GreatWall International Cancer Center
CIK or CIK-DC Immunotherapy


"Instead of using surgery, chemotherapy, or radiotherapy, researchers from the National
Institutes of Health are finding so-far limited but inspiring success in a new approach for
fighting cancer, using the immune system to attack the tumors the way it would be a cold or
flu."   - CNN.com (August 2006)


About Immunotherapy


Treatment to stimulate or restore the body's natural abilities of the immune (defense) system to
fight infection and disease or to protect the body from some of the side effects of treatment.

How does immune system work?

Staying alive and well is a very complicated task. The body contains an amazing array of
systems to protect itself against invaders, called the immune system. The immune system
protects the body in several ways:

By creating a barrier that prevents bacteria and viruses from entering your body.
By detecting and eliminating those bacteria or viruses that manage to get into the body, before
they have a chance to reproduce and proliferate.
Eliminating those viruses or bacteria that have managed to reproduce in sufficient numbers to
start causing problems.
Finding cancerous (or other unwanted cells) and eliminating them.
The most obvious parts of the immune system are the barriers we can easily see -- like our
skin, eyes, nose, and mouth. Skin is tough and resistant to bacteria and secretes antibacterial
substances. Tears and mucus contain an enzyme that breaks down the cell walls of many
bacteria. Saliva is also anti-bacterial. And if any microbes make it past the saliva, the acids in
the stomach are the next level of protection.

Most bacteria and viruses do not get through the body's first line of defenses. But some do,
and once inside the body, the immune system deals with germs and microbes on a different
level - the level of attack and conquer. For most people, viral and bacterial infections are the
most common causes of illness. These usually run their course until the body builds up
immunity to those particular microbes and recovers. But most people are most concerned with
the internal workings of the immune system.

What are CIK cells?

Surgery, radiotherapy, chemotherapy and biotherapy is the mostly used methods for tumor
treatment at present. Cytokine-induced killer (CIK) cells are immune cells that can seek and kill
tumor cells.

CIK cells were discovered in 1986 by Professor Lanier, an esteemed American scientist.
Further in-depth research was later conducted at the Stanford University Medical Center in the
U.S. by Dr Robert Negrin , Pei-Hua Lu, PhD & colleagues.

CIK has proved in medical practice to be the most efficient adopted immunotherapy,which is
one kind of biotherapy. It shows good efficacies in treating malignant tumors in clinical, such
as, leukaemia, melanoma, malignant lymphoma, renal cell carcinoma, metastatic renal
carcinoma, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, and gastric
cancer.

CIK cells are generated in vitro from single peripheral blood mononuclear cell (PBMC) by
addition of interferon-gamma (IFN-γ), interleukin (IL)-2, IL-1 and antibody against CD3 (anti-
CD3 mAb), with surface markers for both T-cell (TCR-α/β, CD3) and NK cell (CD56).
Compared to the lymphokine-activated killer (LAK) and tumor-infiltrating lymphocytes (TIL)
used in the former adoptive immunotherapy, CIK has an enhanced proliferation and ability to
kill tumors, with low toxicity and few side effects. CIK biotherapy could kill cancerous cells
directly, regulate and strengthen the immunity and restore to the maximum extent the normal
cell growth regulator, without any damage to immune system and function. It provides a
thorough new method to treat tumors.

How do CIK cells kill tumor cells?

a. CIK cells are non-major histocompatibility complex (MHC). Thus CIK cells are capable of
recognizing and killing different types of tumor cells though different mechanisms. The cytolytic
activity of CIK cells makes themselves fuse with tumor cells and release cytoplasmic granules
that dissolve the tumor.

b. CIK cells, after induced and transfected by dendritic cells, have a strengthened ability to
proliferate and kill tumors, and a greater precision to target, and they can kill tumor cells by
inducing apoptosis.

c. CIK cells produce IL-2, IL-6, IFN-r and other anti-tumor cytokines

d. CIK cells injected back to human could reactivate the immune system and enhance the
immune functions.

What is DC-CIK immunotherapy?

DC-CIK biotherapy uses CIK cells induced and transfected by dendritic cells (DC). Dendritic
cells are the most powerful type of antigen-presenting cell. DC can present the tumor antigen
to DIK cells and doubly activate DIK cells' ability to recognize cancerous cells.

Compared to CIK biotherapy, while maintains the therapeutic effects, DC-CIK biotherapy has a
greater precision to seek and kill tumor cells and helps to increase the sensibility of cancerous
cells to chemotherapy.

What are the indications of CIK immunotherapy?

CIK is not restricted by histocompatibility of tumors and kills all types of tumors. And it has a
better therapeutic effect on cancer with high expression of antigens. CIK biotherapy has an
impressive efficacy on liver cancer, lung cancer, colon cancer, breast cancer, ovarian cancer,
as well as on malignant tumors as myeloid leukemia, melanoma, renal cell carcinoma,
metastatic renal cell carcinoma, malignant lymphoma (except T-cell lymphoma), non-Hodgkin’s
lymphoma and so on.

This treatment can be applied to cancer patients in any stage, and have good short-term
effects for both early stage patients and advanced stage ones. CIK cells eliminate small lesions
not available for surgery and tiny cancerous cells scattered in the body to delay or prevent the
metastasis or recurrence of tumor. And it would have a better efficacy if combined with surgical
resection, intervention, radiofrequency therapy, cryoablation.


What are the contraindications of CIK immunotherapy?

a. Pregnancy and lactation

b. Uncontrolled severe infection

c. Severe allergic constitution

d. RH negative

e. T-cell lymphoma

f. Epilepsy

g. AIDS


What are the features of CIK immunotherapy in clinical?


CIK biotherapy is presently the first choice of adopted immunotherapies. It has the following
features:

a. CIK cells can recognize the tumor cells and are not toxic to normal cells.

b. CIK cells have a wide spectrum against tumors and are also sensitive to multi-drug resistant
tumor cells.

c. CIK biotherapy helps to enhance immunity and have specific antiviral ability.

d. CIK cells are very safe to use since they are activated autologous cells.

e. CIK cells effectively remove the remnant cancerous cells or small lesions, and prevent the
tumor recurrence.

f.  biotherapy, when combined with radiotherapy or chemotherapy, enhances the efficacies and
reduces the toxicity, side effects, and infections.

g. For those advanced stage patients who have no chance for surgery or for those who suffer
recurrence or metastasis, large dosage of CIK repeated transplant can quickly relieve the
symptoms of advanced cancer patients, improve the quality of life (increased appetite,
improved sleep and enhanced physique) and prolong the survival time. And in some cases,
the tumors are shrinked and even disappear, and long-term survival is achieved.

h. Since CIK can regulate the immunity, during the treatment of tumor, patients may experience
that skin is glossy, varicosis disappears, speckles fade, and grey hair turns black.

What are the adverse reactions of CIK immunotherapy?

CIK cells are induced activated autologous cells. Therefore, CIK biotherapy is very safe. No
serious adverse reactions are observed. In small number of cases, rise of body temperature
(37.2℃-40℃) was observed in 2-10 hours after reinfusion. Generally, the temperature would
drop back to normal in 2-10 hours, and only a few patients need antipyretics to alleviate the
fever.


How are the CIK immunotherapeutic cycles organized?


Usually one CIK biotherapeutic cycle lasts 14-30 days. Mononuclear cells are first collected
from peripheral blood (PBMC). Cells are cultured, induced, activated and compounded in GMP-
standardized laboratory for 10 days. Reinfusion can be applied everyday from after the 10th
day of cell culture according to the requirements.

The number of treatment cycles and the interval depend on the following aspects:

a. Level of immunity (age, physical strength, stress, monophagia, nutrition, and other disease)

b. Clinical stage and lesions (tumor size and metastasis or not. A lump of 1 cm3 approximately
has 1 billion cancerous cells.)

c. Living habits (food, sleep, work, sports, etc.)

d. Treatments have been or will be taken (surgery, chemotherapy, radiotherapy, etc.)

f. Evaluation on stage (blood tests and imaging reports)

e. Consumption capability of the patients

f. Expectation and understanding on curative effect to achieve by the patient and the family
members.


Summary of treatment plan based on long-term clinical practices:


Clinical stage of the cancer/ Treatment dosage

                           Stage I              Stage II               Stage III                          Stage IV  

                              Tumor < 2cm           Tumor > 2cm          Recurrence, metastasis,       Multiple metastases,
                                                                                                      surgery not available              survival with tumor

Treatment cycle   3 treatments            6 treatments            9 treatments                             more than 12
                                                                                                                     treatments
Interval between  3-9 months              3-6 months              1-3 months                               1-3 months
cycles


Dosage at 2 x 109 CIK cells per treatment.


How CIK cells are divided?

CIK cells can be divided by their sources:

a. Allogeneic CIK

Peripheral blood mononuclear cells are collected from healthy blood type O donors, and then
are cultured, transfected and cloned in GMP-standardized laboratory. Usually, reinfusion will
be available in a week after appointment.

Application group:

Patients of all stages within five years, especially for patients in advanced stage or with high
blood lipid. Allogeneic CIK has adequate sources of cells and can be reinfused repeatedly with
large dosage. Therefore it can be used to rescue advanced cancer patients and give the
patients hope and comfort by improving the quality of life.

How many times are the CIK cells reinfused?

Usually, reinfusions will be applied 1-6 times a week at the dosage of >1×109. Reinfusion lasts
for 2 hours. It has no toxicity or side effects, and causes no pain.

b. Cord blood CIK

Mononuclear cells are collected from healthy cord blood, and then are cultured, transfected
and cloned in GMP-standardized laboratory. Usually, reinfusion will be available in a week after
appointment.

Application group:

Patients of all stages within five years, especially for patients in advanced stage or with high
blood lipid. Allogeneic CIK has an adequate sources of cells and can be reinfused repeatedly
with large dosage. Therefore it can be used to rescue advanced cancer patients and give the
patients hope and comfort by improving the quality of life.

How many times are the CIK cells reinfused?

Usually, reinfusions will be applied 1-6 times a week at the dosage of >1×109. Reinfusion lasts
for 2 hours. It has no toxicity or side effects, and causes no pain.

c. Autologous CIK

Peripheral blood mononuclear cells are collected from the patient, and then are cultured,
transfected and cloned in GMP-standardized laboratory. Times of reinfusion depend on
number and quality of cells collected.

Application group:

Patients in stable condition that are confirmed cancer for 3-5 years, or sub-healthy patients.

How many times are the CIK cells reinfused?

Usually, reinfusions will be applied 1-6 times a week at the dosage of >1×109. Reinfusion lasts
for 2 hours. It has no toxicity, side effects and pain.


Note before take the blood test.

a. NO greasy food for 3 days before the test

b. NO blood transfusion or treatment for 3 days before the test

c. Breakfast can be taken in the morning of phlebotomizing. But NO greasy food.

d. Peripheral blood is taken for 20-50 ml/ each culture.



Clinical summary of CIK immunotherapy

a. How does CIK strengthen the effect of surgery?

Surgery can remove the local lesions quickly, but can do nothing to metastatic cancerous cell
and small lesions. And the immunity of patients decreases sharply. Immediate application of
CIK immunotherapy after surgery, could rapidly remove scattered small lesions and cancerous
cells, prevent recurrence and metastasis effectively, and increase the immunity.

b. How does CIK immunotherapy enhance the efficacy of radiotherapy?

Radiotherapy can only destroy part of cancerous cells. It cannot kill the cancerous cells in
blood, nor can it destroy small metastatic or hidden lesions, which may lead to recurrence. In
addition, when radiation is killing cancerous cells, it kills large number of leukocytes as well,
which is a great harm to normal tissue function. However, CIK cells have an impressive ability
to distinguish and destroy cancerous cells, with no side effects to normal cells. CIK cells can
track and destroy cancerous calls in blood as well as small metastatic or hidden lesions in the
body to inhibite cancer recurrence. Therefore CIK biotherapy can be applied before, during
and after radiotherapy.

c. How does CIK immunotherapy enhance the efficacy of chemotherapy?

Chemotherapy has a good efficacy to kill cancerous cells in blood. But the chemicals used in
chemotherapy have poor stability and penetrating ability inside the body. In addition, certain
malignant tumors develop resistance to the chemicals. Thus, chemotherapy is nearly of no use
to control metastatic or hidden lesions. In the process of chemotherapy, the body's blood
immune system is significantly disrupted, causing a series of side effects, such as hair loss,
vomiting, loss of appetite, rash, and so on. To maximize effectiveness of chemotherapy while
minimizing the side effects, immune system function must be improved. Addition of CIK cells to
the chemotherapy can inhibit the resistance to the chemotherapy chemicals, lower the infection
rates in chemotherapy, and increase the sensitivity of cancerous cells to chemotherapy.
Therefore, CIK should be applied throughout the chemotherapy.

d. Comparison of CIK immunotherapy to the other biotherapies.

i) Cytokines: Interferon, Thymosin and Interleukin, as representatives. They function by
stimulating the immune cells to proliferate and activate, and they are relatively cheap and
commonly used. Cytokines are mainly used for supporting immunotherapy.

ii) Cells: LAK and CIK, as representatives, featured in anti-tumor whole cells. CIK cells were
first introduced later than LAK cells. CIK cells have a much higher ability of proliferation and
tumor killing activity than the LAK. The efficacy of CIK is 73 times of LAK's. CIK cells are
independent of MHC restriction. Unlike LAK cells, CIK cells need no IL-2 to kill tumor, and thus
to avoid the side effects from IL-2. Concerned of cost, CIK is dozens of times more effective
than CIK. So CIK is the safest, most advanced, and most effective method of biotherapies.

Generally speaking, CIK biotherapy is most promising biotherapies, due to its merits in broad
spectrum of killing tumors, rapid proliferations in vitro, no serious adverse reactions, mature
and safe technology, high efficiency and acceptable price.

Clinical Study Reference

1. Curative Effects on 145 Solid Type Carcinoma with Cultured CIK and DC Cells, YING
Mingang, ZHENG Qiuhong, et al., Journal of Fujian Medical University, 2007, 41: 218-221   

2. Short-term Curative Eficacy of Cytokine-induced Killer Cells Combined Micro-invasive
Treatments on Hepatocellular Carcinoma, ZHOU Qi-Ming, WU Pei-Hong, et al., Chinese Journal
of Cancer, 2006, 25: 1414-1418

3. Evaluation of Safety and Efficiency of Treatment with Autologous Cytokine-Induced Killer
Cell for Hepatocellular Carcinoma,  SHI Ming, WANG Fusheng, et al., Med. J. Chin. PLA, 2004,
29: 333-35   

4. Clinical Study on the Treatment of Advanced Hepatocellular Carcinoma by CIK Cells, ZHANG
Nan-zheng, XU Yong-mao, et al., Journal of Southeast China National Defence Medical
Science, 2006, 8: 84-87   

5.The Level and Clinical Significance of CIK Cells in Peripheral Blood of Patients with
Advacned Lung Cancer, LI Yuanxia, QIAO Xiaojuan, Chinese Journal of Clinical Oncology,
2007, 34: 986-88   

6. Clinical Observation on Auto-Cytokine Induced Killer Cells Assisting Treatment of non-
Hodgkin lymphoma, HU Jia-sheng, FUJin-xiang, et al., Chin J Hemorh., 2007, 17(1): 61-63  

7. The Effect to Immune System and Epstein-barr Virus in the Nasopharyngeal Carcinoma
Patients by the Adoptive Immunotherapy of Auto-cytokine Induced Killer Cells, Qin Hai-yan, Hu
Wei-han, et al., Modern Oncology, 2007, 15(12): 1747~1749

8. A Clinical Trial of Cytokine Induced Killer Cells in the Treatment for Nasopharyngeal Cancer,
SUI Jun, LI Xiao-jiang, et al., Journal of Oncology, 2008, 14: 35-37   

9. The Effect of CIK Cells combined with IL-2 on the Treatment of Renal Cell Carcinoma, LEI
Kai-jian, DU Yi-pin, et al., Acta Academiae Medicanae Zunyi, 2005, 28: 67-68   

10. Clinical Observation of Co-treatment with Autologous CIK Cells and Dendritic Cells for
Postoperative Advanced Gastric Carcinoma, GONG Xinjian, LIU Junquan, et al., Chinese
Journal of Clinical Oncology, 2007, 34: 803-06  

11. Side Effects of Cytokine-induced Killer Cells in the Elder People with Advanced Gastric
Carcinoma, JIANG Jing-ting, WU Chang-ping, et al., Tumor, 2006, 26: 950-52    

12. The Cell Culture in vitro and the Immune Characteristics of CIK from Tongue Cancer
Patients, CAO Faming, ZHOU Jian, et al., Acta Universitatis Medicinalis Anhui, 2007, 42: 644-
48   

13. Treatment of Advanced Non-small Cell Lung Cancer by Chemotherapy Combined with
Autologous Cytokine-induced Killer Cells, YANG Xuan-xuan, JIANG Jing-ting, et al., Suzhou
University Journal of Medical Science, 2008, 28: 237-240    

14. Clinical Study on the Treatment of Patients with Advaced Gynecological Oncology by
Cytokine-induced Killer Cells, LIU Xiao-liang, SHI Ling-yan, et al., Tumour Journal of the World,
2008, 17: 139-41    





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Last Updated ( Tuesday, 09 September 2008 23:15 )