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Therapies that boost the antitumor immune response, known as immunotherapies, are clinically effective, and the field is evolving rapidly. One of the longest used cancer immunotherapies is the BCG vaccine (bacillus Calmette-Guérin, a bovine mycobacterium). It was observed that injecting BCG into the lesions of skin melanoma and bladder cancer activates and recruits the immune cell into the tumor, leading to tumor regression. Treatment with interleukin-2 was shown to improve survival rates in certain melanomas and renal cell cancers, although interleukin-2 treatment is limited by the toxicity of a systemic inflammatory response.
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Another approach to cancer immunotherapy involves the use of tumor-infiltrating lymphocytes (TILs). The basis for this approach is the observation that some cancers are infiltrated by lymphocytes (NK cells and cytotoxic T cells) that appear to be destroying the cancer cells. These lymphocytes are recovered from the surgically removed cancer, grown in cell culture until a large number of cells are obtained, activated with interleukin-2, and returned to the patient in the expectation that the TILs will “home in” specifically on the cancer cells and kill them.
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Monoclonal antibodies directed against CTLA-4 and PD-1 (see Chapter 60) are effective in enhancing the immune response against cancer cells. CTLA-4 and PD-1 on T cells inhibit the co-stimulatory signal, and antibody against these proteins blocks this inhibitory effect. This removal of an inhibition, or checkpoint, enhances the immune response against the tumor, and therefore, this strategy is called checkpoint blockade immunotherapy. Not surprisingly, checkpoint blockade therapies are limited by the fact that some patients develop autoimmune diseases as a consequence of off-target immune activation.
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Finally, another successful approach has produced sustained remission in patients with certain leukemias and lymphomas. These remissions are induced by infusion of chimeric antigen-receptor modified T (CAR-T) cells that target proteins on the surface of the leukemic B cells. When the CAR-T cells recognize these proteins, e.g. CD19 that is found on malignant B cells, they release cytokines, perforin, and granzymes, killing the cells much as a cytotoxic T cell recognizes and kills virus-infected cells (see Chapter 60).
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These “cell-based” therapies are extremely expensive because they require manipulating each individual patient’s cells and then reinfusing them as an autologous transplant. In addition, CAR-T cells can cause systemic inflammatory responses due to excessive cytokine release, and because healthy B cells also have CD19, patients must take pooled intravenous immunoglobulin (IVIG) replacement to counteract the persistent B-cell deficiency that occurs. The first commercial CAR-T cell therapy was approved by the US Food and Drug Administration for B-cell leukemia in 2017.