Immunotherapy for colon cancer: antibodies targeting antigens
Currently, tumor-targeting mAbs used in colon cancer include: (1) cetuximab, targeting the epidermal growth factor receptor (EGFR), can inhibit cancer cell-intrinsic vital signal transduction pathways. (2) Panitumumab is another antibody targeting EGFR that is approved for first-line therapy for EGFR-expressing metastatic colorectal carcinoma. (3) Bevacizumab, targeting vascular endothelial growth factor (VEGF) and interfering with the trophic interaction between neoplastic cells and the tumor stroma, is approved for use in patients affected by colon cancer.
Immunotherapy for colon cancer: blockade of immune checkpoint
Studies applying blockade of immune checkpoints for colorectal cancer conclude molecules: CTLA4, PD-1, PD-L1, GITR, OX40.
Immunotherapy for colon cancer: cancer vaccines
Autologous tumor cell vaccines: A strategy in anti-cancer therapies has been the use of cancer cells to develop vaccines. Cancer cells provide surface antigens that are targets for a desired immune response. Autologous tumor cell vaccines are tumor cells collected from patients, processed with adjuvant bacillus CalmetteGuérin (BCG) or infected with virus, and are re-administered to the patient.
Peptide vaccines: Peptide vaccines for colon cancer patients are generally well-tolerated; however, a high frequency of reactions were observed at the injection site due to the use of adjuvants such as incomplete Freund's adjuvant, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and BCG. Another kind of peptide vaccine is tumor associated antigens which are self-antigen expressed on colon cancer cells such as CEA, mucin, epidermal growth factor receptor, squamous cell carcinoma antigen recognized by T cells 3 (SART3), β-human chorionic gonadotropin (β-hCG), survivin-2B, p53 or mutated KRAS. Vaccination of these peptide vaccine elicit humoral and cellular immune response in some patients but is related with poor clinical activity.
Dendritic cell vaccines: Dendritic cells (DCs) play a pivotal role in initiating and regulating the immune response and
adjuvants act primarily as DC activators. Developing DC-based vaccines against colon cancer has been going on for decades. DCs are isolated from a cancer patient. Then DCs are either loaded with peptides derived from tumor antigens, or loaded with tumor cell lysates in vitro. DCs can be engineered to express co-stimulatory molecules and cytokines by transfection with recombinant genes such as CD40L to increase the ability of DCs to induce T cell responses. After activation, the DC vaccine isthen re-administered back into the patient.
Viral-vector vaccines: Viral-vector vaccines based on human tumor associated antigens have been tested in patients with CRC, in combination with or following standard therapy.
Immunotherapy for colon cancer: adoptive cell therapy
Tumor-infiltrating lymphocytes: One strategy of adoptive cell therapy is autologous tumor-infiltrating lymphocytes (TILs), in which lymphocytes are isolated from resected tumors, activated and expanded and are given back to patients together with IL-2. Currently TIL therapy is under investigation for the treatment of many tumors. In a phase I clinical trial, TILs from tumor specimen was activated and were administered with IL-2 to 14 patients with resected metastatic colon cancer. The results showed that TILs immunotherapy and chemotherapy have similar effect on disease-free survival.
Cytokine-induced killer cells: Another adoptive cell immunotherapy involved cytokine-induced killer (CIK) cells. Compared to
lymphokine-activated killer (LAK) cells, CIK cells can be obtained more easily and has demonstrated a higher tumor-specific cytotoxic activity. So far, only one clinical trial with CIK cells for colorectal cancer patients was conducted.
Engineered lymphocytes: Another way of adoptive cell therapy involves Genetically engineered T cells expressing T cell: In another phase I trial, autologous peripheral blood lymphocytes (PBL) were genetically engineered to express a murine TCR against CEA and consequently were given to three patients with metastatic colorectal cancer. All patients demonstrated considerable decreases in serum CEA levels and one patient had an objective clinical regression. On the other side, severe transient inflammatory colitis was also observed in all three patients.
Trials to explore the usage of immunotherapy are under active investigation and will continue to contribute to our increasing knowledge of immunotherapeutic and benefit colon cancer patients.
Huang L et al. Immunotherapy for colorectal cancer[J]. Am J Digest Dis, 2015, 2(1): 11-28.
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