Antibody inducing polyvalent cancer vaccines

Abstract

The great majority of cancer patients can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on the antigenic epitope and vaccine design. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H and the mucin backbone MUC1, and cancer cells expressing these antigens. Other antigens required additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against tumor cells than the unmodified antigens. Tn, sTn and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer cell surface. The optimal approach for Le(Y), KSA, PSMA, and CA125 (MUC16) remains to be determined. Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required due to tumor cell heterogeneity, heterogeneity of the human immune response and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, Phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.