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

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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.

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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.

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

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.

Cancer vaccine:how far are we from curing cancer?

Ruhul Choudhury and Lindy 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.

Novel tumour antigens and the development of optimal vaccine design (2018)

Victoria A Brentville, Suha Atabani, Katherine Cook and Lindy G Durrant

ABSTRACT: The interplay between tumours and the immune system has long been known to involve complex interactions between tumour cells, immune cells and the tumour microenvironment. The progress of checkpoint inhibitors in the clinic in the last decade has highlighted again the role of the immune system in the fight against cancer. Numerous efforts have been undertaken to develop ways of stimulating the cellular immune response to eradicate tumours. These interventions include the identification of appropriate tumour antigens as targets for therapy. In this review, we summarize progress in selection of target tumour antigen. Targeting self antigens has the problem of thymic deletion of high-affinity T-cell responses leaving a diminished repertoire of low-affinity T cells that fail to kill tumour cells. Thymic regulation appears to be less stringent for differentiation of cancer–testis antigens, as many tumour rejection antigens fall into this category. More recently, targeting neo-epitopes or post-translational modifications such as a phosphorylation or stress-induced citrullination has shown great promise in preclinical studies. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Previous vaccines have targeted CD8 T-cell responses but more recently, the central role of CD4 T cells in orchestrating inflammation within tumours and also differentiating into potent killer cells has been recognized. The design of vaccines to induce such immune responses is discussed herein. Liposomally encoded ribonucleic acid (RNA), targeted deoxyribonucleic acid (DNA) or long peptides linked to toll-like receptor (TLR) adjuvants are the most promising new vaccine approaches. These exciting new approaches suggest that the ‘Holy Grail’ of a simple nontoxic cancer vaccine may be on the horizon. A major hurdle in tumour therapy is also to overcome the suppressive tumour environment. We address current progress in combination therapies and suggest that these are likely to show the most promise for the future.

Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial

Poulam M. Patel, Christian H. Ottensmeier, Clive Mulatero, Paul Lorigan, Ruth Plummer, Hardev Pandha, Somaia Elsheikh, Efthymios Hadjimichael, Naty Villasanti, Sally E. Adams, Michelle Cunnell, Rachael L. Metheringham, Victoria A. Brentville, Lee Machado, Ian Daniels, Mohamed Gijon, Drew Hannaman and Lindy G. Durrant

ABSTRACT: A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2–8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (ρ < 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (ρ < 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (ρ = 0.027).

We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.