Immunomonitoring of CTT

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Immunomonitoring of CTT (WG3) will focus on 3 scientific aspects:

1. Identification of immunological biomarkers and COP for CTT immune monitoring

2. Development of standardised immunomonitoring panels for CTT

3. Evaluation of immunomonitoring panels and COPs of CTT

The main objective of the work being carried out in this WG, Immunomonitoring of CTT, is the standardisation of immunomonitoring of CTT as an ancillary to clinical- or surrogate outcomes, e.g. imaging. To achieve this, relevant immunomonitoring parameters have to be identified, assays to be standardised and validated (CE-marked) and applied across trials at multiple centres.

 

1. Identification of immunological biomarkers and Correlates of Protection (COPs) for CTT immune monitoring
This task will focus on the identification of markers to be used for monitoring the immune response upon treatment with CTT. The markers will be divided into 3 groups: a) standard biomarkers independent of type of disease and CTT product used (e.g. pro- and anti-inflammatory cytokines), b) disease- specific biomarkers (e.g. anti-citrullinated protein antibodies for RA) and c) CTT product-specific biomarkers (e.g. CTLA4 for Tregs, ILT3 or ILT4 for tolDCs). Current knowledge on markers for CTT will be gathered using both literature and own experience, ongoing and finished clinical trials, in vitro models and preclinical models. The obtained information will be integrated and critically evaluated.

This task will interact with the ongoing COST Action BM 0907: “ENTIRE: From immunomonitoring to personalised immunotherapy” that will define reference values of the “immunotype” of control (healthy) individuals. A FACTT will also interact with the “ONE Study”, in which immune monitoring of renal transplanted patients treated with different CTT will be performed. Furthermore, A FACTT will approach the ITN to integrate their knowledge and opinion in relation to biomarkers for CTT.

Furthermore, the in vitro effect of CTT products will be analysed in co-cultures of different CTT products with PBMC of candidate patients and controls. In case less standardised techniques are relevant (e.g. micro-RNA analysis), analysis of samples from different centres will be concentrated in single centres. This approach allows for the identification of interesting new biomarkers.

Altogether, this task will gather knowledge on suitable immune monitoring parameters, evaluate these for usefulness in terms of efficacy and applicability as standardised parameter and COP. Subsequently they will be divided in specific parameters to be evaluated in specialised European centres and general parameters to be evaluated by all groups participating in the WG3. The obtained knowledge will be summarised and distributed within the parties and subsequently the defined panels of monitoring parameters will be used in Task 7 and Task 8. Outputs from this Task may define general biomarkers of tolerance, which will be applicable in numerous situations outside of CTT, e.g. weaning of therapy in transplant patients and AID; definition of true immunological remission.

2. Development of standardised immunomonitoring panels for CTT
The goal of this task is to define feasible and standardised immunomonitoring panels for CTT. In vitro and ex vivo approaches will be employed to validate the three types of immunomonitoring panels, defined in the previous task, across different centres. To this end, existing and newly developed SOPs for immunomonitoring techniques will be exchanged. Depending on the nature of the biomarkers, different methodology will be used: e.g. flow-cytometry, functional assays, analysis of soluble factors by ELISA and/or transcriptional signatures in whole blood or leukocyte subsets. Samples will be sent to multiple centres to determine the feasibility to standardise detection of biomarkers (RNA- and protein based markers) in individual centres, always after approval of local Ethic Committees. For cell-based approaches, specific SOPs will be developed for performance and acquisition of data. Analysis will be centralised to a few centres. Furthermore, ex vivo assays and markers will be developed which capture the MoA (resulting from WG1 and WG2) of specific CTT so that these can be used along CTT-based proof-of-concept trials as an important additional outcome parameter (besides e.g. clinical parameters such as disease activity scores) at single- and multiple European centres.

3. Evaluation of immunomonitoring panels and COPs of CTT
In this task, the immunomonitoring protocols developed in the previous task will be applied to ongoing and new trials to improve comparison of results of these trials. Some of the partners of A FACTT are currently ready to start or have already started Phase I/IIa clinical trials in patients. When feasible, samples of peripheral blood of these patients will be (re)-analysed with the newly defined immunomonitoring panels by the groups performing the trials. A thorough analysis of samples of treated patients with CTT will enormously facilitate the definition of common biomarkers for immunomonitoring of CTT and correlation of the immunomonitoring results with the clinical outcome.

 

And as a result of these tasks, A FACTT aimes to achieve:

• Establishment of standardised immunomonitoring protocols, divided in standard/ disease- specific/ and CTT product-specific panels

• Extended knowledge on the MoA of CTT

• Start of evaluation of immune responses to CTT in clinical trials using the developed immunomonitoring protocols

• Furthermore, the immunomonitoring results can be used to improve the quality of CTT products by evaluating the specific clinical outcome in individual studies in an evidence based approach, with the ultimate goal to have standardised production guidelines for each type of CTT, creating the opportunity to compare CTT approaches in a multi-centre fashion.

• Consensus papers on immune monitoring for CTT in journals which focus on clinical studies (i.e. Science Translational Medicine, Journal Transl Med, Clinical Immunology and Journals of the respective disease specific societies).

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