Cancer Vaccines in Clinical Trials

Recent advances in understanding how cancer cells escape recognition and attack by the immune system are now giving researchers the knowledge required to design cancer treatment vaccines that can accomplish both goals (1625).

Although researchers have identified many cancer-associated antigens, these molecules vary widely in their ability to stimulate a strong anticancer immune response. Two major areas of research are aimed at addressing this issue. One involves the identification of novel cancer-associated antigens, or neoantigens, that may prove more effective in stimulating immune responses than the already known antigens. For example, a neoantigen-based personalized vaccine approach that is in early-phase clinical testing involves the identification and targeting of patient-specific mutated antigens to create treatment vaccines for patients with glioblastoma and melanoma (2627). The other major research area involves the development of methods to enhance the ability of cancer-associated antigens to stimulate the immune system. Research is also under way to determine how to combine multiple antigens within a single cancer treatment vaccine to produce optimal anticancer immune responses (28).

Improving our understanding of the basic biology underlying how immune system cells and cancer cells interact will be very important for developing cancer vaccines. New technologies are being created as part of this effort. For example, a new type of imagingtechnology allows researchers to observe killer T cells and cancer cells interacting inside the body (29).

Researchers are also trying to identify the mechanisms by which cancer cells evade or suppress anticancer immune responses. A better understanding of how cancer cells manipulate the immune system could lead to the development of drugs that block those processes, thereby improving the effectiveness of cancer treatment vaccines (30).

For example, some cancer cells produce chemical signals that attract white blood cells known as regulatory T cells, or T regs, to a tumor site. T regs often release cytokines that suppress the activity of nearby killer T cells (1831). The combination of a cancer treatment vaccine with a drug that prevents the inactivation of killer T cells might improve the vaccine’s effectiveness in generating potent killer T cell antitumor responses.

Immune checkpoint modulators may also improve the effectiveness of cancer vaccines (32). These modulators target another immune regulatory mechanism used by cancer cells to evade destruction, one that involves immune checkpoint proteins such as PD-1, which is expressed on the surface of T cells. The binding of PD1 to specific partner proteins (or ligands), called PD-L1 and PD-L2, on the surface of some normal cells or cancer cells creates an “off” signal that tells the T cell not to mount an immune response against those cells. (This binding keeps the immune system from overreacting against normal cells and prevents autoimmunity.) Some tumor cells express high levels of PD-L1, which causes T cells to shut down and helps the cancer cells evade immune destruction. Antibodies that block the binding of an immune checkpoint protein to its ligand on a cancer cell remove this “off’ signal and allows an immune response to proceed against the cancer cells.

Several such antibodies have been approved by the FDA for treatment of some cancers and are showing promising effects in other cancers (33). Because these agents allow T cells against cancer to be more effective, it is expected that they will also improve the effectiveness of cancer vaccines. Indeed, they have been found to do so in animal models, and clinical trials that combine a vaccine with PD1 or PD-L1 inhibition are ongoing (34).

A number of vaccines designed to treat specific cancers are currently under development (3538). These include dendritic cell vaccines for metastatic renal cell carcinoma, glioblastoma, and metastatic hormone-refractory prostate cancer; autologous tumor cellvaccines for colorectal cancer and follicular lymphoma; anti-idiotype vaccines for lymphomas and some solid tumors; vaccines designed to stimulate an immune response against hormones required for the growth and survival of gastrointestinal malignancies; allogeneic vaccines for lung cancer; and a DNA-based vaccine for metastatic breast cancer.