Abstract
Patients with colorectal carcinoma (CRC) continue to have variable clinical outcomes despite undergoing the same surgical procedure with curative intent and having the same pathologic and clinical stage. This problem suggests the need for better techniques to assess the extent of disease during surgery. We began to address this problem 35 years ago by injecting patients with either primary or recurrent CRC with 125I-labeled murine monoclonal antibodies against the tumor-associated glycoprotein-72 (TAG-72) and using a handheld gamma-detecting probe (HGDP) for intraoperative detection and removal of radioactive, i.e., TAG-72-positive, tissue. Data from these studies demonstrated a significant difference in overall survival data (p < 0.005 or better) when no TAG-72-positive tissue remained compared to when TAG-72-positive tissue remained at the completion of surgery. Recent publications indicate that aberrant glycosylation of mucins and their critical role in suppressing tumor-associated immune response help to explain the cellular mechanisms underlying our results. We propose that monoclonal antibodies to TAG-72 recognize and bind to antigenic epitopes on mucins that suppress the tumor-associated immune response in both the tumor and tumor-draining lymph nodes. Complete surgical removal of all TAG-72-positive tissue serves to reverse the escape phase of immunoediting, allowing a resetting of this response that leads to improved overall survival of the patients with either primary or recurrent CRC. Thus, the status of TAG-72 positivity after resection has a significant impact on patient survival.
Highlights
On a global basis, colorectal carcinoma (CRC) is ranked third in incidence and second in cancerrelated mortality [1]
The 125I-labeled murine monoclonal antibody (mMoAb) to tumor-associated glycoprotein-72 (TAG-72) do not themselves reset the tumor-associated immune response (TAIR) in CRC patients. These mMoAbs serve as a preferential locator of exposed the GalNAca1-Ser/Thr (Tn), Sialylated Tn (STn), and ST epitopes on the TAG-72 molecules that are bound to receptors on the cells of the innate and adaptive immune response
Publications describing the pattern of aberrant glycans—the tumor-associated glyco-code—in suppressing the antitumor immune response caused us to reexamine its possible role in explaining the results of our long-term survival data using TAG72 AntigenDirected Cancer Surgery (ADCS) for the treatment of patients with primary and recurrent CRC
Summary
Colorectal carcinoma (CRC) is ranked third in incidence and second in cancerrelated mortality [1]. The critical lectins on leukocytes that bind TAG-72-associated TACAs in CRC include Sialic Acid Recognizing Ig-like Lectins (Siglecs), the C-type lectin Macrophage Galactose-type Lectin (MGL), and Dendritic Cell-Specific ICAM-3 Grabbing NonIntegrin (DC-SIGN). In CRC, the terminal sialic acid residues on STn, ST, SLex/a, and SLey/b TACA primarily bind to the single carbohydrate recognition domain of Siglecs-3, -7, and -9 on iDCs, macrophages, monocytes, and NK cells and by Siglec-15 on tumor-associated macrophages (TAMs). The 125I-labeled mMoAbs to TAG-72 do not themselves reset the TAIR in CRC patients These mMoAbs serve as a preferential locator of exposed Tn, STn, and ST epitopes on the TAG-72 molecules that are bound to receptors on the cells of the innate and adaptive immune response. The inability of removing the radioactive tissue precludes resetting of the tumor immune response and leads to recurrent disease and/or decreased patient survival
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