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Cancer Vaccines, Adjuvants, and Delivery Systems

Samantha J. Paston, Victoria A. Brentville, Peter Symonds and Lindy G. Durrant

ABSTRACT: Vaccination was first pioneered in the 18th century by Edward Jenner and eventually led to the development of the smallpox vaccine and subsequently the eradication of smallpox. The impact of vaccination to prevent infectious diseases has been outstanding with many infections being prevented and a significant decrease in mortality worldwide. Cancer vaccines aim to clear active disease instead of aiming to prevent disease, the only exception being the recently approved vaccine that prevents cancers caused by the Human Papillomavirus. The development of therapeutic cancer vaccines has been disappointing with many early cancer vaccines that showed promise in preclinical models often failing to translate into efficacy in the clinic. In this review we provide an overview of the current vaccine platforms, adjuvants and delivery systems that are currently being investigated or have been approved. With the advent of immune checkpoint inhibitors, we also review the potential of these to be used with cancer vaccines to improve efficacy and help to overcome the immune suppressive tumor microenvironment.

Combination vaccine based on citrullinated vimentin and enolase peptides induces potent CD4-mediated anti-tumor response

Victoria A Brentville, Rachael L Metheringham, Ian Daniels, Suha Atabani, Peter Symonds, Katherine W Cook, Mireille Vankemmelbeke, Ruhul Choudhury, Poonam Vaghela, Mohamed Gijon, Ghislaine Meiners, Willem-Jan Krebber, Cornelis J M Melief, Lindy G Durrant

ABSTRACT: Background  Stress-induced post-translational modifications occur during autophagy and can result in generation of new epitopes and immune recognition. One such modification is the conversion of arginine to citrulline by peptidylarginine deiminase enzymes.

Post-translational modifications such as citrullination are excellent targets for cancer therapy

V.A. Brentville, M. Vankemmelbeke, R.L. Metheringham, L.G. Durrant

ABSTRACT: Under conditions of cellular stress, proteins can be post-translationally modified causing them to be recognized by the immune system. One such stress-induced post-translational modification (siPTM) is citrullination, the conversion of arginine residues to citrulline by peptidylarginine deiminase (PAD) enzymes. PAD enzymes are activated by millimolar concentrations of calcium which can occur during apoptosis, leading to precipitation of proteins, their subsequent uptake by B cells and stimulation of antibody responses. Detection of anti-citrullinated protein antibodies (ACPAs) is a diagnostic of rheumatoid arthritis (RA), where immune complexes stimulate inflammation around the joints. More recently, autophagy has been shown to play a role in the presentation of citrullinated peptides on MHC class II molecules to CD4+ helper T cells, suggesting that citrullination may be a way of alerting immune cells to cellular stress.  Additionally, inflammation-induced IFNγ and concomitant MHC class II expression on target cells contributes to immune activation. Stressful conditions in the tumour microenvironment induce autophagy in cancer cells as a pro-survival mechanism. Cancer cells also over express PAD enzymes and in light of this the hypothesis that citrullinated peptides stimulate CD4+ T cell responses that would recognize these siPTM’s produced during autophagy has been investigated. The induction of potent citrullinated peptide-specific CD4 responses has been shown in both humans and HLA transgenic mouse models. Responses in mouse models resulted in potent anti-tumour responses against tumours expressing either constitutive or IFNγ-inducible MHC class II. The anti-tumour effect relied upon direct recognition of tumours by specific CD4 T cells suggesting that citrullinated peptides are attractive targets for cancer vaccines.

T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; Targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy

Victoria A Brentville, Peter Symonds, Katherine  W Cook, Ian Daniels, Tracy Pitt, Mohamed Gijon, Poonam Vaghela, Wei Xue, Sabaria Shah, Rachael E Metheringham, and Lindy Durrant

ABSTRACT: Post-translational modifications are induced in stressed cells which cause them to be recognised by the system. One such modification is citrullination where the positive charged arginine is modified to a neutral citrulline. We demonstrate most healthy donors show an oligoclonal CD4 response in vitro to at least one citrullinated vimentin or enolase peptide. Unlike rheumatoid arthritis patients, these T cell responses were not restricted by HLA-DRB1 shared epitope (SE) alleles, suggesting they could be presented by other MHC class II alleles. As HLA-DP is less polymorphic than HLA-DR, we investigated whether the common allele, HLA-DP4 could present citrullinated epitopes. The modification of arginine to citrulline enhanced binding of the peptides to HLA-DP4 and enhanced high-frequency CD4 responses in HLA-DP4 transgenic mouse models. Our previous studies have shown that tumours present citrullinated peptides restricted through HLA-DR4 which are good target for anti-tumour immunity. In this study, we show that citrullinated vimentin and enolase peptides also induced strong anti-tumour immunity (100% survival, p < 0.0001) against established B16 tumours d and against the LLC/2 lung cancer model (p = 0.034) both expressing HLA-DP4. Since most tumours do not constitutively express MHC class II molecules, models were engineered that expressed MHC class II under the control of an IFNγ inducible promoter. Immunisation with citrullinated peptides resulted in 90% survival (p < 0.001) against established B16 HHD tumour expressing IFNγ inducible DP4. These studies show that citrullinated peptides can be presented by a range of MHC class II molecules, including for the first time HLA-DP4, and are strong targets for anti-tumour immunity.

Post-translationally modified antigens are good targets for cancer immunotherapy but some patients have antigen specific T-regs that may need to be neutralized

Suha Atabani, Victoria Brentville, Ian Daniels, Ruhul Choudhury, Katherine Cook, Poulam Patel and Lindy Durrant

Improving selection criteria for post translationally modified CD4 epitopes using computer algorithms.

K Cook, P Symonds, A Skinner, S Shah, R Metheringham, S Paston, V Brentville and L Durrant

Carbamylation of lysine residues mediated by MDSCs in the tumour environment make excellent targets for CD4 T cell mediated cancer immunotherapy

K Cook, W Xue, I Daniels, P Symonds, M Gijon, D Boocock, C Coveney, A Miles, P Vaghela, R Choudhury, S Shah, S Atabani, R Metheringham, V Brentville and L Durrant

Targeting citrullinated vimentin and enolase with cytotoxic CD4 T cells, relies upon MHC-II expression by tumors, reduces myeloid suppressor cells and directly kills tumor cells

V Brentville, R Metheringham, I Daniels, S Atabani, P Symonds, K Cook, R Choudhury, P Vaghela, M Gijon, G Meiners, W-J Krebber, CJM Melief and L Durrant

Citrullinated glucose-regulated protein 78 is a candidate target for cancer immunotherapy

V Brentville, J Chua, S Atabani, P Symonds, K Cook, R Choudhury, I Daniels, S Shah and L Durrant

An ultraspecificmonoclonal antibody recognises a novel marker on stem memory T cells and induce cell proliferation and differentiation in vitro and in vivo

J Chua, E Cid, M Vankemmelbeke, R McIntosh, R Metheringham, I Daniels, V Brentville and L Durrant

Cancer vaccine:how far are we from curing cancer?

Ruhul Choudhury and Lindy Durrant

Healthy individuals have a repertoire of CD4 cells that recognize and respond to citrullinated peptides - a possible new target for cancer immunotherapy?

Ruhul Hasan Choudhury, Ian Daniels, Vicky Brentville, Katherine Cook, Peter Symonds, Poonam Bilimoria, Suha Atabani, Rachael Metheringham, Lindy Durrant 

CRI 2018 : Post translationally modified homocitrulline induced by MDSCs can be an effective anti-tumour target for CD4 T cells

K. Cook, W. Xue, P. Symonds, M. Gijon, P. Vaghela, R. Choudhury, S. Shah, S. Atabani, R. Metheringham, V. Brentville, L. Durrant 

CRI 2018 : Pre-existing citrulline specific CD4 T cells can be efficiently harnessed for tumour therapy

V. Brentville, P. Symonds, K. Cook, I. Daniels, S. Atabani, R. Choudhury, P. Vaghela, R. Metheringham, M. Gijon, W. Xue, L. Durrant

CRI 2018 : Targeting gastrointestinal tumors with constant region-engineered anti-glycan antibodies

M. Vankemmelbeke, T. Kirk, C. Papagregoriou, S. Aziz, J.X. Chua, R.S. McIntosh, L.G. Durrant

Current Strategies to Enhance Anti-Tumour Immunity (2018)

Katherine W. Cook, Lindy G. Durrant and Victoria A. Brentville

ABSTRACT: The interaction of the immune system with cancer is complex, but new approaches are resulting in exciting therapeutic benefits. In order to enhance the immune response to cancer, immune therapies seek to either induce high avidity immune responses to tumour specific antigens or to convert the tumour to a more pro-inflammatory microenvironment. Strategies, including vaccination, oncolytic viruses, and adoptive cell transfer all seek to induce anti-tumour immunity. To overcome the suppressive tumour microenvironment checkpoint inhibitors and modulators of regulatory cell populations have been investigated. This review summarizes the recent advances in immune therapies and discusses the importance of combination therapies in the treatment of cancers.