Impact of minimal tumor burden on antibody response to vaccination

Abstract

Four randomized phase III trials conducted recently in melanoma patients in the adjuvant setting have been based in part on the correlation between antibody responses in immunized patients and improved survival. Each of these randomized trials demonstrated no clinical benefit, although again there was a significant correlation between antibody response after vaccination and disease free and overall survival. To better understand this paradox, we established a surgical adjuvant model targeting GD2 ganglioside on EL4 lymphoma cells injected into the foot pad followed by amputation at variable intervals. Our findings are (1) comparable strong therapeutic benefit resulted from treatment of mice after amputation with a GD2-KLH conjugate vaccine or with anti-GD2 monoclonal antibody 3F8. (2) The strongest correlation was between antibody induction in response to vaccination and prolonged survival. (3) Antibody titers in response to vaccination in tumor challenged mice as compared to unchallenged mice were far lower despite the absence of detectable recurrences at the time. (4) The half life of administered 3F8 monoclonal antibody (but not control antibody) in challenged mice administered was significantly shorter than the half life of 3F8 antibody in unchallenged controls. The correlation between vaccine-induced antibody titers and prolonged survival may reflect, at least in part, increased tumor burden in antibody-negative mice. Absorption of vaccine-induced antibodies by increased, although not detected tumor burden may also explain the correlation between vaccine-induced antibody titers and survival in the adjuvant clinical trials described above.

Phase I Trial of a Bivalent Gangliosides Vaccine in Combination with β-Glucan for High-Risk Neuroblastoma in Second or Later Remission

“…Benefit is optimal in the adjuvant setting, with ablation of micrometastasis. 43 The anti-neoplastic mechanisms include opsonization, antibody-dependent cellular cytotoxicity (ADCC), and complement-mediated cytotoxicity (CMC). The ADCC involves leukocytes of all types, including neutrophils, macrophages, and natural killer cells.…”

Synthesis and characterization of a novel chemically designed (Globo)3–DTPA–KLH antigen

“…One of the carbohydrates associated with tumors was first isolated from breast cancer MCF-7 cells and called Globo H by Hakomori 7 and Bremer et al 29 It is now known that Globo H is present on many cancer cells, including prostate, ovary, lung, pancreatic, gastric, and colon cancers, 24 and high levels of anti-Globo H antibody can be detected in serum samples of breast cancer patients. 30 , 31 These findings indicate that Globo H could be used as a potential target in cancer therapy and cancer-vaccine development.…”

A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation

“…However, results of previous studies suggest that maximum immunotherapy efficacy is obtained when administered in the setting of minimal disease. 34 To this extent we have become interested in pursuing immunotherapy following surgery, which may create "minimal disease" state.…”