Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 379

One of the major challenges in the clinical application of stem cells is graft-versus-host disease, which often results after allogeneic transplantation. This obstacle is further complicated by disparities in human leukocyte antigen (HLA) matching, particularly when the stem cell donor is not of the same sex as the recipient, often causing fatal graft-versus-host disease (GVHD). One beneficial role of using allogeneic stem cells is that it elicits a graft-versus-leukemia (GVL) response that eliminates tumor cells, thus facilitating in achieving remission of leukemia. Although GVL is strongly associated with GVHD, these could be fully distinguished from each other. Thus, it is possible for GVL to occur without any indications for GVHD. Research studies have also shown that T cells are capable of differentiating antigens of GVHD and GVL.

Earlier approaches to reducing the mortality rate associated with GVHD in allogeneic HSCT involved the elimination of a majority of the donor T cells in peripheral blood before transplantation. Although this method reduces the risk of developing GVHD, it is also increases the chances for relapse, tissue rejection, and microbial infections. A clinical trial thus examined the effectiveness of selectively excluding only the T cells that are responsible for inducing GVHD and retaining those that facilitate in eliciting a GVL response. The selective removal of T cells entailed coincubation of donor T cells with stimulator cells of the recipient, thus allowing the identification of cells with specific surface markers such as CD25 and CD69. This setting facilitates in recognizing cells based on their rate of proliferation and capacity in retaining photoactive fluorochromes, which can then be used as bases for various cell-targeting techniques such as fluorescence-based cell sorting (FACS), cell separation using magnetic beads, and photodynamic purging.

Using a study population of 16 elderly patients with later-stage hematologic cancer, the selective removal of GVHD-inducing T cells from peripheral blood through the use of cyclosporine and the anti-CD25 immunotoxin was conducted after reduced-intensity conditioning using cyclophosphamide, melphalan, or busulfan in combination with fludarabine. The results of the clinical trial showed that 46 percent and 12 percent of the patients were of grades II to IV and grades III to IV GVHD, respectively, which were relatively lower than previous reports of 58 percent and 34 percent GVHD rates, respectively, using unselected T cells for HSCT allografting.

A more recent clinical trial examined the efficacy and safety of vorinostat in attenuating GVHD in allogeneic HSCT. Vorinostat in combination with standard immunosuppressant drugs (i.e., mycophenolate mofetil and tacrolimus) following reduced-intensity conditioning was administered to a total of 50 patients who were diagnosed with advanced stages of hematologic cancers. The conditioning regimen consisted of fludarabine and busulfan at doses of 40 mg/m²/day for four days and 2 mg/kg/day for two days, respectively. Vorinostat, which inhibits the activity of histone deactylases, was administered approximately 10 days prior to the HSCT and continued for the next 100 days.

The results of the clinical trial showed that 22 percent of the patients showed grades II to IV GVHD, which were still relatively lower than that using non-manipulated T cells. The study participants also developed other non-hematological side effects such as imbalances in electrolyte levels, elevated liver enzyme levels, hyperglycemia, and microbial infections. The significantly lower incidence of acute GVHD suggests that the prophylactic regimen was safe yet required additional testing to examine other possible adverse reactions that could develop using this strategy.

Another recent clinical trial investigated the efficacy and safety of a new regimen for reduced-intensity conditioning to decrease the incidence of GVHD, as well as augment the engraftment of hematopoietic stem cells for allografting. This multicenter, international clinical trial included a total of 56 patients aged 0 to 40 years who have been diagnosed with chronic granulomatous disease. Approximately 21 of these patients had a relative who acted as his or her HLA-matched donor, whereas 35 patients had HLA-matched donors who were not related to them. A majority of the patients (75 percent) were determined to have high-risk characteristics of the disease. The regimen for reduced-intensity conditioning consisted of fludarabine, busulfan, and serotherapy using 10 mg/kg of anti-thymocyte globulin for five days or 2.5 mg/kg thymoglobulin for eight days. HLA matching was based on HLA-9/10. The clinical trial showed a 93 percent total survival and an 89 percent event-free survival at 21 months post-treatment. Predictive calculations indicated a 96 percent total survival rate and a 91 percent event-free survival rate at two years post-treatment. Interestingly, the incidence of GVHD in this cohort was 4 percent for grades III to IV, which is the lowest reported rate to date (as of 2014).