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Tumor Immunology (I):
Cancer Immunosurveillance & Immunoedi8ng
Christopher Choi, PhD
Center for Immunotherapy
Oncology for Scien:st
Learning Objec8ves

Immune surveillance and immune edi/ng of cancer

Immunotherapy of cancer
Goal of Tumor Immunology
The ul'mate goal of tumor immunology is to induce clinically effec've an'-­‐tumor immune responses that would discriminate between tumor cells and normal cells in cancer pa'ents
Types of Cancer
 Carcinoma: arising from epithelial 'ssue, such as glands, breast, skin, and linings of the urogenital, diges've, and respiratory systems (89.3% of all cancers)  Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive produc'on of lymphocytes (5.4% of cancers)
 Leukemia: disease of bone marrow causing excessive produc'on of leukocytes (3.4% of all cancers)
 Sarcoma: solid tumors of muscles, bone, and E8ology of Cancer
1.
2.
Transforma:on of germline cells: inheritable cancers (<10%, Rb, BRCA1, 2) Transforma:on of soma:c cells: noninheritable cancers (>90%)
Environmental factors:
UV (skin cancer), chemicals (lung cancer), pathogens (HPV causes cervical cancer, helicobacter causes stomach cancer)
Genetic Factors
Environmental Factors
Discovery of an/-­‐tumor immune response
Evidence for Tumor Immunity
Spontaneous regression: melanoma, lymphoma
 Regression of metastases aLer removal of primary tumor: pulmonary metastases from renal 
carcinoma
Infiltra:on of tumors by lymphocytes and macrophages: melanoma and breast cancer
 Lymphocyte prolifera:on in draining lymph nodes
 Higher incidence of cancer aLer immunosuppression, immunodeficiency (AIDS, 
Anti-tumor immunity via cross
priming
Tumor Immunology
 Cancer immunosurveilance: immune system can recognize and destroy nascent transformed cells  Cancer immunoedi:ng:
tumors tend to be gene:cally unstable; thus immune system can kill and also induce changes in the tumor resul:ng in tumor escape and recurrence
Evidence for Elimination (cancer
immunosurveillance)
Mice lacking perforin show an increased
frequency of lymphomas
 Mice lacking RAG and STAT1 develop gut
epithelial and breast tumors
 Mice lacking gamma delta T cells are
susceptible to skin tumors induced by topical
application of carciongens
 Immunosurveillance is against virusassociated tumors rather than against
common spontaneous tumors

Elimination or Tolerance? affinity
Elimination: mutated tumor antigens
Elimination: abnormal expression of
antigens
Evidence for Equilibrium (occult
tumors)
The occurrence of cancer
in recipients of organ
transplants: melanoma
after kidney transplant
Evidence for Escape (detectable
tumors)
1)
Immune responses change tumors such that
tumors will no longer be seen by the
immune system: tumor escape
2)
Tumors change the immune responses by
promoting immune suppressor cells:
immune evasion
Escape: immune system sculpts
tumors
GM-CSF
VEGF MDSC
MCP-1
Summary
Environmental factors such as UV, chemicals,
pathogens (viral and bacterial infections)
 Immune responses have a dual function:
immunosurveillance and immunoediting of
tumor (elimination, equilibrium, escape)
 Immunoediting: immune responses can
change tumors to be hidden from recognition
by the immune system and tumors can
promote immune suppressor cells: T regs and
myeloid-derived suppressor cells (MDSC)

Suggested Reading
Janeway’s Immunobiology, 7th edition: Chapter
15; Pgs. 672-678
Tumor Immunology (II):
Cancer Immunotherapy
Learning Objective

Learn how to harness the immune system to
kill tumors: immunotherapy
Cancer Immunotherapy
How to kill tumors without killing normal cells?
To induce an immune response against the
tumor that would discriminate between the
tumor and normal cells:
Adaptive immunity
Tumor antigens
 Tumor




Specific Antigens (TSA)
Are only found on tumors
As a result of point mutations or gene rearrangement
derive from viral antigens
Tumor Associated Antigens (TAA)




Found on both normal and tumor cells, but are overexpressed
on cancer cells
Developmental antigens which become derepressed. (CEA)
Differentiation antigens are tissue specific
Altered modification of a protein could be an antigen
Tumor antigens
Tumor antigens
Immunotherapy

Adoptive T cell therapy (AIT)

Passive immunotherapy using antibodies

Active-specific immunotherapy by using
vaccines
AIT + IL-2
against
melanoma
AIT + IL-2 against melanoma
Before
After
Transfer tumor-specific T cell receptor
genes using retroviral vectors into
patients’ T cell before AIT
AIT for B cell lymphoma
Passive immunotherapy
Passive immunotherapy
Passive immunotherapy: mAbs
Herceptin: anti-HER-2/neu in breast
cancer patients
 Rituximab: anti-CD20 in patients with
non-Hodgkin’s lymphoma
 Bevacizumab: anti-VEGF in patients with
advanced colorectal cancer

Limitations: clearance by soluble Ags, antigenic variation of
the tumor, inefficient killing or penetration into the tumor
mass
Passive immunotherapy:
immunotoxins

Anti-CD22 Ab fused to a fragment of
Pseudomonas toxin in patients with B-cell
leukemia (hairy-cell leukemia)
Passive immunotherapy: druglinked antibodies

Anti-CD20 antibodies linked to a
radioisotope yttrium-90 in patients with
refractory B-cell lymphoma

Antibody-directed enzyme/pro-drug
therapy (ADEPT): Antibodies linked to
an enzyme that metabolizes a nontoxic
pro-drug to the active cytotoxic drug
Vaccination: cross presentation of
tumor antigens by APCs
T cell activation
T cell killer function
Signal I
T cells
Tumor
Signal II
Vaccination

Cell-based vaccines using irradiated
tumors with adjuvants such as BCG

Peptide- and protein-based vaccines

DNA vaccines
Vaccination: increase
immunogenicity of tumor cells
Vaccination

HPV vaccine for the prevention of
cervical cancer

Oncophage (gp96): a tumor-derived heat
shock protein vaccine against kidney
cancer and melanoma
Vaccination: Oncophage
Immunological Battle Ground
Tumor immunity
Tumor
growth
The tumor environment is an immunological battle ground: Good
vs. Bad
Summary

Manipulation of tumors for the expression of
new antigens is a promising approach for the
induction of anti-tumor immune responses

Vaccines may be effective against residual
tumors but AIT and passive immunotherapy
have potentials for the treatment of primary
tumors
Suggested Reading
Janeway’s Immunobiology, 7th edition: Chapter
15; Pgs. 672-678
Tumor Immunology (III):
Cancer Immunotherapy
Learning Objec8ve

Learn what’s required to get these immunotherapies into the clinic
Evolution of the Regulations
Example 1:
• 1937 elixir of sulfanilamide tragedy
Sulfanilamide was a drug used to treat streptococcal infections and
had been used effectively and safely for some time. It was only
available in tablet and powder form, so the demand for a liquid form
was growing, especially to use in small children. Sulfanilamide did
not dissolve in water. Eventually a solvent was found, but the chemists
only tested the new solution for flavor, fragrance, and appearance and
failed to note that the solvent was diethylene glycol, commonly used as
anti-freeze. When The S.E. Massengill Co. of Tennessee put
“Elixir Sulfanilamide” to market, 107 people died from taking it. This
tragedy showed the need to establish drug safety before marketing
and led to the Food, Drug, and Cosmetic Act of 1938.
Example 2:
• 1960 Thalidomide Incident
Thalidomide was supposedly a safe sedative and had been available
without a prescription in Germany since 1957 and in England since
1958. There was a push to get it approved for use in the United States.
Dr. Frances O. Kelsey of the FDA was assigned to review it for approval,
but she demanded to see more studies before approval. She learned of
reports that use of the drug during pregnancy to treat morning sickness
was associated with the development of neuritis (nerve inflammation).
She was the single person responsible for holding up approval of
thalidomide to be sold in the United States. In 1962, reports came in
from Europe of infants who were born with deformed limbs or no limbs
at all, because their mothers had taken thalidomide during pregnancy.
An estimated 10,000 babies were born with birth defects. Dr. Kelsey
later received the government’s highest civilian honor, The President’s
award for Distinguished Federal Civilian Service, from John F. Kennedy
for her part in preventing a major medical disaster in the United States.
The result of this incident was the Kefauver Harris Amendment of 1962,
which required “stricter limits on the testing and distribution of new
drugs”
and which recognized that “effectiveness (should be required) to be
established prior to marketing.”
The Code of Federal Regulations (CFR)
• the codification of the general and permanent rules and
regulations
• published in the Federal Register by the executive departments
and agencies of the Federal Government of the United States
http://www.access.gpo.gov/cgi-bin/cfrassemble.cgi?
title=200221
• divided into 50 Titles that represent broad areas subject to
Federal regulation
• Title 21: Food and Drugs (administered by the FDA and the
DHHS)
Parts 1-99: e-records, public hearings, GCP, color additives
Parts 100-169: food for human consumption
Parts 170-199: food additives, food substances
Parts 200-299: drugs for human use
Parts 300-499: new drugs, IND, drug marketing
Parts 500-599: food and drugs for animals
Parts 600-699: biologics, blood & blood components,
● Animal testing
● Toxicological assessment
● Comprehensive histological
examination
– Cell survival post transplantation
– Cell migration
– Cellular fate
● Plasticity,
Differentiation,Transdifferentiation,
Fusion
– Tissue integration
– Tumorgenicity
● Hyperplastic or unregulated growth
Clinical Trial Phases
Clinical trials are made up of dis'nct parts called phases.
● Phase I clinical trials are used to show that a new treatment is safe for a small group of people.
● Phase II clinical trials provide more informa'on about the safety of the new treatment and how well it works to treat cancer.
● Phase III clinical trials compare the new treatment with the standard treatment in a large group of people.
CMC for Cell Based Therapies
• IND package
– Provide as much detail as possible
• Characteriza'on of the Cell Product
– Morphologic evalua'on
– Detec'on of phenotype-­‐specific cell surface
an'gens
– Unique biochemical markers
– Gene and protein expression analysis
– Cellular impurity profile assessment
– Biological ac'vity assay – Potency
– MHC/HLA expression -­‐ Compa'bility
DC Manufacture
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