Colon Cancer and Immunotherapy: CD40 Ligand as a Potential Therapeutic Target

CD40 and its ligand CD40L (CD154), members of the tumor necrosis factor (TNF) super-family, have a key role in the functions of the immune system. It is well known that CD40 is widely expressed in monocytes, dendritic cells, endothelial cells, epithelial cells, platelets and fibroblasts. However, CD40 expression was observed not only in cells related to the immune system, but also in cells of several different types of carcinomas, such as in the ovary, breast, lung, renal, melanoma and colon among others. CD40 it appears to initiate the differentiation and the proliferation of certain cell types.

Colon Cancer and Immunotherapy: CD40 Ligand
Colon Cancer and Immunotherapy: CD40 Ligand

The CD40 ligand CD154 has been most commonly observed on activated CD4+ T lymphocytes and secondly on activated CD8+ T lymphocytes, eosinophils and B lymphocytes as well. Connection of the CD40 with its ligand CD154, results in the activation of both the humoral and cellular immune response systems via the professional antigen presenting cells (APCs) and T cells.

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Tumor Genomic Profiling Reports from Different Vendors

Genetic profiling of cancer aims to identify molecular variants in the tumor that might help guide patient management. For instance, it is recommended that KRAS and NRAS genes be genotyped in metastatic colon cancer tissue and patients with mutations in codons 12, 13 of exon 2, codons 59, 61 of exon 3, and codons 117 and 146 of exon 4 should not be treated with either cetuximab or panitumumab. Similarly, amplification of the MET gene is also associated with poor response to cetuximab and panitumumab therapy. Large clinical studies have found that a mutation in codon 600 of BRAF is a negative prognostic factor in metastatic colorectal cancer.

Tumor Genomic Profiling
Tumor Genomic Profiling

Increasing utility of multi-gene tumor profiling for patient management has led to an increase in the utilization of Next- Generation Sequencing (NGS) assays in order to identify clinically informative variants in multiple genes. These complex assays require careful planning on multiple design parameters: panel design (i.e. selection of genes and number of targets to include), assay type, NGS platforms, variant calling algorithms, thresholds to call Copy Number Variation (CNV) and rearrangements. Additionally, multiple interpretive considerations need to be included in this planning (e.g. how to interpret the oncogenicity of a variant, or its ability to activate a particular pathway, and what clinical utility to report for the variant based on literature assessment).