A large international study coordinated by University Hospital Regensburg and Charité – Universitätsmedizin Berlin has demonstrated the safety of new cell therapy approaches for use in kidney transplant recipients. Transplant recipients were shown to require lower levels of immuno-suppression in order to prevent organ rejection. This reduces the risk of side effects such as viral infections.
Transplant recipients usually receive immuno-suppressants to prevent organ rejection. However, these drugs cannot provide an absolute guarantee that rejection will not occur at a later stage. Furthermore, immuno-suppression is often associated with severe side effects such as intolerances, infections, or other problems. Cell therapy offers an alternative treatment approach. This involves the use of specific immune cells, which are isolated and expanded in vitro. Known as ‘regulatory cell products’, these cells are then infused into the transplant recipient in order to restore their immune system.
Charité was one of a number of institutions involved in the international ONE Study consortium, which was led by Professor Dr Edward K Geissler of University Hospital Regensburg. The Berlin-based members of the consortium were primarily responsible for testing the safety and efficacy of cell therapy in kidney transplant recipients as well as effects on their immune system. Research centres based in several different countries worked to a standardised protocol to develop a range of regulatory cell products, which were then tested in clinical trials. These therapies, which were administered to transplant recipients either before or after their surgery, comprised regulatory T cell and macrophage products, as well as products made of dendritic cells, which produce anti-inflammatory messengers. Results were then combined and compared with a reference patient group who had received standard-of-care immuno-suppression. Patients were then followed up for a further 60 weeks.
“The new cell therapy was able to reduce the need for immuno-suppression in approximately 40 percent of patients, thereby minimising the risk of side effects,” says the study’s first author, Professor Dr Birgit Sawitzki of the Institute for Medical Immunology on Campus Virchow-Klinikum. The regulatory cells were shown to be just as safe as the drugs used in standard treatment and did not result in higher rejection rates. “Particularly remarkable was the fact that none of the patients given regulatory cells developed herpes infections, which often lead to dangerous complications in transplant recipients,” notes Sawitzki.
Sawitzki’s team was primarily responsible for the development and implementation of standardised immune monitoring – the monitoring of immune cell populations in the blood. “Before transplantation, patients showed altered immune cell composition, and regulatory cells were better than standard therapy at restoring normal composition,” explains Sawitzki. She adds: “This means there are new, safe treatment options which can help to reduce the dose of conventional immuno-suppressants and the risk of viral infections.” There are plans for further, larger studies to confirm the efficacy of regulatory cell therapy.
Background: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.
Methods: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232.
Findings: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT.
Interpretation: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.
Funding: The 7th EU Framework Programme
Birgit Sawitzki, Paul N Harden, Petra Reinke, Aurélie Moreau, James A Hutchinson, David S Game, Qizhi Tang, Eva C Guinan, Manuela Battaglia, William J Burlingham, Ian S D Roberts, Mathias Streitz, Régis Josien, Carsten A Böger, Cristiano Scottà, James F Markmann, Joanna L Hester, Karsten Juerchott, Cecile Braudeau, Ben James, Laura Contreras-Ruiz, Jeroen B van der Net, Tobias Bergler, Rossana Caldara, William Petchey, Matthias Edinger, Nathalie Dupas, Michael Kapinsky, Ingrid Mutzbauer, Natalie M Otto, Robert Öllinger, Maria P Hernandez-Fuentes, Fadi Issa, Norbert Ahrens, Christoph Meyenberg, Sandra Karitzky, Ulrich Kunzendorf, Stuart J Knechtle, Josep Grinyó, Peter J Morris, Leslie Brent, Andrew Bushell, Laurence A Turka, Jeffrey A Bluestone, Robert I Lechler, Hans J Schlitt, Maria C Cuturi, Stephan Schlickeiser, Peter J Friend, Tewfik Miloud, Alexander Scheffold, Antonio Secchi, Kerry Crisalli, Sang-Mo Kang, Rachel Hilton, Bernhard Banas, Gilles Blancho, Hans-Dieter Volk, Giovanna Lombardi, Kathryn J Wood, Edward K Geissler
Charité – Universitätsmedizin Berlin material
The Lancet abstract