16-17 Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth. Using monoclonal antibodies to destroy tumors requires that a tumor-specific antigen be expressed on the tumor’s cell surface, so that antibody can direct Fig. 16.18 Chimeric antigen receptors (CARs) expressed in T cells can confer antitumor specificity to a patient’s lymphocytes. Bottom panel: a chimeric antigen receptor, CART-19, is composed of an extracellular single-chain antibody that binds to CD19 that is fused to intracellular signaling domains from 4-1BB and the CD3ζ chain. Top row of panels: a lentivirus, a type of retrovirus, is used to express the gene encoding CART-19 in the T cells harvested from a patient diagnosed with ALL. After in vitro activation and expansion, the transfected CART-19 cells are infused into the patient and exert cytotoxic actions against CD19-expressing tumor cells as well as nontransformed B cells. T cells are harvested from the blood of a patient with a B-cell tumor A retrovirus encoding an anti-CD19 CAR infects T cells that are activated with antibodies to CD3 and CD28 Infected T cells express an anti-CD19 CAR T cells are infused into patient to mediate antitumor activity CD19 anti-CD19 Anti-CD19 CAR 4-1BB signaling domain Anti-CD19 CAR chimeric receptor tumor cell T cell T cell CD3˜ chain ITAMs VH TCR CD28 CD3 VL
Fig. 16.19 Monoclonal antibodies that recognize tumor-specific antigens have been used to help eliminate tumors. Tumor-specific antibodies of the correct isotypes can lyse tumor cells by recruiting effector cells such as NK cells and activating them via their Fc receptors (left panels). Another strategy has been to couple the antibody to a powerful toxin (center panels). When the antibody binds to the tumor cell and is endocytosed, the toxin is released from the antibody and can kill the tumor cell. If the antibody is coupled to a radioisotope (right panels), binding of the antibody to a tumor cell will deliver a dose of radiation sufficient to kill the tumor cell. In addition, nearby tumor cells could also receive a lethal radiation dose, even though they do not bind the antibody. Antibody fragments have started to replace whole antibodies for coupling to toxins or radioisotopes.
the activity of a cytotoxic cell, toxin, or even radioactive nuclide specifically to the tumor (Fig. 16.19). Some of the cell-surface molecules targeted in clinical trials are shown in Fig. 16.20, and some of these treatments have now been licensed. Striking improvements in survival have been reported for breast cancer patients treated with the monoclonal antibody trastuzumab (Herceptin), which targets the receptor HER-2/neu. This receptor is overexpressed in about one-quarter of breast cancer patients and is associated with a poor prognosis.