Lecture 26 0503 2012_class

Antibody humanized mabs the goal mabs treating the

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Unformatted text preview: umanized MAbs: The Goal MAbs: Treating the cancer cells left behind after Treating surgery or those beginning to spread to some other sites some Treatment of metastatic disease Active Immunotherapy: Vaccines Active 1940s and 1950s – it was found that when 1940s tumors are induced in mice they bore antigens which could be used to immunize other mice against transplants of the tumors tumors It was also shown that T lymphocytes from It immunized animals could transfer immunity against the tumors to healthy animals. animals. Melanoma Melanoma It was found that melanoma patients have It a small portion of T cells that mount a specific immune response against their tumor cells tumor In the early 1990s two types of tumor In antigens responsible for the T cell response have been identified. These antigens are primary candidates for cancer vaccine vaccine Major Categories of Cancer Vaccines Major Whole Cancer Cells Inactivated cancer cells Cancer cells engineered to secrete cytokines Cancer cells engineered to express co-stimulatory molecules like B-7 Tumor Peptides Tumor Proteins Dendritic Cells are isolated from the blood, exposed to tumor antigens and then reinjected into the patient Viral and Bacterial Vectors Genes coding for tumor antigens are incorporated into viral or bacterial Genes genomes. They draw immunity to themselves and the encoded antigens. antigens. Dendritic cell cancer vaccine Dendritic Dendritic cell precursors are isolated from Dendritic cancer patients cancer The cells are grown in the laboratory in the The presence of tumor antigens presence The dendritic cells pick up the antigens The and expose them on their surface and The cells are injected back to the same The patients and are expected to activate T cells cells Dendritic cell vaccine for prostate cancer (Dendreon, Phase III clinical trial in 2004) Phase In early 2002, the first Phase III clinical trial in 127 patients failed In because statistical significance was not achieved because It was demonstrated that a sub-set of the patients with a less It aggressive form of the disease benefits from the treatment aggressive Enhancement of tumor immunogenicity immunogenicity Cancer Vaccines: Near Future Cancer Vaccination is the most promising Vaccination approach for human cancers that are cause by viruses such as cervical cancer (> 97% are caused by HPV) Vaccine: Hurdles Vaccine: 1. Autoimmune response 2. Economical burden 3. Tumor cells mutation to avoid the Tumor immune attack immune Tumor Tactics to Avoid Immune Attack Attack Altering their characteristics Immunoselection – variants of tumor cells without the Immunoselection antigens that were used to “teach” immune cells “teach” Suppressing the immune response Immunosupression can be caused by tumor cell Immunosupression products products Hiding from the immune response Dense tumor stroma can provide shielding effect Outpacing the immune response Growing fast Adaptive Immunotherapy Adaptive Isolation of T cells Activation of the T cells in vitro Activation in Re-injection back to the same patient Application: treating viral infections and Application: tumors in patients with immune systems that are weakened by disease and therapy that Interactions between tumor cells and CTLs and Left panels: tumor cells displaying novel peptides (e.g. tumor antigens) to activated CTLs will killed by CTLs Middle panels: cells lacking MHC I complexes will be resistant to CTLs, but will be attacked by NK cells Right panels: if cells that initially lacking MHC I expression are transfected with MHC gene than they will become sensitive to CTLs....
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