Simple SummaryCytotoxic T lymphocytes (CTLs) play an important role in controlling tumours, and an improved understanding of how they accomplish this will benefit immunotherapeutic cancer treatment... Show moreSimple SummaryCytotoxic T lymphocytes (CTLs) play an important role in controlling tumours, and an improved understanding of how they accomplish this will benefit immunotherapeutic cancer treatment strategies. Stimulation of CTLs by targeting their CD137 receptor is a strategy currently under investigation for enhancing responses against tumours, yet so far only limited quantitative knowledge regarding the effects of such stimulation upon CTLs has been obtained. Here, we develop mathematical models to describe dynamic in vivo two-photon imaging of tumour infiltrating CTLs, to characterise differences in their function either in the presence or absence of a CD137 agonist antibody. We showed that an increased antiproliferative effect and a more sustained presence of CTLs within the tumour were the most important effects associated with anti-CD137 treatment.Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. Moreover, we found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation. Show less
Wijk, R.C. van; Sar, A.M. van der; Krekels, E.H.J.; Verboom, T.; Spaink, H.P.; Simonsson, U.S.H.; Graaf, P.H. van der 2020
The zebrafish infected with Mycobacterium marinum is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis infections in humans. To translate... Show moreThe zebrafish infected with Mycobacterium marinum is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and MUSA, is studied over an extended period using an established model‐based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm‐derived strain E11 and human‐derived strain MUSA were grown undisturbed up to 221 days and viability of cultures (CFU/mL) was determined by plating at different time points. Non‐linear mixed effects modelling using the MTP model quantified the bacterial growth, the transfer between fast‐, slow‐, and non‐multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20‐25 days for E11 and MUSA, respectively, followed by a decrease to a new plateau. Natural growth of both E11 and MUSA was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow‐multiplying state, for MUSA in the fast‐multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, while MUSA showed more aggressive growth behaviour. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of anti‐tuberculosis drug development. Show less
