Abstract:
We have focused our efforts on delineating cancer-associated epitopes expressed on carcinoma cell surface mucin molecules for use in ASI. We used entirely synthetic carbohydrate, peptide, and glycopeptide epitopes expressed on carcinoma cell surface mucin molecules; formulated them into immunotherapeutic 'vaccines'; and tested them in animal models and in some cases, in human cancer patients (pts) in Phase I clinical trials. The Thomsen-Friedenreich (TF) antigen (beta Gal1----3 alpha GalNAc) and the sialyl-Tn antigen (alpha NANA2----6 alpha GalNAc) are strongly expressed on a variety of human carcinomas with little expression on most normal tissues. Mice immunized with synthetic TF conjugated to KLH (TF-KLH) plus RIBI adjuvant produce TF-specific antibody, TF-specific DTH reactions and increased survival following challenge with a highly aggressive mouse mammary adenocarcinoma (TA3-Ha) expressing a mucin (epiglycanin) with multiple TF epitopes. Low-dose cyclophosphamide, which inhibits mucin-induced immune suppression, increases the effectiveness of the TF-KLH 'vaccine.' Mice immunized with STn-KLH plus RIBI adjuvant produced IgG MAbs which showed specific binding to alpha NANA (2----6) alpha GalNAc, (but not beta NANA [2----6] alpha GalNAc), to ovine submaxillary mucin (which has multiple STn epitopes) and human tumor cells expressing STn epitopes. Based on these preclinical animal model results, 2 Phase I clinical trials have been completed using TF-KLH plus DETOX in 12 ovarian cancer pts and sialyl-Tn plus DETOX in 12 breast cancer pts. Specific humoral responses were noted including a vigorous hapten-specific IgG response. Complement-mediated cytotoxic antibodies against appropriate tumor cell targets developed in most of the pts following immunization. The antibody responses are appropriately hapten inhibitable. All of the ovarian cancer pts had extensive metastatic disease on entry into the trial. A significant correlation between CD4:CD8 ratios at trial entry and survival was noted in these pts. One of the ovarian cancer pts who was immunized with the STn-KLH formulation after having completed her full course of TF-KLH immunizations demonstrated a specific sequential humoral immune response to each hapten. Two of the breast cancer pts entered the trial with widespread disease, but the remaining 10 pts entered with minimal metastatic disease with measurable metastatic lesions in all cases. Three of the 12 pts showed progressive disease despite ASI, including the 2 pts who had widespread disease on trial entry. Four pts demonstrated stable disease for 7-12 mo after trial entry and 1 pt showed progressive disease after 8 mo of stable disease. Two pts showed a mixed response, both subsequently having disease progression. One pt had a good partial response for approx 7 mo then showed progressive disease several months following her ASI. One additional pt had a partial response which has been maintained for approx 6 mo. Phase II/III studies will be required to confirm the efficacy of our synthetic ASI formulations. Such studies have now been approved for colorectal, pancreatic and breast cancers at multiple sites in Canada.
Keywords: Animal Antigens, Tumor-Associated, Carbohydrate/*THERAPEUTIC USE Breast Neoplasms/PATHOLOGY/THERAPY Clinical Trials, Phase I CD4-CD8 Ratio Human *Immunotherapy Mice Neoplasm Metastasis Neoplasms/*THERAPY Ovarian Neoplasms/PATHOLOGY/THERAPY ABSTRACT 931230
M93C0831
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