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Immune Response to Cancer

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on 17 October 2015

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Transcript of Immune Response to Cancer

7)
6)
=
Barriers
to block the pathogen from entering the body
- includes
physical, chemical, mechanical
, and
genetic
barriers




Third Line
Second Line
First Line
Tumor Antigens Types
Supplementary Cytokines
Cytokines can be introduced into the immune system in order to
stimulate and amplify
certain aspects of the
immune system

E.g. supplemental
interleukin 2,
which promotes proliferation of NK cells called LAK (
lymphokine activated killer
) cells to cause the lysis of cancer cells (Cancer Support Community, 2015)
Monoclonal Antibodies
= Artificial
antibody clones
of a parent plasma cell (
B cell
) which
target specific tumor cell antigens
(Talaro & Chess, 2014)



IMMUNE RESPONSE
IMMUNOTHERAPY
Immune Response
to Cancer

Humoral
B-cells transform into plasma cells which can produce
antibodies
specific to tumor antigens
Antibodies can induce cancer cell death by
Blocking
essential cell receptors
Indirectly by
attacking cells
required to support the cancer (vasculature, stromal cells)
Promoting immune-mediated cell
killing mechanisms
of macrophages, NK cells, and complement
Cell-Mediated
Involves the response of
T cells
Major method by which the host fights cancer, specially
T Helper 1&2 cells
and
Cytotoxic T cells
Cancers cells detected by presentation of tumor antigens by MHC molecules


Adaptive/Acquired Immunity
= “the use of natural and synthetic substances to
stimulate or suppress the immune response
(as in patients with anaphylaxis or severe allergies), to treat deficits, or to
interfere with the growth
of malignant neoplasms” (“Immunotherapy,” 2014)

Cancer Vaccines
-> Not relevant to recognition and/or destruction of tumor cells as they originate within the body
(Talaro & Chess, 2015)
11)
Examples
Immune
Surveillance
Immunoediting Theory
= cancer cells are able to
change their immunogenicity
, which helps them to
avoid detection
by the host’s immune system

it characterizes the interactions of both the host and the cancer cells as a process consisting of three phases:

Phase 1: Elimination

Phase 2: Equilibrium

Phase 3: Escape




Tumor Antigens
“a protein or carbohydrate that is either
expressed by cancerous cells
but not by healthy cells or is expressed by cancerous cells in much greater concentrations than by healthy cells” (“Cancer Antigen,” 2014)

*
Since the expression of tumor antigens is
unique to tumor cells
, tumor antigens can be used as
targets
for the immune system

-> can be used as
tumor markers
Tumor Marker
Description
Substances/changes produced by the body in
response to cancer


Including the following:
proteins
gene expressions
DNA changes

They can be found in:
blood
urine
stool
bodily fluids
tumor & other tissues

* They can be produced by
cancer AND normal cells
“serves as a biochemical
indicator
for the possible presence of
malignancy
” (“Tumor Marker,” 2014)

Are used to:
Detect
Diagnose
Stage
Help determine treatment plan & prognosis
Monitor treatment effectiveness
Monitor for the recurrence

However, there are some
limitations
...
Not every type of cancer has a specific tumor marker
Presence of tumor markers are not sufficient to diagnose
Variability in tumor marker expressed for same type of cancer in different individuals
Clinical
Significance
Interferons
Macrophages
recognize tumor markers
on cancer cells
Secretes
lytic factors
into cancer cells, such as
tumor necrosis factor alpha
(TNFα) and reactive nitrogen intermediates
The rate of this process can be increased by the presence of antibodies bound to tumor antigens (
opsonization
)
May also destroy cancer cells by
phagocytosis
Why does it Fail?
Definition
Biological/Immunological Response Modifiers
= “an agent that
intensifies normal immune responses
” (“Biological Response Modifier,” 2014)
Examples include:
Interferon
Interleukin-2 (IL-2)
Monoclonal antibodies

They are the components through which immunotherapy functions

Used when treatment relies on the immune system to attack cancer cells (targeted therapy)


Questions
Which tumor marker would be helpful in diagnosing liver cancer? Is this a tumor antigen? If so, is this a tumor-specific antigen or a tumor-associated antigen?

In what ways would the immune system protect against the development of liver cancer?

Is there a reason why the immune system was ineffective at stopping the development of liver cancer?

What cancer vaccine might have prevented M.L. from developing liver cancer? Would giving the vaccine be helpful now? Why or why not?
CASE
STUDY

M.L. is a 26 year-old man admitted to the ER complaining of
decreased appetite, nausea, vomiting, fatigue, yellowing of the skin and eyes, and pain in the abdomen
. Further assessment reveals a large
palpable mass
under the ribs on the right side and
hypoglycemia
. Patient history reveals M.L. contracted
HIV
from
sharing needles 3
years ago; however, the patient admits that he only
takes his medications “occasionally”
because of the adverse effects. Patient also states that he continues to take
recreational drugs
because the drugs “make him feel better about his life.” Blood tests show high levels of hepatitis B surface antigens (HBsAg) present in M.L. The attending physician arrives with the diagnosis of chronic hepatitis B infection and suspects liver cancer.
(Diamandis, Fritsche, Lilja, Chan & Schwartz, 2002)
1)
3)
9)
10)
12)
7)
IFNs are produced by the
T-cell immune response
to cancer
interferon-gamma
(IFN-γ) activates
macrophages
to target cancer cells
IFNs may also induce amplification of
NK cells
, which also target cancer cells
IFN-γ also up-regulates expression of
MHC molecules
on cancer cells, allowing for increased recognition

5)
4)
Natural Killer Cells
recognize tumor markers
on cancer cells
May also recognize cancer cells which have a
lack of MHC molecules
Destruction of cancer cells is via release of
lytic factors
Complement Cascade
controversial
(may actually help cancer proliferation)
Antibody binding to
tumor antigens
may allow activation of complement and lysis of cancer cells by
Membrane Attack Complexes
(MACs)
also results in formation of:
C3a
acts as a chemotactic factor for macrophages
C3b
helps induce release of lytic factors from macrophages
(Adam, Odhay, & Bhoola, 2003)

Examples of Mutations
Limitations
Immunotherapy to fight cancer is
relatively new
physicians may prefer more
conventional therapies
treatments may be
unavailable
due to testing restrictions, or are very
expensive

• limitations of
specificity
:
may be too specific to
recognize the targeted cancer
cancer may
mutate
so the immunotherapy no longer recognizes the target
is best used in early stage cancers, because later stage cancers may become
tolerated by the host immune system
and thus cannot be effectively targeted


the new and sometimes restrictive nature of immunotherapy currently prevents it from being offered as standard therapy for cance
r (Cell-Sci, n.d.)

Examples of Biological Response Modifiers
Types

preventative:
designed to train the immune system to directly recognize and destroyt pathogens which are known to cause cancer, thus
preventing cancer



Therapeutic:
designed to train the immune system to directly recognize and destroy
existing cancer cells
another type of immunotherapy as it activates the immune system and provides artificial, active immunity
Question #1
Which tumor marker would be helpful in diagnosing liver cancer? Is this a tumor antigen? If so, is this a tumor-specific antigen or a tumor-associated antigen?

-Alpha fetoprotein
-This is actually a tumor antigen! It belongs to a special class called oncofetal antigens, which are only expressed in fetuses. Thus, self-tolerance in adults never occurs
-This is an example of a tumor-associated antigen, as it is a the product of unaltered genes

Question #2
In what ways would the immune system protect against the development of liver cancer?

-Class II MHC molecules present tumor antigens to T helper cells which attract and/or increase proliferation of macrophages, NK cells and B-cells
-Macrophages and NK cells secrete lytic factors
-Macrophages may also destroy cancer cells by phagocytosis
-B-cells transform into plasma cells which produce antibodies against the tumor antigens
-Complement activation may also occur from antibody binding
-Class I MHC molecules present tumor antigens to T¬c cells, which will induce apoptosis of the cancer cell


Question #3
Is there a reason why the immune system was ineffective at stopping the development of liver cancer?

-M.L. is immunocompromised due to HIV infection and reluctance to use retroviral medications
-Because M.L. is immunocompromised, his body was probably unable to fight off the hepatitis B virus
-Thus, a chronic infection was permitted to occur, increasing the likelihood of liver cancer
-Again due to being immunocompromised, M.L.’s immune system could not properly fight off developing liver cancer cells, further increasing the likelihood of liver cancer


Question #4
What cancer vaccine might have prevented M.L. from developing liver cancer? Would giving the vaccine be helpful now? Why or why not?

-Hepatitis B vaccine
-It would not be helpful now as the vaccine as it only helps the immune system to fight off (one) causative agent of liver cancer (Hepatitis B). It will not help the immune system to fight off the present liver cancer cells


Learning Goals
Develop an understanding of:
Tumor Antigens
Tumor Markers
Immusurveillance Theory
The host's lines of defense against cancer
Immunoediting
Immunotherapy
Biological/Immunological Response Modifiers
Cancer Vaccines

Apply new knowledge to Case Study
References
Adam, J.K., Odhav, B., & Bhoola, K. (2003). Immune responses in cancer. Pharmacology & Therapeutics, 99 (1), 113-132.

American Cancer Society. (2015). Monoclonal antibodies to treat cancer. Retrieved from: http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-monoclonal-antibodies

Biological Response Modifier. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Bisht, M., Bist, S.S., & Dhasmana, D.C. (2010). Biological response modifiers: Current use and future prospects in cancer therapy. Indian Journal of Cancer, 47 (4), 443-451.

Cancer. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Cancer Antigen. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Cancer Support Community. (2015, March). Types of immunotherapy. Retrieved September 17, 2015, from
Cancer Support Community: http://www.cancersupportcommunity.org/MainMenu/About-Cancer/Your-
Immune-System-Cancer-Treatment/Types-of-Immunotherapy.html

Cel-Sci. (n.d.). Limitations of current immunotherapies. Retrieved from http://www.cel-sci.com/limitations_of_current_immunotherapies.html

Cell-Mediated Immunity. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Chu, W. (2013, January 28). Tumor necrosis factor. Cancer Letters, 328 (2), 222-225.

Diamandis, E.P., Fritsche, H.A., Lilja, H., Chan, D.W. & Schwartz, M.K. (2002). Tumor markers: Physiology, pathobiology, technology and clinical applications. USA: ACC Press

Giarelli, E. (2007). Cancer vaccines: A new frontier in prevention and treatment. Retrieved September 18, 2015, from Cancer Network: http://www.cancernetwork.com/review-article/cancer-
vaccines-new-frontier-prevention-and-treatment

Hubert, R. J., &VanMeter, K. C. (2014). Gould’s pathophysiology for the health professions (5th ed.). St. Louis, MO: Elsevier Saunders.

Humoral Immunity. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Immunotherapy. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Kim, R., Emi, M., & Tanabe, K. (2007). Cancer immunoediting from immune surveillance to immune escape. Immunology, 121 (1), 1-14.

Kimball, J.W. (2014). Immune Surveillance. Retrieved from
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/ImmSurveillance.html

Macrophage. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

McKarney, L. (2007). Sipuleucel-T (Provenge): Active cellular immunotherapy for advanced prostate cancer (Issues in Emerging Health Technologies Issue 101). Ottawa: Canadian Agency for Drugs and Technologies in Health.

National Cancer Institute. (2011). Tumor Markers. Retrieved from
http://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
Natural Killer Cell. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

Propper, D.J., Chao, D., Braybrooke, J.P., Bahl, P., Thavasu, P., Balkwill, F., Turley, H., Dobbs, N., Gatter, K., Talbot, D.C., Harris, A.L., & Ganesan, T.S. (2003). Low-dose IFN-γ induces tumor MHC expression in metastatic malignant melanoma. Clinical Cancer Research, 9, 84-92.

Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G., Wienert, S., Van den Eynden, G., Baehner, F.L., Penault-Llorca, F., Perez, E.A., Thompson E.A., Symmans, W.F., Richardson, A.L., Brock, J., Criscitiello, C., Bailey, H., Ignatiadis, M., Floris, G., Sparano, J., Kos, Z., Nielsen, T., Rimm, D.L., Allison, K.H., Reis-Filho, J.S., Loibl, S., Sotiriou, C., Viale, G., Badve, S., Adams, S., Willard-Gallo, K., & Loi, S. (2015). The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer. Annals of Oncology, 26(2), 259-217.

Scott, A., Wolchok, J., & Lloyd, J. (2012). Antibody therapy and cancer. Nature Reviews Cancer, 12,
278-287.

Talaro, K. P., & Chess, B. (2015). Foundations in microbiology (9th ed.). New York, NY: McGraw-Hill Education.

Tumor Marker. (2014). In D. Vernes (Ed.), Taber’s cyclopedic medical dictionary (22nd ed.). Philadelphia, PA: F. A. Davis Company.

A theory that states that the immune system has the ability to not only
recognize and destroy
invading pathogens but to do the same with
cancerous cells
Potential
cancer cells arise frequently
through life but the immune system destroys them as fast as they appear
Immune recognition
depends on detection of
tumor antigen

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1) http://www.lookfordiagnosis.com/mesh_info.php?term=Antigens%2C+Neoplasm&lang=1
2)
3) https://www.blendspace.com/lessons/mmMT8Vd5gNB7LQ/three-lines-of-defence
4) http://www.nature.com/nri/journal/v12/n7/fig_tab/nri3244_F1.html
5) http://nutritionaloncology.org/cancerCells&Inflammation.html
6) http://www.biologyexams4u.com/2013/01/humoral-immune-response-or-antibody.html
7) Talaro, K. P., & Chess, B. (2015). Foundations in microbiology (9th ed.). New York, NY: McGraw-Hill Education.
8) http://www.lifetein.com/Tumor-Antigens.html
9) http://thetruthaboutcancer.com/benefits-immunotherapy-enhancing-patient-immunity-fight-cancer/
10)
11) http://www.cancernetwork.com/review-article/cancer-vaccines-new-frontier-prevention-and-treatment
12) http://localusnews.com/2014/03/11/26-year-old-man-found-shot-to-death-in-portsmouth/
13) http://edusanjalbiochemist.blogspot.ca/2013/07/tumor-marker-introduction.html
14) https://courses.candelalearning.com/biologymajors/chapter/chapter42-the-immune-system/
15) http://bioserv.fiu.edu/~walterm/FallSpring/Immune/phys_complete_2.htm
16) http://www.slideshare.net/MMASSY/innate-important-lecture
17) http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/biological/types/about-monoclonal-antibodies
Picture & Video
References
Relevance to Nursing
Examples
Alemtuzu
mab
(Campath®)

Trastuzu
mab
(Herceptin®)

Ado-trastuzu
mab
emtansine (Kadcyla®)


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Full transcript