Relapse is the most common cause of treatment failure for advanced cancer, even those treated with autologous hematopoietic cell transplantation (HCT). Effective tumor-specific immunotherapy may decrease relapse, however, this will fail if the immune system is unable to respond. We developed a strategy to test immune responses with a single injection of the bona fide neo-antigen KLH. The model was first tested in 37 normal volunteers using three KLH vaccines: Intracel KLH, Biosyn KLH, and Biosyn KLH + adjuvant. Despite finding the immunogenic epitope conserved in both products, intact Intracel KLH induced a better response compared to a purified 350/390 kDA subunit of KLH contained in the Biosyn KLH product. Addition of a synthetic oil adjuvant (Montanide ISA51) restored the response to a single injection of Biosyn KLH. A quantitative readout measured by a KLH-specific cellular and humoral response with isotype switching 1 month after KLH vaccination was established. To test the integrity of the adaptive immune response in cancer patients, we vaccinated 14 patients post-HCT and 19 patients with advanced cancer with KLH vaccines that elicited a 100% response rate in normal volunteers. In marked contrast to normal subjects, both responses were significantly impaired up to 16 months after autologous HCT with an intermediate response in advanced cancer patients. KLH vaccines are safe and require only a single injection to test neo-antigen responses providing an optimal platform for definitive testing of strategies to improve diminished immune recovery after chemotherapy or post-HCT.