Posts in Category: Technology - Moditope

Cancer Vaccines, Adjuvants, and Delivery Systems

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 responses

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

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

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.

CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, Paris, 25-28 September 2019

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

Autophagy, citrullination and cancer (2016)

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.

Progress in Vaccination against Cancer 2015

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