Cellular immunotherapy therapy is the process of harvesting the body’s own immune cells, culturing them in vitro to increase their number thousands of times and enhance their targeted killing function, and then returning them to the body to kill pathogens, cancer cells, and mutated cells in the blood and tissues.
Currently, the main therapies include: cytokine-induced killer cell (CIK) therapy, dendritic cell (DC) therapy, DC+CIK cell therapy, natural killer cell (NK) therapy, ACTL tumor cell targeting therapy, CLS therapy, DC-T cell therapy, etc.
I. Cytokine-induced killer cell (CIK) therapy
1.What is CIK cell ?
Cytokine induced killer cell (CIK) is a new type of immunologically active cell, which is a heterogeneous group of cells obtained by co-culturing human peripheral blood single nuclei cells with various cytokines in vitro for a period of time. CIK cells have the advantages of rapid proliferation, high tumor-killing activity, broad tumor-killing spectrum and non-MHC-restricted tumor killing. Currently, CIK therapy is considered to be the preferred option for next-generation antitumor over-the-top immunotherapy.
2.What are the characteristics of CIK cells in the process of anti-tumor therapy?
(1) CIK cells proliferate rapidly and can expand in a large number within a short period of time, and the ratio and number of effector cells CD3+CD56+ is even
The ratio and number of effector cells CD3+CD56+ are significantly increased, which can reach more than 1000 times;
(2) CIK cells have a mechanism to recognize tumors, but no toxic effect on normal cells.
(3) CIK cells have high tumor killing activity and a wide spectrum of tumor killing, and are equally sensitive to a variety of drug-resistant tumor cells.
(4) CIK cells are a typical individualized biological therapy model. It is derived from autologous T-lymphocytes, and the transfusion of these cells can increase the tumor-killing activity and enhance the immunity of the body, thus exerting a dual effect on tumor treatment.
(5) The tumor-killing activity is not affected by immunosuppressive agents such as CsA and FK506.
(6) It has little toxicity to normal bone marrow hematopoietic precursor cells.
(7) Can resist tumor cell-induced apoptosis of effector cells Fas-FasL.
3.How do CIK cells play an anti-tumor role ?
(1) CIK cells on the direct killing of tumor cells CIK cells can secrete perforin (proforin, PFP) and granzyme (granzyme), through the perforin/granzyme pathway-mediated killing of target cells.
(2) CIK cells produce a large number of cytokines after activation, exerting tumor-inhibiting and tumor-killing effects CIK cells produce a large number of inflammatory cytokines after activation, such as IL-2, IL-4, IL-10, IFN-γ, TNF-α, etc., which not only have direct inhibitory effects on tumor cells, but also indirectly kill tumor cells by regulating the responsiveness of the body’s immune system.
(3) Inducing tumor cell apoptosis
CIK cells can activate tumor cell apoptosis genes, and the expression of anti-apoptotic genes such as FLIP, Bcl-2, Bcl-xl, DAD1 and survivin are upregulated in CIK cells. These reasons together lead to the fact that CIK cells can induce apoptosis of tumor cells through the Fas/FasL signaling pathway, thus providing effective tumor killing.
Natural killer cell (NK) therapy
1.What are NK cells?
Natural killer cells (NK) are the third group of lymphocytes alongside with T and B cells. They can directly kill target cells non-specifically, and this natural killer activity neither requires prior sensitization by antigens nor antibody participation, and is not limited by MHC. The number of NK cells in human body is small, accounting for about 10%-15% of the total number of lymphocytes in peripheral blood, about 3%-4% in spleen, and also in lung, liver and intestinal mucosa, but rare in thymus, lymph nodes and thoracic duct.
2. Anti-tumor mechanisms of NK cells.
(1) Natural cytotoxicity
Natural cytotoxicity refers to the effect of killing target cells directly without antibody-mediated or pre-sensitization. Unlike ADCC, this effect requires multiple surface receptors to bind to target cells to deliver cytolytic signals.
(2) Antibody-dependent cell-mediated cytotoxicity (ADCC)
NK cells can also be mediated through surface IgG Fc receptors (FcγRIII) to recognize and kill tumor- or virus-infected target cells that bind specifically to IgG antibodies.
(3) NK cells mediate target cell apoptosis.
(4) NK cells produce a large number of cytokines, such as IFN-y, TNF-a, GM-CSF, IL-3, M-CSF, etc., which regulate the immune activity of macrophages, DC cells, T cells, B cells and endothelial cells.
3.What are the indications for NK cell therapy for tumors?
NK cell therapy is effective for early, middle and late stage malignant glioma, malignant melanoma, malignant lymphoma, kidney cancer, lung cancer, esophageal cancer, liver cancer, colon cancer, breast cancer, ovarian cancer and other malignant solid tumors; some tumor patients who are temporarily not suitable for surgery, intervention or other treatments can also be treated with NK cells to improve the immune function of the body. In addition, NK cells are also involved in the regulation of many functions and injuries in the body, and have important roles in stem cell function, cardiovascular disease, liver and kidney diseases.
Autologous dendritic cell (DC) therapy
1.What are DC cells?
Dendritic Cells (DC) originate from precursor cells in bone marrow and are the strongest antigen-presenting cells known in the body, 1000 times stronger than ordinary antigen-presenting cells, which can stimulate T lymphocytes to differentiate into cytotoxic T lymphocytes with anti-tumor activity after loading tumor antigens and specifically kill tumor cells.
2.The mechanism of action of DC cells
DC cells can exert their anti-tumor immune effects through various mechanisms.
(1) Induction of cellular immunity
After DCs ingest tumor antigens, they process them into peptide-MHC molecular complexes and express them on the cell surface, which in turn bind to T cell receptor (TCR) on the surface of T cells. cytotoxic T lymphocyte, CTL)-mediated immune response.
(2) Enhancement of humoral immunity
On the one hand, DC promotes antibody production by promoting the production of antigen-specific CD4+ helper T cells (Th); on the other hand, DC acts directly on B cells to promote the secretion of immunoglobulins. DC directly induces the differentiation of initial and memory B cells into plasma cells through the secretion of type I interferon (IFN), which produces large amounts of immunoglobulin IgM.
(3) Secretion of multiple cytokines or chemokines
IL-12 secreted by DCs can induce the differentiation of Th0 cells to Th1 cells and initiate cellular immune response, while inhibition of IL-12 production promotes IL-10 secretion and Th2 cell polarization. DCs also secrete a specific chemokine that selectively chemotacticizes initial T cells and enhances the induction of immune response.
(4) DCs directly inhibit the growth of tumor cells by interacting with certain tumor cells.
(5) DCs sensitized by tumor antigen can release a vesicular vesicle exosomes with antigen-presenting ability, which contains a large number of MHC-I and II class molecules.
IV. DC-CIK cell therapy
1.What is DC-CIK cells
DC-CIK cell immunotherapy refers to the use of dendritic cells (DC) and cytokine-induced killer cells (CIK) in vitro co-culture of a large number of expansion of the activated immune cells back into the patient’s body, can directly kill tumor cells, while the auxiliary or stimulation of the body’s own immune system, improve or enhance the patient’s immune function, to achieve the purpose of inhibiting or killing tumor cells.
2.The mechanism of action of DC-CIK cells
DC cells are known as radar for finding tumor cells, which can actively search and identify tumor cells in the body along with blood throughout the body, and pass the information to immune active cells, prompting their activation and massive proliferation. It can remove residual tiny metastatic lesions, prevent the spread of tumor cells and recurrence, and improve the immunity of the body. The mechanism by which DC-CIK cells exert anti-tumor effects is as follows.
(1) Release intracellular perforin, granzyme and other active substances into the tumor cells to lyse them.
(2) Inducing apoptosis of tumor cells through the Fas-FasL pathway.
V. ACTL tumor cell targeting therapy
AAV-DC-CTL™ tumor cell targeting therapy technology is to transform non-pathogenic wild-type adeno-associated virus (AAV) into recombinant adeno-associated virus carrying specific tumor-associated antigenic determinants through genetic recombination technology, infecting peripheral blood mononuclear cells (Monocytes. Mo) of patients, and transforming them into DC cells with powerful antigen presentation function after cytokine induction. DC cells with strong antigen-presenting function. The DC cells obtained by this technique stimulate the patient’s T-lymphocytes in vitro to produce cytotoxic T-lymphocytes (CTL) that are effective in killing tumor cells. The resulting CTL are tumor antigen-specific, i.e., targeted, and only kill tumor cells positive for one or several specific tumor-associated antigens and PSMA-positive tumor neovascular endothelial cells, with no effect on antigen-negative cells.
CTL cells are a subpopulation of CD8+ T cells, which are specific T cells with direct killing effect on certain viruses and tumor cells, and constitute an important defense line of the body against viruses and tumors together with natural killer cells.
CTL killing mechanisms are.
1.Release of perforin, granzyme, lysis of target cells.
2, mediating apoptosis of target cells through FasL.
The main action pathway : AAV-TAAs transfected DC- CTL targeted killing of tumor cells DC stimulates lymphocytes to produce CTL.