Patient-tailored production of leukemia-reactive CD4+ and CD8+ T-cell populations for adoptive immunotherapy

Patient-tailored production of leukemia-reactive CD4+ and CD8+ T-cell populations for adoptive immunotherapy

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative therapy for patients with chemotherapy-refractory acute myeloid leukemia (AML). Its im-munotherapeutic benefit is based on the immunologic graft-versus-leukemia-effect of the donor lymphocytes transferred during transplantation. Unfortunately, this effect is often accompanied by severe and detrimental reactions against vital organs of the patient, and/or sometimes the effect is not strong enough to prevent a leukemia relapse after HSCT. The objective of this project is to develop an officially approved manufacturing protocol for patient-specific leukemia-reactive CD4+ and CD8+ T-cells for infusion into leukemia patients after allogeneic HSCT, with the aim of significantly reducing patients’ risk of graft rejection and leukemia relapse. Preliminary work done by the University Medical Centre in Mainz/ Germany shows that AML-reactive CD4+ and CD8+ T-cells can very reliably be generated in a culture derived from donor lymphocytes. This is achieved by the cytokine-induced stimu-lation of phenotype-naive T-cells from healthy donors against primary AML-blasts from patients with the same tissue characteristics. This laboratory protocol is now being further developed by the University Medical Centre in Mainz using already available good manufacturing practice (GMP) reagents to allow GMP-compliant production of leukemia reactive T-cells to treat patients in the future. At the same time, Miltenyi Biotec is developing reagents and culture devices that are not yet available for clinical use. These consist of a newly designed GMP-compliant isolation reagent for CD45RO-positive cells with which specific naive T-cells from the blood of healthy donors can be isolated, and a GMP-compliant micro-structured cell culture system to improve culture conditions of AML-reactive T-cells and enable the production of sufficient numbers of cells. To date, antigen-specific stimulation and expansion of T-cells from naïve precursors is suboptimal under available GMP-concordant conditions to obtain enough lymphocytes that can be applied to patients. The T-cells produced in this way are tested for efficacy and safety in a humanized mouse model of the University Medical Centre in Mainz. After establishing and validating the GMP protocol by the Red Cross Blood Transfusion Service Baden-Württemberg/Hessen, a manufacturing license will be requested to conduct clinical trials with patient-specific leukemia-reactive donor T-cells beyond the funded CI-3 project.

Keywords 

  • Cellular immunotherapy
  • Leukemia
  • T-cells
  • Stem cell transplantation
  • GMP

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