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Cancer Immunotherapy

Biotechnology and Genetic Engineering
by

Yusuf Pekmezci

on 23 June 2016

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Transcript of Cancer Immunotherapy

William Coley (1862 – 1936)
Active Immunotherapy
Passive Immunotherapy
Cancer Immunotherapy
M.Yusuf Pekmezci 01040801
Immuno-therapy : treatment designed to change immunity to a disease by enhancing the resistance of the immune system or reducing the immune response to an active disease process.
Activation
IT.
Suppression IT.
use of the immune system to reject cancer
Cancer IT.
The main premise is stimulating the patient's immune system to attack the malignant tumor cells
2 major applications exist
Cancer
IT.
Active Immunotherapy
Passive
Immunotherapy
William Coley (1862-1936)
American bone surgeon and cancer researcher, pioneer of cancer immunotherapy
Developed a vaccine (aka Coley's toxin) to cure tumors
He realized after high fever due to infection can cause remission
He found a sarcoma case study of one patient , whose tumor disappeared following a high fever from erysipelas infection, now known as Streptococcus pyogenes
Later Coley decided to use a mixture of dead Streptococcus pyogenes and dead Serratia marcescens bacteria
In 1891 - He intentionally injected his toxin to Mr.Zola. His tonsils and throat cancer cured.
In 1893- He injected the toxin to a sixteen-year-old boy with a massive abdominal tumor. After 4 months the tumor was gone and boy lived healthy.
Other doctors in Europe and USA reported the same succesful treatment.
In 1901, x-ray therapy was started to be used broadly and displaced with Coley's toxin.
History of Cancer Vaccines
Two types of vaccines
target infectious agents that cause or contribute to the development of cancer
For already developed cancer.
They are intended to delay or stop cancer cell growth;
to cause tumor shrinkage;
to prevent cancer from coming back;
or to eliminate cancer cells that have not been killed by other forms of treatment.
Preventive
Therapeutic
Product by Merck & Co.
Vaccine that helps protect against 4 types of HPV.
In girls and young women ages 9 to 26, GARDASIL helps protect against 2 types of HPV that cause about 75% of cervical cancer cases.
VLPs, that correspond to HPV types 6, 11, 16, and 18
Between 2008-2012 more
than 1,5 million girls were
vaccinated with Gardasil
in UK.
Cervarix, is a bivalent vaccine.
VLPs of HPV types 16 and 18.
Initial evidences showing preventive effect to other HPV caused cancer ( anal, vaginal) and precancerous lessions on genital
Product by Glaxo SmithKleine
Worldwide, cervical cancer is second most common and the fifth most deadly cancer in women.
It affects about 16 per 100,000 women per year and kills about 9 per 100,000 per year.
Worldwide, in 2008, it was estimated that there were 473,000 cases of cervical cancer, and 253,500 deaths per year.

Before vaccinations, costs for treatment in USA was estimated around $6billion/ year.

Complete doses of vaccination costs 390 $/person.
Hepatitis B Vaccine
Globally as of 2008 liver cancer is the third leading cause of cancer death at 700,000 per year, after lung cancer (1.4 million deaths) and stomach cancer (740,000 deaths)
The FDA has also approved a cancer preventive vaccine that protects against HBV infection. Chronic HBV infection can lead to liver cancer. The original HBV vaccine was approved in 1981, making it the first cancer preventive vaccine.

Since 1986 vaccine is produced by yeast cells, into which the genetic code for HBsAg has been inserted.(First recombinant vaccine)

Today, most children in the United States are vaccinated against
HBV shortly after birth.
Vaccine price is between 30-100$/dose.
Cervical Cancer
Monoclonal Antibodies, cytokines
-Targeted
-using the cancer receptor site to bind to the surface
of the cells
- blocking signals that tell cancer cells to grow and divide uncontrollably
-targeted cancer therapies can help stop cancer progression and may induce apoptosis
- Do not generate immunological memmory
Vaccines, active cellular i.t.
Activating body's immune response against tumors
either spesific or non-spesific
Vaccines - protective or theraupetic
The total number of deaths of cancer is not recorded in Turkey.
But estimations are the total incidence is 0.2 % and increasing, with 150.000 new cases every year.
$3,15billion/year spent by healthcare.
The NIH estimates overall costs of
cancer in 2010 at
$263.8
billion:
$102.8
billion for direct medical
costs (total of all health expenditures);

$20.9
billion for indirect
morbidity costs (cost of lost
productivity due to illness);
$140.1
billion for indirect mortality
costs (cost of lost productiv ity
due to premature death)
Some Facts about Cancer
the second most common
cause of death
in the U.S. with an
estimated
571.950
deaths in 2011
-more than
1500
people in a day!
©2011, American Cancer Society, Inc., Surveillance Research
Although cancer cells are derived from normal tissues, the changes they undergo should be sufficient for the immune system to recognize and destroy them. In fact, many nascent cancers may be destroyed by the immune system before they develop.
The fact that cancers do develop implies that either the immune system
fails
to recognize the alterations that give rise to cancer or that cancer cells are actively
evading
the immune response.
Cancer and Immune System are Directly Releated
(Provenge®, manufactured by Dendreon)
FDA has approved
sipuleucel-T in 2010
It must be prepared specifically for each patient. In metastatic prostate cancer, it has extended survival by about four months. It costs $93,000 for a course of treatment.
Active Cellular Immunotherapy Theraupetic Cancer Vaccine
Granulocyte-macrophage colony-stimulating factor (GM-CSF
Prostate cancer
Melanoma
Kidney cancer
Colorectal cancer
Lung cancer
Breast cancer
Leukemia
Non-Hodgkin lymphoma
This approach has shown great promise. It is being studied for use in other cancers:
Antibodies are a crucial component of the immune system, circulating and binding to foreign antigens expressed on cells. Once bound, cells are marked for destruction by macrophages and complement.

diagnosis
monitoring,
treatment of disease.
Targeting cancer cells
Act on other cell types and molecules necessary for tumor growth, e.g. neutralizing growth factors and thereby inhibit tumor expansion.
Monoclonal Antibodies
Application in two main ways
Treatment with Antibodies
By ADCC or CDC
Naked antibodies
a toxin, a cytotoxic agent, or a radioisotope
Using conjugates
The ability for the antibody to specifically bind to a tumor-associated antigen increases the dose delivered to the tumor cells while decreasing the dose to normal tissues.RIT requires a tumor cell to express an antigen that is unique to the neoplasm or is not accessible in normal cells.

To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body.

Ibritumomab tiuxetan- follicular lymphoma.
Iodine (131I) tositumomab - Relapsed folicular lymphoma
Radio Immunotherapy
Ibritumab- murine antibody
chemically
linked to a chelating
agent which binds
yttrium-90.
90Y is a beta radiator.
Tositumomab is a murine
anti-CD20 antibody,
covalently bound to 131I.
emiting both beta and
gamma radiation,
and is broken down
rapidly in the body
Antibody-drug conjugate
They consist of an antibody linked to a payload drug (often cytotoxic)
The antibody causes the ADC to bind to the target cancer cells. Often the ADC is then internalized by the cell and the drug is released to do its damage. Because of the targeting, the side effects should be lower and give a wider therapeutic window.
Gemtuzumab ozogamicin
is a drug-linked monoclonal
antibody that was used to treat acute myelogenous leukemia from 2000-2010. It was withdrawn from market in June 2010 when a clinical
trial showed the drug increased
patient death and added no
benefit over conventional
cancer therapies.
While antibodies targeted to disease-causing antigens can be effective under certain circumstances, in many cases, their efficacy may be limited by other factors. In the case of cancer tumors, the microenvironment is immunosuppressive, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient, against his or her own tumor tissue.
Cytokines are the messengers of the immune system.Cytokines are substances, either proteins or glycoproteins, secreted by immune cells. They have autocrine and paracrine functions, so that they function locally or at a distance to enhance or suppress immunity. In cancer therapy, we generally use cytokines to enhance immunity.
Cytokines
Cytokines
for Cancer IT.
IFN-alfa
IL-2
IL-12
Interferon alfa has many roles.
It upregulates genes like MHC class I, tumor antigens, and adhesion molecules.
It is also an anti-angiogenic agent.
Promotes B and T cell activity stimulate macrophages, even dendritic cells, and upregulates Fc receptors.
Its activity in cancer is well documented. Approved by
FDA in renal cell carcinoma.
A recombinant form of IL-2 for clinical use is manufactured by Prometheus Laboratories Inc with the brand name Proleukin.
It has been approved by the Food and Drug Administration (FDA) for the treatment of
malignant melanoma and renal cell cancer and is
in clinical trials for the treatment of chronic viral
infections, and as a booster (adjuvant) for
vaccines.
IL-12 is a heterodimeric protein that promotes NK and T cell activity and is a growth factor for B cells. It has demonstrated antitumor activity in mouse models. Alone, IL-12 shows minimal potential for therapeutic effect.

However, IL-12 may have value as a vaccine
adjuvant. When IL-12 was paired with peptide
vaccines in patients with resected
stage 3 and 4 melanoma, IL-12
boosted the response
to the vaccine.
Some cytokines, play a key role in modulating the immune response, and have been tried in conjunction with antibodies.
While only cytokine may cause systemic inflammation, resulting in serious side effects and toxicity, a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets the cytokine's activity to a specific environment such as a tumor, are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side-effects.
Conclusion:
Immunotherapy may be the next great hope for cancer treatment. While monoclonal antibodies, cytokines, and vaccines have individually shown some promise, it is likely that our best strategy to combat cancer will be to attack on all fronts. Clearly, different strategies demonstrate benefit in different patient populations. It may be that the best results are obtained with vaccines in combination with a variety of antigens, or vaccine and antibody combinations.
Through these concerted efforts, our ultimate achievable goal may be a durable anti-tumor immune response that can be maintained over the course of a patient's lifespan.
References
dictionary.reference.com
cancer.gov
gardasil.com
carvarix.com
cdc.gov
dandreon.com
cancer.org
meds.com
wikipedia
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