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Cancer Immunotherapy - I
Tumor immunity can be enhanced by providing the co-stimulatory signal that are necessary for activation of CTL precursors (CTL-Ps). Mouse CTL-Ps when incubated with melanoma cells in vitro then antigen recognition occurs. In the absence of a costimulatory signal, CTL-Ps do not proliferate and differentiate into effector CTLs. B7-transfected tumor cells might induce a CTL response in vivo. P. Linsley and colleagues injected melanoma-bearing mice with B7+ melanoma cells. Regressed in more than 40% of the mice. S. Townsend and J. Allison vaccinated mice against malignant melanoma. Human melanoma antigens are shared. In this approach, the tumor antigen(s) expressed by a patient’s tumor would be determined. Patient would be vaccinated with an irradiated B7-transfected cell line. Mouse dendritic cells cultured in GM-CSF are incubated with tumor fragments. Then reinfused into the mice activate both TH cells and CTLs specific for the tumor antigens. These experiments have led to a number of approaches aimed at expanding the population of APCs. So that these cells can activate TH cells or CTLs specific for tumor antigens. One approach that has been tried is to transfect tumor cells with the gene encoding GM-CSF.
Cancer Immunotherapy - II
For expansion of DC population, culture dendritic cells from peripheral-blood progenitor cells in the presence of GM-CSF, TNF-α, and IL-4. These cytokines induce the generation of large numbers of DCs. If these dendritic cells are pulsed with tumor fragments, then reintroduced into the patient. A number of adjuvants, attenuated strains of Mycobacterium bovis and Corynebacterium parvuum are used to boost tumor immunity. These adjuvants activate macrophages, increasing their expression of various cytokines. These activated macrophages are better activators of TH cells. A variety of experimental and clinical approaches have been developed that use recombinant cytokines either singly or in combination and augment the immune response against cancer. Cytokines in cancer immunotherapy are IFN-α, β, and γ, GM-CSF, TNF. Complexity of the cytokine network itself makes it very difficult to know precisely. Some cytokines act antagonistically. Systemic administration of high levels of a given cytokine causes serious and even life-threatening consequences. Large quantities of purified recombinant interferons i.e. IFN-α, IFN-β, and IFN-γ, are now available. Each of which has shown some promise treatment of human cancer. All three-interferon increase class I MHC expression on tumor cells. IFN-γ increase class II MHC expression on macrophages. It is possible that some of the antitumor effects of the interferons related to this ability to directly inhibit tumor-cell proliferation.
Cancer Immunotherapy - III
In some instances, the tumor necrosis factors TNF-α and TNF-β have been shown to exhibit direct antitumor activity. In the presence of TNF-α or TNF-β, a tumor undergoes visible hemorrhagic necrosis and regression. TNF-α has also been shown to inhibit tumor-induced vascularization (angiogenesis). Animal studies have shown that lymphocytes can be activated against tumor antigens in vitro culturing them with x-irradiated tumor cells in the presence of IL-2 and added tumor antigens. These activated lymphocytes mediate more effective tumor destruction than untreated lymphocytes. While sensitizing lymphocytes to tumor antigens by this method S. Rosenberg discovered cells called lymphokine-activated killer (LAK) cells. Rosenberg found infusion of LAK cells plus recombinant IL-2 into tumor bearing animals mediated effective tumor-cell destruction. In Clinical Trials of LAK cells, cancer regression was seen in some patients. A number of undesirable side effects Associated with the high levels of IL-2 required for LAK cell activity were also observed.
Cancer Immunotherapy - IV
Tumors contain lymphocytes that have infiltrated the tumor presumably are taking part in an antitumor response. The activated tumor-infiltrating lymphocytes are called TILs. Many TILs have a wide range of antitumor activity which appear to be indistinguishable from LAK cells. Some TILs cells have specific cytolytic activity. In one study, TIL populations were expanded in vitro from biopsy samples taken from patients with malignant melanoma, renal-cell carcinoma, and small-cell lung cancer. Renal-cell carcinomas and malignant melanomas showed partial regression in 29% and 23% of the patients. Monoclonal antibodies have been used in various ways. Anti-idiotype monoclonal antibodies gain some success in treating human B-cell lymphomas and T-cell leukemias. A monoclonal anti-idiotypic antibody (Ab-2) against the B-lymphoma membrane-bound antibody is produced ex vivo. It binds selectively to the idiotypic determinants on the immunoglobulin of B-lymphoma cells, making these cells susceptible to complement mediated lysis. After four injections with this anti-idiotype MAB tumors began to shrink. Patient entered an unusually long period of complete remission.
Cancer Immunotherapy - V
Recently, Levy and his colleagues have used direct immunization of immune system. In a clinical trial with 41 B-cell lymphoma patients, rearranged immunoglobulin genes of the lymphomas are isolated and used to encode the synthesis of recombinant Ig. In Anti-Idiotype Approach, each of the Igs was coupled to keyhole limpet hemocyanin (KLH). The patients were immunized with their own tumor-specific antigens, idiotypically unique Ig produced by their own lymphomas. This approach is very nature patient-specific. A variety of tumors express increased levels of growth-factor receptors. An anti-HER2 monoclonal antibody was raised in mice. Except for the sequences encoding the antibody’s CDRs. Mouse Ig sequences were replaced with human Ig counterparts. This prevents the generation of human anti-mouse abs (HAMAs) and allows the patient to receive repeated doses of “humanized” anti-HER2 in large amounts (100 mg or more). Antibodies to tumor-specific or tumor-associated antigens can be coupled with radioactive isotopes, chemotherapy drugs, or potent toxins of biological origin. In such “guided missile” therapies toxic agents are delivered specifically to tumor cells. Reagents known as immunotoxins have been constructed by coupling the inhibitor chain of a toxin to an antibody against a tumor-specific c or tumor-associated antigen.