The simplest type of immunological therapy, conceptually at least, is to inject the patient with antibodies that target the cancer cells. This approach has had some successes. About 25% of breast cancers, for example, express unusually high levels of the Her2 protein, a receptor tyrosine kinase related to the EGF receptor that plays a part in the normal development of mammary epithelium. A monoclonal antibody called trastuzumab (trade name Herceptin®) that binds to Her2 and inhibits its function slows the growth of breast tumors in humans that overexpress Her2, and it is now an approved therapy for these cancers (see Figure 20–44). A related approach uses antibodies to deliver poisons to the cancer cells. Antibodies against proteins that are abundant on the surface of a particular type of cancer cell but rare on normal cells can be armed with a toxin that kills those cells that bind the antibody molecule.
A great deal of current excitement centers around a different type of approach, based on the relatively recent recognition that the microenvironment in a tumor is highly immunosuppressive. As a result, the cancer victim’s immune system is prevented from destroying the tumor cells. Recall that, from the thousands of genome sequences thus far determined, we know that a typical cancer cell will contain on the order of 50 proteins with a mutation that alters an amino acid sequence, most of these being “passenger” mutations, as previously explained (see p. 1104). Many of these mutant proteins will be recognized by the patient’s immune system as foreign, but—to allow the cancer cells to survive throughout the course of tumor progression—the cancer cells have evolved a set of anti-immune defenses. These
Figure 20–44 Some anticancer drugs and drug targets in the Ras–MAP-kinase signaling pathway. Each of the signaling proteins in this diagram has been identified as a product of a cancer-critical gene, with the exception of Raf1 and Erk. This Ras– MAP-kinase signaling pathway is triggered by a variety of receptor tyrosine kinases (RTKs), including the EGF receptor (see Figures 15–47 and 15–49). Those drugs that are antibodies end in “mab,” while those that are small molecules end in “nib.” (Adapted from B. Vogelstein et al, Science 339:1546–1558, 2013.) defenses include the expression on the cancer cell surface of one or more proteins that bind to inhibitory receptors on activated T cells.
The normal immune system is subject to complex controls that keep its activity within safe bounds and prevent autoimmunity from developing. The inhibitory receptors that are expressed on the surface of activated T cells have an important normal function: they control the immune response by down-regulating the T cell response under appropriate circumstances. But in the context of a tumor, the down-regulation is inappropriate, because it prevents the organism from killing the cancer cells that are threatening its survival.
In its attack on infectious organisms, the natural immune system usually eliminates every last trace of infection and maintains this immunity in the long term. The challenge is to find ways of recruiting the immune system to attack cancers with similar efficiency and specificity, hunting the cancer cells down by virtue of the tumor-specific antigens that they express. With this aim, a new type of anticancer therapy focuses on overcoming the immunosuppressive environment in a tumor through the use of specific antibodies that prevent the tumor cells from engaging with the inhibitory receptors on T cells. As illustrated in Figure 20–45A, blocking the action of the immune suppressors with such treatments should unleash an immune attack on the cancer cells. Importantly, multiple antigens are recognized as foreign; thus, the cancer cells cannot escape through the mutational loss of a single antigen, making it difficult for the tumor to escape from the T cell attack.