The invention provides methods for treating with cancer vaccines patients whose cancers undergo clonal evolution. The invention makes use of a series of cancer vaccines to stimulate a patients immune system to mount both a humoral and cellular immune response against cancer cells as cancer-specific antigens on the cancer cells change by clonal evolution. Vaccines used in the invention are derived from antigens unique to the cancer. In one aspect of the invention, such unique antigens are determined by generating sequence-based profiles of cancer related nucleic acids. In some embodiments, cancer antigens may be identified in sequence-based profiles of exon sequences from a sample suspected of containing cancer cells in other embodiments in which lymphoid or myeloid cancers are being treated, cancer antigens may be identified in sequence-based clonotype profiles.
