Among the most challenging of clinical targets for
cancer immunotherapy are
Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing
carbohydrate mimetic
peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-
tumor reactivity. However, the activation of immune responses against terminal mono- and
disaccharide constituents of TACA raises concerns regarding the balance between "
tumor destruction" and "tissue damage", as mono- and
disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia
lectin 1 (GS-I), and tissue reactivity of serum
antibodies were compared with the tissue staining profile of GS-I. Tissues from
CMP immunized mice were analyzed using
hematoxylin and
eosin stain, and
Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum
antibodies, and naive serum
antibodies.
CMP immunization enhanced
glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses.