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.

Homocitrullination of lysine residues mediated by myeloid-derived suppressor cells in the tumor environment is a target for cancer immunotherapy

Homocitrullination of lysine residues mediated by myeloid-derived suppressor cells in the tumor environment is a target for cancer immunotherapy

Katherine W Cook, Wei Xue, Peter Symonds, Ian Daniels, Mohamed Gijon, David Boocock, Clare Coveney, Amanda K Miles, Sabaria Shah, Suha Atabani, Ruhul H Choudhury, Poonam Vaghela, Daisy Weston, Rachael L Metheringham, Victoria A Brentville and Lindy G Durrant.
 
ABSTRACT: 
Background  Homocitrullination is the post-translational modification of lysine that is recognized by T cells.
Methods  This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and binding immunoglobulin protein and used human leukocyte antigen (HLA) transgenic mice to assess immunogenicity by enzyme-linked immunosorbent spot assay. Vaccine efficacy was assessed in tumor therapy studies using HLA-matched B16 melanoma expressing constitutive or interferon γ (IFNγ)-inducible major histocompatibility complex class II (MHC-II) as represented by most human tumors. To determine the mechanism behind the therapy, immune cell infiltrates were analyzed using flow cytometry and therapy studies in the presence of myeloperoxidase (MPO) inhibitor and T-cell depletion performed. We assessed the T-cell repertoire to homocitrullinated peptides in patients with cancer and healthy donors using flow cytometry.
Results  Homocitrulline (Hcit) peptide vaccination stimulated strong CD4 T-cell responses and induced significant antitumor therapy in an established tumor model. The antitumor response was dependent on CD4 T cells and the effect was driven mainly via direct tumor recognition, as responses were only observed if the tumors were induced to express MHC-II. In vitro proliferation assays show that healthy donors and patients with cancer have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by MPO inhibition reduced tumor therapy by the vaccine induced T cells (p=0.0018). Analysis of the tumor microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected  B16 melanoma model showed MDSC infiltration and was appropriate to see if the Hcit vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumor and likely reversed the immunosuppressive environment.
Conclusion  We propose that MPO, potentially produced by MDSCs, catalyzes the buildup of cyanate in the TME which diffuses into tumor cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumors containing high levels of MPO expressing MDSCs.
 

 

A novel bivalent DNA vaccine encoding both spike protein receptor-binding domain and nucleocapsid protein of SARS-CoV-2 to elicit T cell and neutralising antibody responses that cross react with variants

A novel bivalent DNA vaccine encoding both spike protein receptor-binding domain and nucleocapsid protein of SARS-CoV-2 to elicit T cell and neutralising antibody responses that cross react with variants

Brentville VA, Vankemmelbeke M, Metheringham RL, Symonds P, Cook KW, Urbanowicz R, Tsoleridis T, Coleman C, Chang K-C, Skinner A, Dubinina E, Daniels I, Shah S, Dixon JE, Pockley AG, Adams SE, Paston SJ, Daly JM, Ball J and Durrant LG.

ABSTRACT: The efficacy of vaccines targeting SARS-CoV-2 is becoming apparent now that the mRNA and adenovirus vector vaccines that have been approved for emergency use are showing promise. However, the longevity of the protective immune response and its efficacy against emerging variants remains to be determined. To improve longevity and future protection against variants, we have designed a DNA vaccine encoding both the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) and its nucleocapsid (N) protein, the latter of which is highly conserved amongst beta coronaviruses. The vaccine elicits strong pro-inflammatory CD4 Th1 and CD8 T-cell responses to both proteins, with these responses being significantly enhanced by fusing the nucleocapsid sequence to a modified Fc domain. We have shown that the vaccine also stimulates high titre antibody responses to RBD which efficiently neutralise in both a pseudotype and live virus neutralisation assay and show cross reactivity with S proteins from the emerging variants Alpha (B.1.1.7) and Beta (B.1.351). This DNA platform can be easily adapted to target variant RBD and N proteins and we show that a vaccine variant encoding the B.1.351 RBD sequence stimulates cross-reactive humoral and T-cell immunity. These data support the translation of this DNA vaccine platform into the clinic, thereby offering a particular advantage for targeting emerging SARS-CoV-2 variants.

 

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.