A Trial of Intra-pleural bacteriaL immunoTherapy in mesothelioma (TILT) – a feasibility study using the trial within a cohort methodology.

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Malignant pleural mesothelioma (MPM) is an incurable, asbestos-related cancer of the chest cavity. Treatment options are limited, although immunotherapy has shown promise in recent trials. This research explored bacterial immunotherapy in MPM, specifically the feasibility and acceptability of a trial of intra-pleural bacterial agents, using an innovative, pragmatic trial design.

Mixed methods were used. The existing literature on intra-pleural bacterial agents in pleural malignancy was summarised. Subsequently, a population-based cohort study was undertaken to examine whether bacteria in the pleural space due to infection were associated with survival in mesothelioma. This was followed by a feasibility study of two intra-pleural bacterial agents in MPM, using the trial within a cohort (TwiC) methodology. Qualitative interviews with participants and their relatives were used to explore experiences of MPM and trial participation.

Previous studies of intra-pleural bacterial agents were methodologically heterogenous and at risk of bias, rendering data synthesis impossible. In contrast to the original hypothesis, pleural infection was associated with shorter survival in mesothelioma, although confounding could have affected this finding.

The trial did not meet the pre-specified recruitment criteria and was therefore deemed unfeasible. Additionally, it was not possible to maintain blinding of control participants and post-randomisation attrition was problematic. Bacterial agents generated significant inflammatory responses but, despite this, the trial processes and methodology were generally acceptable to participants and relatives.

Qualitative interviews revealed that MPM patients sought certainty and absolutes in response to anxiety about their future. This affected their perception of risk and created challenges in communicating uncertainty.

The efficacy of intra-pleural bacterial immunotherapy in MPM remains unproven, but future trials should not employ the TwiC design. Given the importance of quality of life to people with MPM, effective communication about potential side effects and risks of treatment is crucial.
Date of Award26 Nov 2020
Original languageEnglish
Awarding Institution
  • University of Bristol
SponsorsNational Institute of Health Research (NIHR) & North Bristol NHS Trust (NBT)
SupervisorRachael Gooberman-Hill (Supervisor) & Nick A Maskell (Supervisor)


  • Mesothelioma
  • Immunotherapy
  • Pleural
  • Trials within Cohorts

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