Immunotherapy. Active immunotherapy. An active humoral immunotherapy. Active specific immunotherapy. Nonspecific immunotherapy





Numerous immunological mechanisms, both passive and active, can be used to treat tumor diseases.





In passive cellular immunotherapy, specific effector cells directly infuse the patient without additional stimulation and proliferation in the patient's body.


Lymphokine-activated killers(LAK) are endogenous T-cells isolated from the patient’s blood and cultured in the cell culture system by the addition of IL-2. Proliferated LAK cells are then returned to the patient’s bloodstream. Animal studies have shown that LAK cells are more effective against cancer cells than the original endogenous T cells, probably because of their larger number. Clinical studies on the study of LAK cells in humans are ongoing.


Tumor-infiltrative lymphocytes(TIL) possess even greater anti-cancer activity than LAK cells. These cells are proliferated in culture like LAK cells.However, T-cell precursors are isolated from resected tumor tissue. This process theoretically provides a T-cell line, which is more specific than cells derived from the bloodstream.


The simultaneous use of interferon increases the expression of antigens of the main histocompatibility complex (MHC) and tumor-associated antigens (TAA) on tumor cells, thereby increasing the degree of destruction of tumor cells by infusing effector cells. However, it is rarely possible to achieve remission with this method. A new approach that may provide a significant clinical effect is the use of genetically modified T-cells expressing receptors that recognize TAA with high specificity for tumor cells.





The administration of exogenous antibodies constitutes passive humoral immunotherapy. Anti-lymphocytic serum is used in the treatment of chronic lymphocytic leukemia and in T- and B-cell lymphomas, leading to a temporary decrease in the number of lymphocytes and the size of lymph nodes.


Monoclonal anticancer antibodies can be attached to toxins (for example, ricin, diphtheria) or radioisotopes, and the antibodies deliver these toxins directly to the tumor cells. Another technique is the use of bispecific antibodies or such an arrangement of antibodies, when one antibody reacts with a tumor cell, and the second with a cytotoxic effector cell. This technique brings into close contact effector cells with tumor cells, which increases the antitumor activity. These treatments are most effective in the early stages of the disease, although the potential clinical benefit remains unclear.


Active specific immunotherapy



The design of the method consists in inducing a cellular immune response in the patient's body with a malignant neoplasm, which is a more effective treatment method than passive immunotherapy. Induction of the host’s immune response, when the spontaneous response was insufficient, usually includes methods for enhancing the presentation of tumor antigens to the host effector cells.


Autochthonous tumor cells(cells taken from the host organism) are re-fused to the host after using the exvivo technique (for example, irradiation, neuraminidase treatment, conjugation with hapten, hybridization with other cell lines), which reduces the malignant potential and increases their antigenic activity. Genetic modulation of tumor cells for the production of immunostimulating molecules [including cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF) or IL-2, co-stimulatory molecules such as B7-1 and allogeneic class I MHC molecules ] can also be used to attract effector molecules and enhance the systemic antitumor response. Recent clinical studies with GM-CSF modified tumor cells have shown promising preliminary results.


Allogeneic tumor cells(cells isolated from other patients) are used in patients with acute lymphoblastic leukemia and acute myeloid leukemia. Remission is induced by intensive chemotherapy and radiation therapy; irradiated allogeneic tumor cells that have been subjected to genetic or chemical modification in order to increase their immunogenic potential are infused into the patient.Alternatively, allogeneic tumor cells may be introduced together with the Calmette-Guerin bacillus vaccine (BCG) or other adjuvants to enhance the immune anti-tumor response. The use of this technique led to an increase in the duration of remission or an increase in the frequency of achieving remission, as reported in a series of clinical studies, but not all.


The development of vaccines based on tumor antigens is the most promising approach in cancer immunotherapy. The number of tumor antigens, unambiguously recognized by specific T cells isolated from patients with malignant tumors, is increasing.


Cell specific immunity(involvement of cytotoxic T cells) can be induced by specific antigens. Certain TAAs may be administered to patients in the form of peptides (usually in conjunction with immunogenic adjuvants) or DNA encoding specific proteins (via recombinant viruses).


Recent studies have demonstrated that the most powerful response can be obtained if TAAs are delivered using antigen-presenting cells (dendritic cells).These cells are obtained from patients, loaded with the necessary TAA, and then reinfused internally to stimulate the endogenous T-cell response to specific antigens. Moreover, these cells can be genetically modified to secrete additional stimulants of the immune response.


In another treatment method, antigen-presenting cells and tumor cells are combined to use the full spectrum of potential TAAs. Dendritic cells are loaded with lysates of tumor cells or dead tumor cells or are combined with live tumor cells. These methods are currently at the stage of clinical research.


Nonspecific immunotherapy



Interferons (IFN-a p y) are glycoproteins with antitumor and antiviral activity. Depending on the dose, interferons can either increase or decrease cellular and humoral immunity. Interferons also inhibit cell division and certain synthesis processes in various cells. Human clinical studies have demonstrated that interferons have antitumor activity in various neoplastic processes,including hairy cell leukemia, chronic myeloid leukemia, AIDS-associated Kaposi's sarcoma, non-Hodgkin's lymphoma, multiple myeloma, and ovarian cancer. However, the use of interferon is associated with significant side effects, such as fever, malaise, leukopenia, alopecia and myalgia.


Certain bacterial adjuvants(BCG and derivatives, suspension of the dead Corynebacterium parvum) have antitumor activity. They are used alone or in combination with tumor antigens to treat a wide range of tumors, usually in combination with intensive chemotherapy or radiation therapy. For example, direct infusion of BCG into tumor tissue leads to regression of melanoma and an increase in survival without signs of disease in bladder cancer and may help increase the remission period for acute myeloid leukemia, ovarian cancer and non-Hodgkin lymphomas.

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