Title: Treating mesothelioma with Intra-pleural Lipoteichoic acid (the TILT Trial): A feasibility study using the ‘Trial within a Cohort’ methodology
Funder: Department of Health and Social Care

Abstract: BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive cancer of the lung lining. It is incurable, with median survival less than 1 year from diagnosis1-7. Chemotherapy extends survival by 2.8 months, but is not suitable for everyone2,4. The UK has the highest mortality rates for MPM worldwide, with 2535 people dying from it in 20123. Incidence is rising, and is predicted to peak in the next decade1,3,4. MPM is an attractive target for immunotherapy as it evades the immune response that usually inhibits tumour growth10-13. MPM suppresses populations of protective T cells in the pleura10-13. The ability to overcome this is associated with longer survival14-17, and drugs that stimulate T cell activity are currently undergoing clinical trials18-23. T cells are stimulated by pleural infection. Observational studies report enhanced survival in patients with lung cancer and pleural infection24-29. A similar phenomenon has been reported in a series of patients with pleural infection and malignant effusions, in which patients with MPM and pleural infection lived over a year longer than non-infected patients30. Intra-pleural bacteria have been used as pleurodesis agents for years, with some demonstrating concomitant anti-tumour activity31-42. Attenuated bacterial agents have been shown to control pleural fluid and prolong survival in malignant pleural effusions secondary to lung cancer43-47. In MPM, mice injected with staphylococcus enterotoxin demonstrated florid T cell responses in association with reduced tumour growth48. This research will investigate lipoteichoic acid (LTAT), a cell wall component of gram positive bacteria that stimulates T cells via Toll-Like Receptors49,50. LTAT induces anti-tumour cytokines in vitro51,52 and causes tumour shrinkage and prolonged survival in mice53,54. In a phase 1 trial in humans, LTAT was associated with low toxicity and high rates of pleurodesis49. LTAT appears to be a promising immunotherapeutic agent that warrants investigation in MPM. STUDY DESIGN This project will investigate intra-pleural LTAT in MPM using an innovative trial design, the Trial within a Cohort (TwiC)55. Participants will be identified from an existing observational cohort, maintained by Bristol Pleural Trials Unit, and invited to participate in enhanced follow-up. From this group, 20 eligible participants will be randomly selected to receive LTAT.The TwiC methodology has many potential benefits for MPM trials, including enhanced recruitment, reduced attrition, a patient-centred consent process and acknowledgement of patient preference55-58. TwiCs have been used in cancer trials and are acceptable to participants and ethics committees56,57,58.AIMSCHAR(13) + CHAR(10) The overall aim of this research is to explore the role of intra-pleural LTAT in people with MPM, and assess the feasibility and acceptability of the TwiC methodology. The study aims to answer the question Is it feasible to undertake a TwiC of intra-pleural LTAT in MPM and is it acceptable to patients and relatives? This question will be answered via 3 work-streams (WS): WS1 is a systematic review of the evidence for intra-pleural bacterial agents in pleural malignancy. WS2 is a feasibility study of intra-pleural LTAT using the TwiC methodology. WS3 is a qualitative study exploring the acceptability of WS2 to participants and their relatives. ANTICIPATED OUTCOMES The results from this research will inform the design of a full-scale efficacy TwiC of intra-pleural LTAT in MPM. WS1 will provide supporting evidence for the trial. WS2 will determine whether a full-scale trial is achievable and will provide preliminary information contributing to its design. WS3 will ascertain whether the TwiC methodology is acceptable to participants and their relatives. As well as investigating a new potential treatment for this incurable disease, this research may support an innovative methodolgy for future MPM research. Therefore, it may improve both the experience and life expectancy of future MPM patients, and facilitate research in this under-researched area.

Lay abstract: INTRODUCTION Mesothelioma is an aggressive cancer that affects the outside lining of the lung. One person dies from mesothelioma every four hours in the UK, and this figure is predicted to rise over the next ten years1-7. Many charities and major funders, including NIHR, have highlighted mesothelioma as an important area of research8,9. Mesothelioma is currently incurable, and chemotherapy extends life by just three months on average1-7. Unfortunately, not everyone can have chemotherapy, as the powerful drugs can do more harm than good in some people2. It is crucial that we find new treatment options that can be offered to everyone with this disease. The immune system identifies and attacks cancer cells within the body. However, mesothelioma hides from the immune system by reducing the number of protective immune cells in the lung lining10-13. People with mesothelioma who can overcome this, and maintain high numbers of immune cells in the lung lining, appear to live longer14-17. The immune system also responds to infection. We have noticed that patients with mesothelioma live longer after having infection in the lung lining30. We think this is because immune cells move to the lung lining to attack the infection, and are able to attack the mesothelioma at the same time. STUDY DESIGN This research aims to assess whether agents that mimic infection (bacterial agents) could be injected into the lung lining to treat mesothelioma. The study will also test a novel research design (Trial within a Cohort) to see whether it can be used in larger mesothelioma trials. The project consists of three work-streams: WS1: Summary of existing research Bacterial agents were first used in the 1950s, with varying degrees of success. More recently newer agents have been tested in people with cancer. The results are inconsistnet because each trial used different methods and different analyses.WS1 will review all these trials and assess how reliable the results are. We will then combine all the information and hopefully get a reliable answer as to whether these agents are effective at treating cancer. WS2: A test' trial of a bacterial agent This will be a trial of a bacterial agent called LTAT. The trial will use a novel design that aims to replicate real-life clinical practice, and to take patients' wishes into account. The aim is to see whether this design could be used in a larger trial of LTAT in mesothelioma. We have a database (cohort) of patients treated by us since 2008. From this cohort we will invite people with mesothelioma to participate in an observational study, with regular assessments, blood tests and CT scans. From these people, 20 people will be randomly chosen to be offered LTAT. The rest of the group won't be told about LTAT, because in real-life, doctors don't tell patients about treatments they won't receive. They will act as a comparison group. All participants will be followed up with the same tests. At the end of the trial we assess various practical issues relating to the trial, e.g. how long it took to recruit participants, how many people agreed to receive LTAT and how many people completed the trial.The aim is to decide whether it would be possible to do the same trial on a larger-scale.Medical information collected during WS2 will be used to decide which measurements we should use in the larger trial. This information will also help decide how many people will be needed in the subsequent trial. WS3: Interviews with participants and relatives We will interview a selection of participants from WS2 and their relatives/carers to ask what it was like to participate in the research, whether they had any problems with it, and what could be done differently in future. We hope to gain insight into participants' experiences of the test' trial that will help us make the subsequent trial acceptable, and attractive to future participants. The results of this research will be used to decide whether a larger trial of LTAT in mesothelioma is possible and whether this trial design is the right one to use. We hope, eventually, to show that LTAT is an effective treatment for mesothelioma, and that this research design can be used for future trials. COMMUNICATION We will present our results at patient support groups and publish them in the British Lung Foundation patient newsletter. We will display the results on the MesoWarriors Facebook page.We will present the results at international conferences and submit the final scientific articles for publication in high impact, peer-reviewed journals.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS