Fig. 16.21 An effective vaccine against human papilloma virus (HPV) induces antibodies that protect against HPV infection. Serotype 16 of HPV (HPV-16) is highly associated with the development of cervical cancer. In a clinical trial, 755 healthy uninfected women were immunized with a vaccine generated from highly purified noninfectious ‘viruslike particles’ (VLP) consisting of the capsid protein L1 of HPV-16 and formulated with an alum adjuvant (in this case aluminum hydroxyphosphate sulfate). In comparison with the very low titers of antibody in placebo-treated uninfected women (green line), or women previously infected with HPV who received placebo (blue line), the women treated with the viruslike particle vaccine (red line) developed high titers of antibody against the L1 capsid protein. None of these immunized women subsequently became infected by HPV-16. An anti-HPV vaccine marketed as Gardasil is now available and recommended for use in girls and young women as a protection from cervical cancer caused by HPV serotypes 6, 11, 16, and 18. mMU, milli-Merck units.
The HPV-16 vaccine induces high titers of specifc antibody that persist long after vaccination 1000 uninfected recipients of placebo recipients previously infected with HPV-16 placebo recipients not previously infected with HPV-16
Another drug–antibody conjugate, brentuximab vedotin, links an anti-CD30 antibody with a different microtubule inhibitor and is approved for certain forms of relapsed lymphomas.
A variation on this approach is to link an antibody to an enzyme that metabolizes a nontoxic pro-drug to the active cytotoxic drug, a technique known as antibody-directed enzyme/pro-drug therapy (ADEPT). With this technique, a small amount of enzyme localized by the antibody can generate much larger amounts of active cytotoxic drug in the immediate vicinity of tumor cells. Monoclonal antibodies linked to radioisotopes (see Fig. 16.19) have been successfully used to treat refractory B-cell lymphoma, using anti-CD20 antibodies linked to yttrium-90 (ibritumomab tiuxetan). These approaches have the advantage of also killing neighboring tumor cells, because the released drug or radioactive emissions can affect cells adjacent to those that bind the antibody. Monoclonal antibodies coupled to γ-emitting radioisotopes have also been used successfully to image tumors for the purposes of diagnosis and monitoring tumor spread.
16-18 Enhancing the immune response to tumors by vaccination holds promise for cancer prevention and therapy.
In addition to CAR T cells and monoclonal antibody-based therapies, there are two other major approaches to cancer immunotherapy. Cancer vaccines are based on the idea that tumors are intrinsically poorly immunogenic, and the vaccine should act to supply the immunogenicity. A second approach, called checkpoint blockade, which we will discuss in the next section, is based on the idea that the immune system has been primed but is held in check by tolerance mechanisms, which can be blocked by therapeutic interventions.