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T-CONTROL Report Summary

Project ID: 601722
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 2 - T-CONTROL (Donor T Cells for Immune Control)

Project Context and Objectives:
Patients with high-risk hematological tumors can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). However, the main causes of failure of HSCT are infections, tumor relapse and over-shooting immune responses of the donor T cells to healthy cells and tissues of the patient or graft-versus host disease (GvHD). Therefore, this treatment is still associated with a high morbidity and mortality, as well as a high economic burden.
Continuing from ALLOSTEM, the main objectives of T-Control were to develop two Streptamer-based GMP (good manufacturing practice) compliant cell selection processes and their corresponding cell products within a three-year project duration. The products are a multi virus- and a tumor-specific CD8+ T cell product (“multi specific T-cell product”), to boost immune function post-transplant for the treatment of infections and residual/recurrent tumor cells after HSCT, and a pT-reg product to suppress the immune function post-transplant for the treatment of GvHD after HSCT. The rationale for developing this product was the urgent medical need to provide treatment options for the two main causes of allogeneic HSCT failure (insufficient immune response to viruses and tumors). This product was successfully developed also in the context of GvHD. Both cell products were planned to be generated using the same cell selection technology (Streptamer technology), but with different aim, namely to meet these two different, major clinical needs. One product should be used to boost insufficient immune responses to infections and residual tumor and the other should suppress overshooting immune responses causing GvHD to improve the outcome of allogeneic HSCT in general.
Based on the results generated so far the T-Control consortium will be able to achieve the first objective, i.e. to produce a multi antigen specific T cell product under GMP conditions and finalisation of the respective clinical trial. Due to the hurdles occurred during the generation of cord blood derived pT-regs by using the Streptamer technology, and also from adult peripheral blood as way-out strategy, the new objective of T-Control is to further develop the pT-reg product but not to initiate a clinical trial. The goal will be to have a clinical product available at the end of the project which will be then used for a clinical trial in another project.

Project Results:
The main causes of failure of allogeneic stem cell transplantation are infections, tumor relapse and over-shooting immune responses of the donor T cells to healthy cells and tissues of the patient (graft-versus host disease).
Following the pre-clinical work on lab scale, also large scale simultaneous isolation of multi antigen specific T cells (mainly virus-specific T cells: HCMV, EBV and Adeno-virus-specific T cells) from the memory repertoire of healthy donors plus the isolation of minor histocompatibility antigen (MiHA) and tumor associated antigen (TAA) specific T cells from the naïve repertoire of healthy donors was established. The protocol of simultaneous isolation of multi antigen specific T cells was then submitted to the Dutch and the German regulatory authorities and the protocol approved in the Netherlands 2015 and after several modifications also by the German authorities in early 2016. 17 patients who had undergone a T cell depleted allograft received the multi antigen specific T cell product so far. With a still short follow up no severe acute graft versus host disease was observed in any of these patients.
Thus, the first aim of T-Control, i.e. a multi-specific T cell product targeting several viruses and residual tumor cells to improve infection and tumor control post-transplant, was successfully achieved. With the products, a clinical trial has been initiated which will allow the product to be developed to market maturity and help to improve the outcome of allogeneic HSCT.
In another work package a protocol allowing the isolation of pT-regs using only 100 to 400x10^6 starting total nucleated cells (TNC) from fresh whole cord blood (CB), using CD25 specific Streptamers was developed. Streptamer-based isolation of Tregs was then optimised for the isolation of CD25+ Tregs from frozen CB units. Tregs characterised phenotypically by flow cytometry as CD4+CD25+CD127low FOXP3+ were obtained at a purity of 74 – 94% and an efficiency of 3 – 20.3%. A SOP describing the isolation of pT-regs from whole CB using CD25 Streptamers was written and submitted and a quality control SOP of the pT-reg cell product was established and submitted, too. In addition, suppressive activity of the Tregs could be documented. A protocol allowing monitoring the p-Treg infused in the patients as well as assessing the proportion of lymphocyte populations present by flow cytometry was designed for a minimal cell requirement assessment of a sample received from the patient. A SOP for pT-regs monitoring was written based on the RBC lysis method and submitted.
Selection was performed in lab scale and the resulting regulatory T cells were also shown to suppress alloreactivity. Unfortunately, after up-scaling in the protocol for clinical application the resulting Tregs were found to loose CD25 expression on the cell surface and also their suppressive activity. As the way out strategy the streptamer technology was applied to select regulatory T cells from adult peripheral blood. But again only very low cell numbers and a lack of purity of the anticipated clinical product after up-scaling of the process remained limiting. Therefore, with no product to hand meeting the requirements of the competent German authority (PEI), regulatory proof could not be obtained and thus no clinical trial could be initiated and patients were not treated with regulatory T cells.

Potential Impact:
Immune cell-based therapy consists of infusion of cells to modulate immunity by inducing, enhancing, or suppressing an immune response. As a proof of principle, we chose hematopoietic stem cell transplantation (HSCT) as the main focus of this proposal. Registries record more than 50,000 HSCTs being performed annually worldwide and this corresponds to more than 25,500 cases annually in Europe. Transplant-related mortality still ranges between 10 and 60% depending on the age and co-morbidities of the patient the underlying malignancy and the matching between donor and patient. The estimated cost of a transplant is around 80,000€, however, when adverse outcomes are encountered, the costs escalate rapidly. This consortium aims to improve the general outcome of HSCT and to develop strategies to reduce HSCT-related complications, thus leading to cost-savings for hospitals and for the EU. With the transfer of a multi antigen specific T cell product developed in WP1 after a T cell depleted HSCT in the clinical trial (WP3) we could show in already 17 patients treated that the incidence of a GvHD could be significantly reduced. By reducing the incidence of acute and chronic graft versus host disease but preventing infectious complications - the two most common complications of allogeneic stem cell transplantation - this could significantly reduce morbidity and mortality for patients undergoing allogeneic stem cell transplantation as well as reduce the main cost drivers for HSCT.
The societal impact of this project is to use selected cellular products derived from T cell subsets from the donor to improve the outcome of allogeneic HSCT. We will expand the number of patients who will benefit from immune cell-based therapies based on (a) an effective immune response against tumor cells, (b) providing protective immunity against opportunistic infections, (c) improving transplant procedures to reduce its risks and to optimize its benefits by the use of subsequent immunotherapy and (d) creating interactions between European populations through donor registries and typing centers. The resultant social benefits will be achieved, in the long-term, via an increased cure of diseases with a high incidence and a consequent decrease in treatment costs and losses, because of a reduction in productivity. The academic/industry partnership is likely to generate commercially valuable intellectual property that may create employment through facilitation of European enterprises in the area of health care. Thus both an improvement in the health care for EU citizens and the development of new technology based pharmaceuticals that can be exploited worldwide will be achieved.
The cell products have the potential to address other indications with currently incurable diseases. For example the multi-specific T cell product is planned to be tested in the treatment of solid tumors (melanoma, renal cell carcinoma, etc.). Currently, the mostly inefficient treatments for these indications are associated with severe side effects. In contrast to cell therapeutics, conventional drugs are dosed in short intervals; cell medications are dosed in long intervals if not once with significantly less side effects. European patients will benefit from these therapeutic means by gaining a better overall survival and a better quality of life.
Spectacular advances of cell therapy of solid tumors such as melanoma have been reported. In this rapidly evolving field the T-control products can make a significant medical and economic contribution. JUNO will license out certain indications to interested pharma partners that have the ability to quickly develop and commercialize the products. The entrance of big pharma companies in the field of cell therapy will boost the development of the anticipated cell products in important indications and their economic impact in Europe and worldwide.

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Life Sciences
Record Number: 189259 / Last updated on: 2016-09-20
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