Cancer vaccine:how far are we from curing cancer?

Ruhul Choudhury and Lindy Durrant

Healthy individuals have a repertoire of CD4 cells that recognize and respond to citrullinated peptides - a possible new target for cancer immunotherapy?

Ruhul Hasan Choudhury, Ian Daniels, Vicky Brentville, Katherine Cook, Peter Symonds, Poonam Bilimoria, Suha Atabani, Rachael Metheringham, Lindy Durrant 

CRI 2018 : Post translationally modified homocitrulline induced by MDSCs can be an effective anti-tumour target for CD4 T cells

K. Cook, W. Xue, P. Symonds, M. Gijon, P. Vaghela, R. Choudhury, S. Shah, S. Atabani, R. Metheringham, V. Brentville, L. Durrant 

CRI 2018 : Pre-existing citrulline specific CD4 T cells can be efficiently harnessed for tumour therapy

V. Brentville, P. Symonds, K. Cook, I. Daniels, S. Atabani, R. Choudhury, P. Vaghela, R. Metheringham, M. Gijon, W. Xue, L. Durrant

CRI 2018 : Targeting gastrointestinal tumors with constant region-engineered anti-glycan antibodies

M. Vankemmelbeke, T. Kirk, C. Papagregoriou, S. Aziz, J.X. Chua, R.S. McIntosh, L.G. 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.

CRI 2017 Peptide/TLR agonist conjugates poster

V. Brentville, K. Cook, P. Symonds, G.G. Zom, W. Xue, R. Metheringham, W-J. Krebber, C.J.M. Melief and L.G. Durrant

CRI 2017 Modi-1, a novel cancer vaccine

L. G. Durrant, R. Metheringham, I. Daniels, K. Cook, P. Symonds, T. Pitt, W. Xue, M. Gijon and V. Brentville

SCIB1 combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors (2016)

Wei Xue, Victoria A. Brentville, Peter Symonds, Katherine W. Cook, Hideo Yagita, Rachael L. Metheringham and Lindy G. Durrant

ABSTRACT:

Purpose: We have previously shown that supraoptimal signaling of high avidity T cells leads to high expression of PD-1 and inhibition of proliferation. This study was designed to see if this effect could be mitigated by combining a vaccine that stimulates high avidity T cells with PD-1 blockade.

Experimental Design: We investigated the anti-tumor effect of a huIgG1 antibody DNA vaccine (SCIB1) and PD-1 blockade.

Results: Vaccination of HLA-DR4 transgenic mice with SCIB1 induced high frequency and avidity T cell responses that resulted in survival (40%) of mice with established B16F1-DR4 tumors. SCIB1 vaccination was associated with increased infiltration of CD4 and CD8 T cells within the tumor but was also associated with upregulation of PD-L1 within the tumor environment. PD-1 blockade also resulted in increased CD8 T cell infiltration and an anti-tumor response with 50% of mice showing long term survival.In line with our hypothesis that PD-1/PD-L1 signaling results in inhibition of proliferation of high avidity T cells at the tumor site, the combination of PD-1 blockade with vaccination, enhanced the number and proliferation of the CD8 tumor infiltrate. This resulted in a potent anti-tumor response with 80% survival of the mice.

Conclusions: There is a benefit in combining PD-1 blockade with vaccines that induce high avidity T cell responses and in particular with SCIB1.

PIVAC 2016 SCIB1 Clinical Trial Poster

L.G. Durrant, C. Ottensmeier, C. Mulatero, P. Lorigan, R. Plummer, R. Metheringham, V.Brentville, S. Adams, L. Machado, I. Daniels, D. Hannaman and P.M. Patel 

PIVAC 2016 Adjuvants for Moditope Poster

Katherine Cook, Peter Symonds, Victoria Brentville, Rachael Metheringham,  Wei Xue and Lindy Durrant

PIVAC 2016 Citrullinated Alpha Enolase Poster

K. Cook, I. Daniels, V. Brentville, R. Metheringham, W. Xue, P. Symonds, T. Pitt, M.Gijon and L. Durrant

PIVAC 2016 Protein Arginine Deiminase Enzymes Poster

R. Metheringham, M. Gijon, I. Daniels, K. Cook, P. Symonds, T. Pitt, W. Xue, V. Brentville and L. Durrant

SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes (2016)

Wei Xue, Rachael L. Metheringham, Victoria A. Brentville, Barbara Gunn, Peter Symonds, Hideo Yagita, Judith M.  Ramage and Lindy G. Durrant

ABSTRACT: Checkpoint blockade has demonstrated promising antitumor responses in approximately 10–40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®
: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NYESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.