A New Frontier<br /> in Immuno-Oncology

A New Frontier
in Immuno-Oncology

Scancell's primary focus is to develop innovative immunotherapies for cancer that stimulate the body’s own immune system. A key challenge in the fight against cancer is that many tumours successfully evade the body’s own natural defences. Scancell’s mission is to overcome this by developing products that stimulate the immune system to treat or prevent cancer.

The field of immuno-oncology is now established as a significant weapon in the war against cancer, driven largely by the approval of immune checkpoint inhibitors. However, checkpoint inhibitors alone are not effective in most patients and so there is still an urgent need to identify optimum treatment combinations and/or develop new classes of therapies to improve the lives of millions of people with cancer. Scancell’s goal is to develop new classes of competitive ‘off the shelf’ therapeutics that are applicable to a broad range of patients with the aim to improve overall response and address the many unmet needs in the treatment of cancer.

Scancell has identified several differentiated approaches to cancer immunotherapy. Moditope® is a completely novel class of cancer vaccines, which is based on stress-induced post translational modifications (siPTMs). Alongside its ImmunoBody® platform, these two technologies provide complementary immune modulation mechanisms capable of stimulating potent CD4 and CD8 T cell responses that can effectively identify, target and kill cancer cells. Moditope® also provides a new pathway for the potential development of CD4-based T cell receptor (TCR) therapy. In addition, Scancell’s anti-glycan antibody platform AvidiMab™ provides a third method of attack against overexpressed tumour targets.

In response to the COVID-19 pandemic, Scancell has turned its clinical expertise in cancer to produce a simple, safe, cost-effective and scalable vaccine to induce both durable T cell responses and virus neutralising antibodies against SARS-Cov-2, the virus that causes COVID-19. The Company believes this combined T cell and antibody approach should give more potent and long-lasting responses, ultimately leading to better protection.

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.