ABSTRACT:  Presentation at the 20th International Congress of the Society for Melanoma Research - Philadelphia, November 6th - 9th, 2023

Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Sarah Danson, Dennis Hadjiyiannakis, Clare Barlow, Martin Highley, Amna Sheri, Amanda Fitzpatrick, Ioannis Karydis, Maria Marples, Robert Miller, Fayaz Master and Lindy Durrant

A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE trial

Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Sarah Danson, Martin Highley, Clare Barlow, Robert Miller, Fayaz Master and Lindy Durrant

Modi-2, a vaccine targeting homocitrullinated self-epitopes, stimulates potent CD4-mediated anti-tumour responses as a therapy for solid cancers

Abdullah Al-Omari, Katherine Cook, Peter Symonds, Anne Skinner, Yaling Zhu, Vince Coble, Nazim Uddin, Priscilla Ranglani, Adrian Parry, Sally Adams, Geoffrey Lynn, Lindy Durrant and Victoria Brentville

Vaccination stimulating post-translational modification specific Th1 responses repolarises the tumour environment to reduce suppressive LAP expressing T cells

Suha Atabani, Katherine Cook, Peter Symonds, Ian Daniels, Ruhul Choudhury, Alissa Wright, Anne Skinner, Victoria Brentville and Lindy Durrant

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Sabaria Shah, Abdullah Al-Omari, Katherine W Cook, Samantha J Paston, Lindy G Durrant and Victoria A Brentville

ABSTRACT:
Complex cellular interactions between the immune system and cancer can impact tumour development, growth, and progression. T cells play a key role in these interactions; however, the challenge for T cells is to recognize tumour antigens whilst minimizing cross-reactivity with antigens associated with healthy tissue. Some tumour cells, including those associated with viral infections, have clear, tumour-specific antigens that can be targeted by T cells. A high mutational burden can lead to increased numbers of mutational neoantigens that allow very specific immune responses to be generated but also allow escape variants to develop. Other cancer indications and those with low mutational burden are less easily distinguished from normal tissue. Recent studies have suggested that cancer-associated alterations in tumour cell biology including changes in post-translational modification (PTM) patterns may also lead to novel antigens that can be directly recognized by T cells. The PTM-derived antigens provide tumour-specific T-cell responses that both escape central tolerance and avoid the necessity for individualized therapies. PTM-specific CD4 T-cell responses have shown tumour therapy in murine models and highlight the importance of CD4 T cells as well as CD8 T cells in reversing the immunosuppressive tumour microenvironment. Understanding which cancer-specific antigens can be recognized by T cells and the way that immune tolerance and the tumour microenvironment shape immune responses to cancer is vital for the future development of cancer therapies.

Modi-1, anti citrullinated neoepitope vaccine alone and combined with checkpoint inhibitors in patients with head and neck, breast, renal and ovarian cancers: ModiFY Phase 1/2 basket clinical trial: report after completion of monotherapy dose finding

Christian Ottensmeier, David J Pinato, Rebecca Herbertson, Anne Armstrong, Stefan Symeonides, Poulam Patel, Sarah J Danson, James Korolewicz, David Cameron, Robert Miller, Fayaz Master, Samantha Paston, Lindy Durrant

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

ABSTRACT:
Although the efficacy of vaccines targeting SARS-CoV-2 is apparent now that the approved mRNA and adenovirus vector vaccines are in widespread use, the longevity of the protective immune response and its efficacy against emerging variants remains to be determined. We have therefore designed a DNA vaccine encoding both the SARS-CoV-2 spike receptor binding domain (‘RBD’) and nucleocapsid proteins, 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 in mice and rats, with 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 in mice that efficiently neutralise in pseudotype and live virus neutralisation assays and show cross reactivity with spike proteins from the variants B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). The vaccine also showed good protection in a viral challenge model in ACE2 receptor transgenic mice. This DNA platform can be easily adapted to target variant proteins and we show that a vaccine variant encoding the Beta variant sequence stimulates cross-reactive humoral and T cell responses. These data support the translation of this DNA vaccine platform into the clinic, thereby offering a particular advantage for rapidly targeting emerging SARS-CoV- 2 variants.

Modi-1, anti citrullinated neoepitope vaccine alone and combined with checkpoint inhibitors in patients with Head and Neck, Breast, Renal and Ovarian Carcinoma: Protocol for the ModiFY Phase I/II Basket Clinical Trial

Lindy Durrant, Fayaz Master, Samantha Paston, Robert Miller, David J Pinato, Rebecca Herbertson, Anne Armstrong, Stefan Symeonides, Christian Ottensmeier