Therapeutic DNA vaccination against colorectal cancer by targeting the MYB oncoprotein

• Published in: Clinical & translational immunology Vol. 4; no. 1; pp. e30 - n/a
• Main Authors: Cross, Ryan S, Malaterre, Jordane, Davenport, Alexander J, Carpinteri, Sandra, Anderson, Robin L, Darcy, Phillip K, Ramsay, Robert G
• Format: Journal Article
• Language: English
• Published: Australia Nature Publishing Group 01.01.2015; John Wiley & Sons, Inc
• Subjects: Antigens; Autoantigens; Cancer; Cancer therapies; CD4 antigen; Cell death; Cell surface; Cell survival; Colorectal cancer; Colorectal carcinoma; Complementary DNA; Cyclophosphamide; Deoxyribonucleic acid; DNA; DNA vaccines; Epitopes; Gene expression; Immune response; Immune system; Immunogenicity; Immunological tolerance; Immunotherapy; Leukemia; Mutation; Oncoproteins; Original; Patients; Peptides; Tetanus; Transcription factors; Tumor cell lines; Tumors; Vaccination; Vaccines
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1038/cti.2014.29

Cancers can be addicted to continued and relatively high expression of nuclear oncoproteins. This is evident in colorectal cancer (CRC) where the oncoprotein and transcription factor MYB is over expressed and essential to continued proliferation and tumour cell survival. Historically, targeting transcription factors in the context of cancer has been very challenging. Nevertheless, we formulated a DNA vaccine to generate a MYB‐specific immune response in the belief MYB peptides might be aberrantly presented on the cell surface of CRC cells. MYB, like many tumour antigens, is weakly immunogenic as it is a ‘self’ antigen and is subject to tolerance. To break tolerance, a fusion vaccine was generated comprising a full‐length MYB complementary DNA (cDNA) flanked by two potent CD4‐epitopes derived from tetanus toxoid. Vaccination was achieved against tumours initiated by two distinct highly aggressive, syngeneic cancer cell lines (CT26 and MC38) that express MYB. This was done in BALB/c and C57BL/6 mouse strains respectively. We introduced multiple inactivating mutations into the oncogene sequence for safety and sub‐cloned the cDNA into a Food and Drug Administration (FDA)‐compliant vector. We used low dose cyclophosphamide (CY) to overcome T‐regulatory cell immune suppression, and anti‐program cell death receptor 1 (anti‐PD‐1) antibodies to block T‐cell exhaustion. Anti‐PD‐1 administered alone slightly delayed tumour growth in MC38 and more effectively in CT26 bearing mice, while CY treatment alone did not. We found that therapeutic vaccination elicits protection when MC38 tumour burden is low, mounts tumour‐specific cell killing and affords enhanced protection when MC38 and CT26 tumour burden is higher but only in combination with anti‐PD‐1 antibody or low dose CY, respectively. Colorectal cancer: Treating by turning on the immune system Therapies that combine anti‐tumor vaccination with immune‐activating drugs could help beat back colorectal cancer. Tumors have strategies for evading the body's defenses, but this resistance can potentially be overcome by training the immune system to recognize cancer's molecular signatures. Robert Ramsay and colleagues at Australia's Peter MacCallum Cancer Centre have devised such a vaccine based on an inactivated version of MYB, a protein that drives colorectal tumor growth. This treatment extended survival in one mouse model, but only if applied early in the disease. However, the researchers found that they could improve the window of effectiveness and rate of response in two different colorectal tumor mouse models by adding drugs that increase immune cell activation. Ramsay and colleagues propose that such an approach might delay or prevent relapse following initial cancer treatment.