About Immunotherapy
Treatment to stimulate or restore the body's natural abilities of the immune (defense) system to fight infection and disease and 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 cells, 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. 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. 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 people are most concerned with the internal workings of the immune system.
What are CIK cells?
Cytokine-induced killer (CIK) cells are immune cells that can seek and kill tumor cells. CIK cells were discovered in 1991 by Lanier and Schmidt-Wolf*. Further in-depth research was later conducted at the Stanford University Medical Center.
CIK has proved in medical practice to be the most efficiently adopted immunotherapy. It shows good efficacies in treating malignant tumors in leukemia, 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 can 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 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 into humans can 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 double the ability to recognize cancerous cells.
Compared to CIK biotherapy, DC-CIK biotherapy has a greater precision to seek and kill tumor cells and helps to increase the sensitivity 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. Also, 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, and ovarian cancer, as well as on malignant tumors such as myeloid leukemia, melanoma, renal cell carcinoma, metastatic renal cell carcinoma, malignant lymphoma (except T-cell lymphoma), and non-Hodgkin’s lymphoma.
This treatment can be applied to cancer patients in any stage, and it has 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. It will have a better efficacy when combined with surgical resection, intervention, radiofrequency therapy, or cryoablation.
What are the contraindications of CIK immunotherapy?
a. Pregnancy and lactation
b. Uncontrolled severe infection
c. Severe allergic constitution
d. T-cell lymphoma
e. Epilepsy
f. AIDS
What are the features of CIK immunotherapy in clinical?
CIK biotherapy is currently 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 with a 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 tumor recurrence.
f.CIK Biotherapy, when combined with radiotherapy or chemotherapy, enhances the efficacy and reduces the toxicity, side effects, and infections.
g.For advanced stage patients who have no chance for surgery and for patients who suffer recurrence or metastasis, large doses of CIK 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. In some cases, the tumors can shrink or even disappear, and long-term survival is achieved.
h.Since CIK can regulate the immunity, during the treatment of the tumor, patients may notice glossy skin, faded speckles, or grey hairs turning black again.
What are the adverse reactions of CIK immunotherapy?
CIK cells are activated autologous cells. Therefore, CIK biotherapy is very safe. No serious adverse reactions are observed. In a small number of cases, a rise of body temperature (37.2℃-40℃) was observed 2-10 hours after reinfusion. Generally, the temperature will 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 starting after the 10th day of cell culture according to the requirements.
The number of treatment cycles and the interval depends 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 that 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:
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Clinical stage of the cancer/ Treatment dosage |
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Stage I |
Stage II |
Stage III |
Stage IV |
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Tumor < 2cm |
Tumor > 2cm |
Recurrence, metastasis, surgery not available |
Multiple metastases, survival with tumor |
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Treatment cycle |
3 treatments |
6 treatments |
9 treatments |
More than 12 treatments |
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Interval between cycles |
3-9 months |
3-6 months |
1-3 months |
1-3months |
Dosage at 1 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 cultured, transfected and cloned in GMP-standardized laboratory. Usually, reinfusion will be available 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.
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 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.
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 have 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, or 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 it does nothing to metastatic cancerous cell and small lesions. Subsequently, 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 a 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 the most promising biotherapy, due to its broad spectrum of merits: killing tumors, rapid proliferations, no serious adverse reactions, mature and safe technology, high efficiency and acceptable price.
* Use of a SCID Mouse/Human Lymphoma Model to Evaluate Cytokine-induced Killer Cells with Potent Antitumor Cell Activity, Ingo G.H. Schmidt-Wolf, Robert S. Negrin, Hans-Peter Kiem, Karl G. Blume, and Irving L. Weissman, Journal of Experimental Medicine, 1991, 174: 139-149 
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
15. Cord blood-derived cytokine-induced killer cells biotherapy combined with second-line chemotherapy in the treatment of advanced solid malignancies, Qi Niu, Wei Wang, Yong Li, Shaowen Qin, Yu Wang, Guangyu Wan, Jingzhi Guan, Wenhua Zhu, http://www.sciencedirect.com/science/article/pii/S1567576910004170