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Control of wayward cells after transplantation

Therapeutic cell transplantation could carry many potential risks for the patients, such as improper migration, excess proliferation, malignant transformation and other possible complications [1]. We have to minimize their occurence and try to move the risk/benefit ratio in favor of the patient. There are many approaches experimentally developed to minimize the risk of adverse events from transplanted cells, but most of them are based on co-introduction with genes that, when turned on by a drug, will lead to their complete elimination. The “proof-of-principle” study [2], recently published in Lancet Oncology [3], demonstrates that a concept like this is really able to work in clinic.

Allogeneic hematopoietic stem cell transplantation with unmanipulated graft for leukemia treatment is frequently complicated by severe graft-versus-host disease (GVHD) due to HLA mismatch. T-cell depleted graft usually prevents this reaction after transplantation, but frequently leads to severe immunodeficiency and high mortality due to infections. Donor-derived immune cells (T-cell clones, NK, mesenchymal stem cells, T-regs) post-transplant infusions attempted to improve immune reconstitution without GVHD in many clinical trials.

The authors of international phase I-II clinical trial [4] used donor T-lymphocytes, which were engineered to express a suicide gene for treatment of patients with high-risk leukemia.

28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene.

This study showed [5] that gene-modified and ex vivo expanded T-cells from the same donor induce immune reconstitution after haploidentical stem cell transplantation. The early reconstitution of immune system and protection against infections was achieved mostly exclusively by T-cell gene therapy, although long-term reconstitution was largely from T-cell depleted (CD34+ enriched) graft.

A truncated form of the human nerve growth factor receptor (NGFR) was used as a “tag” to enable genetic control of wayward cells after transplantation. This is the first “cell tag” technology that has entered to clinical trial phase so far. Using this approach transplanted T-cells were successfully eliminated in case of GVHD development, after they did their job – short-term immune reconstitution.

Because this technique combined gene and cell therapy, potential risks of therapy for the patient are increased and protocols required strict regulatory issues. Many aspects of risk/benefit assessment in cell therapy, genetic control of wayward cells and regulatory issues are discussed in this recent review [1].

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