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:

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.