Tumor/Cancer Immunity,

Immune prophylaxis
 Tumor Immunology
• Tumor immunity occurs in the initial phase of
neoplastic transformation and may
influence disease progression & patient
prognosis.
• Is the study of the antigenic properties of transformed
cells, the host immune response to tumor cells, the
immunologic consequences to the host of the growth of
malignant cells, and the means by which the immune
system can recognize tumor cells and promote tumor
eradication.
• Cells that continue to replicate, fail to differentiate into
specialized cells, and become immortal.
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 Tumor Immunology
• In the development of neoplastic cells, neoantigens
develop at cell surface that permits the host’s IR to
recognize these cells as foreign.
• The function of the immune system is Immune
surveillance - identify & destroy them.
• Immunoediting (immune surveillance) is a process by
which a person is protected from cancer growth and the
development of tumor immunogenicity by their immune
system.
• It has 3 main phases: elimination, equilibrium, escape

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 Tumor Immunology
• CMI is effective surveillance system that eliminates
newly arising (forbidden clones) of neoplastic cells.
• Cancer cells are the progeny of a single transformed cell
or several clones that undergo unregulated cell
proliferation.
• Solid tumors are collections of attached cancer cells
which can metastasize (spread) from their original site.
 Tumor Immunology
• Liquid tumors are leukocyte tumors that circulate in
the blood & may form masses elsewhere in the body
• However, because these tumors closely resemble the
original transformed cells, the immune system tolerates
most tumor types to a variable degree.
• Tumors that have severe mononuclear cell infiltration
have a better prognosis than those that lack it.
• Certain tumors regress spontaneously (e.g. Melanoma
neuroblastoma) suggesting immunological response

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 Protooncogens
 Promitotic (promoting cell division)
 For the malignant transformation is enough mutation in one
copy of the gene protoonkogen (dominant oncogenes)
Antioncogens
 Tumor-suppressor genes
 regulation of cell cycle
 for the malignant transformation should be excluded from
• function both copies of the gene (recessive oncogenes)
 TP53, RB1
Defensive immune response
 tumor cells are weakly immunogenic
 occurs when tumor antigens are presented to T
lymphocytes by activated dendritic cells
 in defense may be involved: non-specific
mechanisms (neutrophilic granulocytes,
macrophages, NK cells, interferons) & antigen-
specific mechanisms (complement activating
antibodies or ADCC, TH1 and TC)
 Tumor Immunology
Etiologies of cancer
1. Environmental factors: UV, chemicals, viral infection
2. Genetic factors: translocation, amplification, mutation

Mutagens (carcinogens)
• physical (e.g - various forms of radiation)
• chemical (e.g - aromatic hydrocarbons)
• biological (mainly various oncogenic viruses)

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UV induced cancers
• Damage or mutation of DNA:
– Melanoma: metastatic, highly immunogenic,
spontaneous rejection
– Non-melanoma cancers:
a. Basal cell carcinoma: rarely spreads
b. Squamous cell carcinoma: can spread
Chemical induced cancers
• Free radicals & other oxidants steal electron from DNA
and cause cancer:
• Anti-oxidants (vitamins A, C): reduces risk
 Tumor Immunology
Virus induced cancers
• DNA viruses:
– Papilloma, Hepatitis B virus, EBV, HHV-8
• RNA viruses:
– Retroviruses: HTLV-I & HTLV-II cause T-cell
leukemia
– Hepatitis C virus
 Tumor Immunology
Tumor suppressor genes
– Some genes suppress tumor formation.
– Their protein product inhibits mitosis.
– When the genes are mutated, the mutant allele behaves
as a recessive & tumor suppression continues.
• Conversion of proto-oncogenes to oncogenes:
– Amplification of c-erbB2 in breast cancer
– Point mutation of c-ras in kidney & bladder cancers
– Chromosome translocation of c-myc in Burkitt’s
lymphoma.

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 Tumor Immunology
• Alteration in tumor suppressor genes
– P53 (protein 53) is a 53 kilodalton.
– p53 is a tumor suppressor gene (its activity stops the
formation of tumors)
– P53 mutation in prostate cancer: failure in cell cycle
arrest or apoptosis of prostate tumors
– The product of the tumor suppressor gene p53 is a
protein that prevents a cell from completing the cell
cycle

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 Tumor antigens
Tumor markers / Tumor Antigens:
• Tumor Ags are newly expressed or over-expressed
Ags during the generation & development of the tumor.
• Some tumor markers are specific for a particular type of
cancer, while others are seen in several cancer types.
• There is alteration of the surface Ags during
transformation of tumors due to viral infection,
chemicals, physical agents.
• Tumor markers alone are not diagnostic for cancer.

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 Tumor antigens
 Based on their patterns of expression, tumor Ags
are classified as:
1. Tumor Associated Antigens (TAA)
• Ags found not only in tumor cells but also in some
normal cells, but the quantity is significantly higher in
tumors than in normal tissues.
• differences in time and local expression
• auxiliary diagnostic markers
• These proteins are produced by the body in response to
cancer growth or by the cancer tissue itself.
• It may be detected in blood, urine, or tissue samples.

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 Tumor antigens
• The oncofetal substances present in embryo or fetus,
diminish to low levels in adult & probably has no normal
function in adults but reappear in the tumor.
a. Oncofetal antigens – reemergence of embryonal
proteins newly produced or present on membranes.
• The quantity of TAA increases proportionally with tumor
growth & decreases with tumor response to treatment.
Oncofetal antigens
– On normal embryonic cells and some tumor cells
– Alpha-fetoprotein (AFP) – hepatoma
– canceroembryonal antigen (CEA) - colon cancer
 Tumor antigens
Two major onco-fetal antigens are:
i. Alpha feto-proteins (AFP) - normally produced by the
liver & yolk sac of a developing baby during pregnancy.
• AFP is produced only as a secreted protein.
• AFP is of importance in diagnosing hepatocellular
carcinoma & may be useful in screening procedures.
• A 5-fold or higher rise in this protein is used for
monitoring hepatoma & testicular cancers.
• AFP level may also be raised in some non-malignant
conditions, such as cirrhosis, hepatitis & other forms of
liver damage.
 Tumor antigens
ii. Carcinoembryonic antigen (CEA):
• A protein found in many types of cells but associated
with tumors and the developing fetus.
• CEA is found both on cell membranes & in secreted
fluid
– E.g. Prostate specific antigens (PSA) for prostate
cancer.
b. melanoma antigens
– MAGE-1, Melan-A
 Tumor antigens
c) antigen HER2/neu
– receptor for epithelial growth factor
– mammary carcinoma
d) EPCAM
– epithelial adhesion molecule
– metastases
e) differentiation antigens of leukemic cells
– present on normal cells of leukocytes linage
– CALLA -acute lymphoblastic leukemia (CD10 pre-B
cells)
 Tumor antigens
2. TSTA – Tumor specific transplantation antigens
• Also called tumor rejection antigens (TRA) - are found
only in tumor cells not present on non-tumor cells
• Unique to a tumor, play important role in tumor rejection
 Evasion mechanisms
Evasion mechanisms of tumor cells from surveillance
1.Antigen masking: Poorly recognized molecules such as
polysaccharide (sialomucin) may cover the tumor cell Ag
• Tumors may not express neoantigens that are
immunogenic.
• Tumor cells escape surveillance & multiply unchecked
2. Dose-response effect:
• Low dose of tumor cells may sneak through & the
immune system may not recognize them - (unable to
stimulate the immune system)
3. Genetic factors: some persons with are poor inducers
of cytotoxic T-cell response.

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 Evasion mechanisms
4. Induce tolerance
5. Produce immunosuppressants: by immunosubversion
(that is, active suppression of the immune response)
6. Outpacing the Immune Response: Tumor cells can
simply proliferate so quickly that the immune response
is not fast enough to keep their growth in check.
Immune response against tumor cells is weak.
7. Immunoselection / editing (selection of non-
immunogenic tumor-cell variants)
8. Hiding from the immune response: immune privileged
sites

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 Immunity to Tumor cells
Cells active in tumor immunity
1. Cytotoxic T cells: recognize tumor Antigens and are
very effective in killing tumor cells.
• Sensitized Tc + MHC I release lymphokine that attack
tumor cells.
2. NK cells
• Lyse & kill tumor cells by direct contact via perforins,
• Kill by ADCC: neutrophils & macrophage have
receptors for Abs (IgG) – cytocidal
3. LAK (lymphokine activated killers) cells
– Large granular lymphocytes (LGL): act non-specifically
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 Immunity to Tumor cells
4. Cytokines or their genes (IL-2, IL-12, IFN-α)
5. T helper (Th) cells
– Recognize the tumor antigens, produce cytokines such
as IFN-γ, also activate macrophages to be tumoricidal
– Provide help to B cells in Ab production
– Provide help to tumor-specific cytotoxic T cells (CTLs)
6. Macrophages
– Important in tumor immunity as APCs to stimulate the
immune response and as potential effector cells to
mediate tumor lysis

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 Immunity to Tumor cells
– Activated M may produce cytotoxic factors (such as
reactive oxygen intermediates, TNF-, etc) that
mediate killing of tumor cells
– Production of nitric oxide (NO), which is a mediator of
tumor apoptosis, may be the most critical mechanism
employed by M.

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 Evidence to tumor Immunity
Evidence to tumor Immunity
• High frequency of cancers in immunosuppressed
patients –
– E.g. Papilloma virus driven cervical cancer; In AIDS
lymph reticular malignancies
 Immunity to Tumor cells

Cells acting on tumor cell

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 Immunoprophylaxis
• The aim of clinical immunology is to correct
abnormal/defective IRs by immune manipulations
Two major approaches possible
1. Immunosuppression: For overactive self-damaging
immunities – e.g. Autoimmune disease, malignancy,
transplantation – drugs such as corticosteroids given
2. Immunopotentiation: for weak immune system –
– Immunization
– Bone marrow transplantation
– Gene therapy
– IV Ig therapy – given
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 Immunoprophylaxis
Immunoprophylaxis
• Prevention of diseases by the administration of
vaccines, immunoglobulins or immunostimulants.
• Conferring immunity to prevent infection.
• It may result from natural (active) or deliberate
exposure to infectious agents or their components
(passive).
• Large number of individuals can be immunized to
achieve herd immunity to interrupt transmissions of
communicable diseases.

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 Vaccines
• Vaccination is a method of giving antigen to stimulate the
immune response through active immunization.
• A vaccine is an immuno-biological substance designed
to produce specific protection against a given disease.
• A vaccine is “antigenic” but not “pathogenic”.
Vaccines can be:
1.Prophylactic (e.g. to prevent or ameliorate the effects
of a future infection by any natural or "wild" pathogen.
2.Therapeutic (e.g. vaccines against cancer are also
being investigated).

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 Vaccines
Types of vaccines
1. Live vaccines
• Made from live infectious agents without amendment
• The only live vaccine is “Variola” - small pox vaccine, made
of live vaccinia cow-pox virus (not pathogenic but
antigenic, giving cross immunity for variola).
Live Attenuated vaccines
• Living mos loose their virulence; so they don’t produce
disease but produce immunity.
• They stimulate both humoral & CMI, local & systemic.
• They are not given to immunocompromised & pregnant
women
• They are heat unstable.

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 Vaccines
Live Attenuated vaccines are prepared by:
a. Repeated subculture in unsuitable condition - e.g.
– BCG for TB
– 17D for yellow fever.
b. Growing at high temp, e.g -
– Pasteur anthrax vaccine
c. Selection of mutant strains of low virulence, e.g-
– Sabin vaccine against poliomylitis
d. Lyophilized preparation - MMR vaccines – Measles,
Mumps, Rubella
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 Vaccines
2. Killed vaccines: virulent bacteria or viruses used to
prepare these vaccines may be killed by heat (60°C) or
by chemicals (formalin, phenol or merthiolate);

Some examples of Killed vaccines:

a- TAB vaccine against Typhoid (enteric fever) [heat]
b- Salk vaccine against poliomyelitis (formalin)
c- Semples vaccine against rabies (phenol)

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 Vaccines
Killed vaccine:
a. Do not stimulate local immunity
b. They do not stimulate Tc response in contrast to live
attenuated vaccines
c. They are safe; They can be given to pregnant woman &
immunocompromised hosts
d. They are short lasting
e. They are heat stable
 Vaccines
3. Toxoids: prepared by detoxifying bacteria toxins by heat
or chemicals.
 Bacterial exotoxins are treated by formalin to destroy
toxicity & retain antigenicity; e.g. diphtheria, tetanus
toxoids.
4. Microbial products/Purified Ags
• Vaccines prepared from bacterial or viral components,
a - Capsular polysaccharide vaccines are:
e.g. meningiococci, pneumococci & H. influenzae
b- Cellular purified proteins of pertussis
c- Purified surface Ag of HB virus, Influenza virus
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 Vaccines
5. Recombinant vaccines
a- Subunit vaccines
– Microbial polypeptides are isolated from the infective
material HBV & influenza virus vaccines
b- Recombinant DNA-derived antigen vaccines:
– Antigens are synthesizing by inserting the coding
genes into E. coli or yeast cell as HBV vaccines.
c- Recombinant DNA avirulent vector vaccines:
– The gene coding for the Ag is inserted into genome of
avirulent vector such as BCG vaccine
d- Synthetic peptide vaccines:
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 Vaccines
– Synthesis of short peptides that correspond to antigenic
determinants on viral or bacterial proteins, e.g cholera
toxins & poliovirus to produce Ab response.
Combined vaccinations
• Immunization against diseases is recommended in
combination (for young children) as:
– Diphtheria, tetanus, pertussis - given as DPT.
– Measles, mumps, rubella - given as MMR
– H. influenzae b (Hib) with DPT
– Hib with inactivated poliomyelitis vaccine (IPV)
– Hib & N. meningitidis (meningococcal meningitis)
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 Vaccines
Requirements of a good vaccine
1. Safe: non-pathogenic
2. Effective
3. Heat stable
4. Cheap
5. Long lasting
6. Ideal – given PO

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 Routes of administration
• Deep subcutaneous or intramuscular route (most
vaccines)
• Oral route (Sabin vaccine, oral BCG vaccine)
• Intradermal route (BCG vaccine)
• Scarification (Small pox vaccine)
• Intranasal route (Live attenuated influenza vaccine)

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 Scheme of immunization
• Primary vaccination
– One dose vaccines (BCG, variola, measles, mumps,
rubella, yellow fever)
– Multiple dose vaccines (polio, DPT, hepatitis B)

• Booster vaccination
– To maintain immunity level after it declines after some
time has elapsed (DT, MMR).

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 Periods of maintained
immunity due to vaccines
• Short period (months): cholera vaccine
• 2 years: TAB vaccine
• 3-5 years: DPT vaccine
• 5 or more years: BCG vaccine
• 10 years: yellow fever vaccine
• Solid immunity: measles, mumps, rubella vaccines.

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 Levels of effectiveness
• Absolutely protective (100%): yellow fever vaccine
• Almost absolutely protective (99%): Variola, measles,
mumps, rubella vaccines, diphtheria, tetanus toxoids.
• Highly protective (80-95%): polio, BCG, Hepatitis B,
pertussis vaccines.
• Moderately protective (40-60%): TAB, cholera vaccine,
influenza killed vaccine.

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 The Cold Chain
• Cold chain: a system of storage & transport of vaccines
at low temperature from the manufacturer to the actual
vaccination site.
• The cold chain system is necessary because vaccine
failure may occur due to failure to store & transport
under strict temperature controls.

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 Vaccination Coverage
• Vaccination coverage: the percent of at risk or
susceptible individuals, or population who have been
fully immunized against particular diseases by vaccines
or toxoids.
• To be significantly effective in prevention of disease on
mass or community level at least a satisfactory
proportion (75% or more) of the at risk population must
be immunized.

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 Tumor immunotherapy
• Immunotherapy for cancer is the stimulation of the
immune system by variety of reagents as vaccines,
infusion of T cells, or cytokines.
• These reagents act through the mechanisms of:
1.Stimulating the antitumor response, either by
increasing the number of effector cells or by producing
soluble mediators such as lymphokines;
2.Decreasing suppressor mechanisms;
3.Altering tumor cells to increase immunogenicity &
make them more susceptible to immunologic defenses
4.Improving tolerance to cytotoxic drugs or radiotherapy
such as stimulating bone marrow function with G-CSF.
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 Tumor Immunotherapy
• Non-specific immunotherapy
– BCG
– Cytokines
• Specific immunotherapy
– Active immunotherapy
• Antibody therapy
• Adoptive transfer of T-cells
– Vaccine-based immunotherapy
– Tumour-based vaccines
– Virus-based vaccines
– Peptide-based vaccines
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 Tumor Immunotherapy
Modalities:
• Monoclonal Abs:- Immunotoxins
• Tumor infiltrating lymphocytes (TIL)
• Cytokine therapy: IL-2, IFN-a, g, TNF-a, Hematopoietic
growth factors (GM-CSF, G-CSF)
• Gene therapy involving ILs
• Lymphokine-activated killer (LAK) cells
• Macrophage activating compounds
• Tc: When Tc are activated by IL-2 in culture & injected IV
into patients, they can reduce tumor mass.

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