Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer

Williams, Benjamin B.; Wall, Meaghan; Miao, Rebecca Yu; Williams, Brenda; Bertoncello, Ivan; Kershaw, Michael H.; Mantamadiotis, Theo; Haber, Michelle; Norris, Murray D.; Gautam, Anand M.; Darcy, Phillip K.; Ramsay, Robert G.

doi:10.1007/s00262-008-0497-2

Cited by 32 publications

(34 citation statements)

References 41 publications

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Section: Discussionmentioning

confidence: 99%

“…Using a different tumor cell line that does not constitutively express MHC class II, others also observed a critical role for DNA vaccineinduced CD4 T cells at the effector phase. 44 It has been suggested that CD4 tolerance is more stringent than CD8 tolerance, 45 so it is tempting to speculate that the effects of ␤-gal administration are mediated via antigen-reactive CD4 rather than CD8 cells.Although it has been long known that incorporation of exogenous helper antigens into immunization protocols could break tolerance to self-antigens, contemporary vaccine design has emphasized more reductionist approaches. Tumor antigen-derived, MHCbinding peptides have been optimized, 46,47 51 and that has already been demonstrated to be active in patients with non-Hodgkin lymphoma.…”

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confidence: 99%

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Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen

Leitner

Baker

Berenberg

et al. 2009

Blood

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Nucleic acid-based vaccines are effective in infectious disease models but have yielded disappointing results in tumor models when tumor-associated selfantigens are used. Incorporation of helper epitopes from foreign antigens into tumor vaccines might enhance the immunogenicity of DNA vaccines without increasing toxicity. However, generation of fusion constructs encoding both tumor and helper antigens may be difficult, and resulting proteins have unpredictable physical and immunologic properties. Furthermore, simultaneous production of equal amounts of highly immunogenic helper and weakly immunogenic tumor antigens in situ could favor development of responses against the helper antigen rather than the antigen of interest. We assessed the ability of 2 helper antigens (␤-galactosidase or fragment C of tetanus toxin) encoded by one plasmid to augment responses to a self-antigen (lymphomaassociated T-cell receptor) encoded by a separate plasmid after codelivery into skin by gene gun. This approach allowed ad- IntroductionPlasmid-encoded antigens have been used to induce immune responses in experimental animals and humans for more than a decade. Plasmid-based nucleic acid vaccines are attractive because of simplicity, low cost, and safety, but suboptimal immunogenicity and limited efficacy against certain pathogens and tumors have limited their utility. A variety of strategies have been developed to enhance DNA vaccine efficacy. These approaches include:(1) modification of DNA vaccines to include improved expression plasmids 1 or incorporation of viral vectors 2 ; (2) modifications of cDNA sequences encoding antigen to enhance antigenicity, 3 codon adjustments to optimize transcription, 1,4 or generation of string-ofepitope constructs incorporating selected subunits of antigens 5,6 ; (3) improved delivery systems, including methods for more efficient in vivo transfection of host cells, such as in vivo electroporation 6 or gene gun 7 ; and (4) the use of adjuvants. 8 Adjuvants include conventional adjuvants, such as Freund adjuvant, and the more recently developed chemically defined ("molecular") adjuvants. The latter are intended to enhance immune responses while avoiding, or at least significantly reducing, adverse effects associated with conventional adjuvants.Entities with a wide variety of biologic effects have been used as chemically defined adjuvants for DNA vaccines, including biologic response modifiers such as cytokines (eg, granulocytemacrophage colony-stimulating factor [GM-CSF] 9 ) and costimulatory molecules 10,11 as well as monoclonal antibodies (mAbs) that block undesired or trigger desired pathways, such as anti-CD40 12 or anti-CD137. 13 An alternative strategy involves codelivery of "helper antigens" (ie, foreign antigens that induce strong T-cell responses) with weak antigens of interest. Helper antigens are selected based on their high immunogenicity and enhance responses to weaker antigens via incompletely characterized bystander effects. Proteins previously used as helper antigens include keyh...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen

Leitner

Baker

Berenberg

et al. 2009

Blood

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“…11, 14 Here we have advanced its application to a therapeutic context in two highly aggressive CRC pre-clinical models. Significant single agent protection is evident when the tumour burden is low.…”

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confidence: 99%

Therapeutic DNA vaccination against colorectal cancer by targeting the MYB oncoprotein

et al. 2015

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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.

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“…To test c-Myb as a therapeutic target in CRC, which devised a DNA fusion vaccine to generate an anti-CRC immune response. c-Myb, like many tumor antigens, is weakly immunogenic as it is a "self" antigen and subject to tolerance [70].Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME).…”

Section: Plant Peptides and Proteinsmentioning

confidence: 99%

Targeting Colon Drug Delivery by Natural Products

Kim¹

2012

Inflammatory Bowel Disease

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Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer

Cited by 32 publications

References 41 publications

Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen

Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen

Therapeutic DNA vaccination against colorectal cancer by targeting the MYB oncoprotein

Targeting Colon Drug Delivery by Natural Products

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