Novel tumour antigens and the development of optimal vaccine design (2018)

Victoria A Brentville, Suha Atabani, Katherine Cook and Lindy G Durrant

ABSTRACT: The interplay between tumours and the immune system has long been known to involve complex interactions between tumour cells, immune cells and the tumour microenvironment. The progress of checkpoint inhibitors in the clinic in the last decade has highlighted again the role of the immune system in the fight against cancer. Numerous efforts have been undertaken to develop ways of stimulating the cellular immune response to eradicate tumours. These interventions include the identification of appropriate tumour antigens as targets for therapy. In this review, we summarize progress in selection of target tumour antigen. Targeting self antigens has the problem of thymic deletion of high-affinity T-cell responses leaving a diminished repertoire of low-affinity T cells that fail to kill tumour cells. Thymic regulation appears to be less stringent for differentiation of cancer–testis antigens, as many tumour rejection antigens fall into this category. More recently, targeting neo-epitopes or post-translational modifications such as a phosphorylation or stress-induced citrullination has shown great promise in preclinical studies. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Previous vaccines have targeted CD8 T-cell responses but more recently, the central role of CD4 T cells in orchestrating inflammation within tumours and also differentiating into potent killer cells has been recognized. The design of vaccines to induce such immune responses is discussed herein. Liposomally encoded ribonucleic acid (RNA), targeted deoxyribonucleic acid (DNA) or long peptides linked to toll-like receptor (TLR) adjuvants are the most promising new vaccine approaches. These exciting new approaches suggest that the ‘Holy Grail’ of a simple nontoxic cancer vaccine may be on the horizon. A major hurdle in tumour therapy is also to overcome the suppressive tumour environment. We address current progress in combination therapies and suggest that these are likely to show the most promise for the future.

CRI 2017 Peptide/TLR agonist conjugates poster

V. Brentville, K. Cook, P. Symonds, G.G. Zom, W. Xue, R. Metheringham, W-J. Krebber, C.J.M. Melief and L.G. Durrant

CRI 2017 Modi-1, a novel cancer vaccine

L. G. Durrant, R. Metheringham, I. Daniels, K. Cook, P. Symonds, T. Pitt, W. Xue, M. Gijon and V. Brentville

PIVAC 2016 SCIB1 Clinical Trial Poster

L.G. Durrant, C. Ottensmeier, C. Mulatero, P. Lorigan, R. Plummer, R. Metheringham, V.Brentville, S. Adams, L. Machado, I. Daniels, D. Hannaman and P.M. Patel 

PIVAC 2016 Adjuvants for Moditope Poster

Katherine Cook, Peter Symonds, Victoria Brentville, Rachael Metheringham,  Wei Xue and Lindy Durrant

PIVAC 2016 Citrullinated Alpha Enolase Poster

K. Cook, I. Daniels, V. Brentville, R. Metheringham, W. Xue, P. Symonds, T. Pitt, M.Gijon and L. Durrant

PIVAC 2016 Protein Arginine Deiminase Enzymes Poster

R. Metheringham, M. Gijon, I. Daniels, K. Cook, P. Symonds, T. Pitt, W. Xue, V. Brentville and L. Durrant

Autophagy, citrullination and cancer (2016)

Lindy G. Durrant, Rachael L. Metheringham and Victoria A. Brentville

ABSTRACT: A cell needs to maintain a balance between biosynthesis and degradation of cellular components to maintain homeostasis. There are 2 pathways, the proteasome, which degrades short-lived proteins, and the autophagy/lysosomal pathway, which degrades long-lived proteins and organelles. Both of these pathways are also involved in antigen presentation or the effective delivery of peptides to MHC molecules for presentation to T cells. Autophagy (macroautophagy) is a key player in providing substantial sources of citrullinated peptides for loading onto MHC-II molecules to stimulate CD4⁺ T cell responses. Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. We therefore investigated if citrullinated peptides could stimulate CD4⁺ T cell responses that would recognize these modifications produced during autophagy within tumor cells. Focusing on the intermediate filament protein VIM (vimentin), we generated citrullinated VIM peptides for immunization experiments in mice. Immunization with these peptides induced CD4⁺ T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. These results show how CD4⁺ cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides produced during autophagy may offer especially attractive vaccine targets for cancer therapy.

Citrullinated Vimentin presented on MHC-II in Tumor Cells is a target for CD4þ T-cell-mediated antitumor immunity (2016)

Victoria A. Brentville, Rachael L. Metheringham, Barbara Gunn, Peter Symonds, Ian Daniels, Mohamed Gijon, Katherine Cook, Wei Xue and Lindy G. Durrant 

ABSTRACT: Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival.However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4⁺ T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-tomesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8⁺ T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate fort he first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy. Cancer Res; 76(3); 548–60. 2015 AACR.

PIVAC 2015 SCIB2 Poster

Wei Xue, Rachael Metheringham, Victoria Brentville, Katherine Cook, Peter Symonds, Ian Daniel and Lindy Durrant

PIVAC 2015 Moditope poster 2

V. Brentville, W. Xue, P. Symonds, K. Cook, B. Gunn, R. Metheringham and L.G. Durrant

PIVAC 2015 SCIB1 resected disease

L.G. Durrant, C. Ottensmeier, C. Mulatero, P. Lorigan, R. Plummer, R. Metheringham, V. Brentville, L. Machado, I. Daniels, D. Hannaman and P.M. Patel

PIVAC 2015 SCIB1 plus checkpoint inhibition

Wei Xue, Victoria Brentville, Rachael Metheringham, Katherine Cook, Peter, Symonds, Ian Daniels and Lindy Durrant

AACR Moditope Poster April 2015

Victoria A.  Brentville, Rachael L. Metheringham, Barbara Gunn, Peter Symonds, Ian Daniels, Mohamed Gijon, Wei Xue and Lindy G. Durrant