Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Morath, Christian
Schmitt, Anita
Kleist, Christian
Daniel, Volker
Opelz, Gerhard
Süsal, Caner
Ibrahim, Eman
Kälble, Florian
Speer, Claudius
Nusshag, Christian
Pego da Silva, Luiza
Sommerer, Claudia
Wang, Lei
Ni, Ming
Hückelhoven-Krauss, Angela
Czock, David
Merle, Uta
Mehrabi, Arianeb
Sander, Anja
Hackbusch, Matthes
Eckert, Christoph
Waldherr, Rüdiger
Schnitzler, Paul
Müller-Tidow, Carsten
Hoheisel, Jörg D.
Mustafa, Shakhawan A.
Alhamdani, Mohamed S.S.
Bauer, Andrea S.
Reiser, Jochen
Zeier, Martin
Schmitt, Michael
Schaier, Matthias
Terness, Peter

¹Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
²TolerogenixX GmbH, Heidelberg, Germany.
³Department of Hematology, Oncology and Rheumatology,
⁴Transplantation Immunology, Institute of Immunology,
⁵Department of Nuclear Medicine,
⁶Department of Clinical Pharmacology and Pharmacoepidemiology,
⁷Department of Gastroenterology,
⁸Department of General, Visceral and Transplantation Surgery,
⁹Institute of Medical Biometry and Informatics,
¹⁰Institute of Pathology, and
¹¹Virology, Center for Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany.
¹²Division of Functional Genome Analysis, DKFZ, Heidelberg, Germany.
¹³Kurdistan Institution for Strategic Studies and Scientific Research, Kurdistan Region, Iraq.
¹⁴Department of Medicine, Rush Medical College, Rush University, Chicago, Illinois, USA.

Address correspondence to: Christian Morath, Department of Nephrology, Heidelberg University Hospital, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Phone: 49.6221.9112.207; Email: [email protected].

Authorship note: CM and A. Schmitt are co–first authors. M. Schaier and PT are co–senior authors.

Received September 23, 2019

Accepted January 22, 2020

Journal of Clinical Investigation 130(5):p 2364-2376, May 1, 2020. | DOI: 10.1172/JCI133595

BACKGROUND

Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.

METHODS

In this phase I trial, patients received either 1.5 × 10⁶ MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 10⁸ MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.

RESULTS

MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 10¹⁰ donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19⁺CD24^hiCD38^hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.

CONCLUSION

MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.

TRIAL REGISTRATION

EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220.

FUNDING

Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.