plasma derived vaccines Hepatitis B
•Polysaccharide conjugates Hib, Pneumo
•Peptide vaccines Malaria
•Subunit vaccines HIV candidates
•DNA vaccines Influenza

•Combination vaccines DPT

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