Haploidentical Stem Cell Transplantation in Patients with Pediatric Solid Tumors: Preliminary Results of a Pilot Study and Analysis of Graft versus Tumor Effects

Abstract

Pediatric patients with relapsed metastatic tumors have a poor prognosis and new treatment strategies are warranted. We present preliminary results of a pilot study, evaluating the feasibility and toxicity of transplantation of haploidentical T and B cell depleted grafts with high numbers of NK cells. 6 patients with relapsed metastatic neuroblastomas (n = 4), rhabdomyosarcoma (n = 1) or Ewing's sarcoma (n = 1) after previous autologous transplantation received CD3/CD19 depleted grafts from mismatched family donors with a median number of 16 x 10 (6)/kg stem cells, 167 x 10 (6)/kg Natural Killer cells and only 5.4 x 10 (4)/kg residual T cells. A melphalan-based, reduced intensity conditioning was used. Despite pretransplant chemotherapy, patients entered transplantation with significant tumor burden. Primary engraftment occurred in 6/6 patients. One patient had secondary graft failure. Hematopoietic recovery was rapid (ANC > 0.5 x 10 (9)/L: 11 days (9-12); independence from platelet substitution: 8 days (7-11)). Four patients had acute GvHD grade II, limited chronic GvHD was observed in 2 patients. No transplant-related mortality and only low toxicity occurred. Four patients died from progression, two patients are alive. Overall median survival time is 6 months (2-11) to date. Analysis of posttransplant NK cell function revealed stable cytotoxic activity against K562 targets, whereas activity against neuroblastoma targets was low. Stimulation with cytokines and use of appropriate antibodies clearly enhanced specific lysis in vitro. In summary, these preliminary results indicate the feasibility and low toxicity even in intensively pre-treated patients with neuroblastomas/sarcomas. This approach may form the basis for posttransplant immunomodulation and other therapeutic strategies. Further experience is warranted to evaluate the method.

Haploidentical SCT in children: an update and future perspectives

“…34,39 Moreover, possible graftversus-tumor effects after haplo-SCT are currently evaluated in children with relapsed solid tumors. 15,56,57 In summary, haploidentical transplantation has been markedly improved by technical advances and consecutive clinical studies. Further efforts will be necessary to evaluate the advantages and limitations of this interesting approach.…”

Reduced‐intensity allogeneic stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation

“…HaploSCT has proven to be feasible and to involve acceptable toxicity in children with hematologic malignancies [33,34]. Although reports concerning haploSCT for NB are still limited, a potential GVT effect has been suggested with low toxicity [12,13,29,30]. Two patients in the present study also received haploSCT.…”

“…Two patients in the present study also received haploSCT. While most previous haploSCT for NB involved T and B cell-depleted grafts or CD34 þ cells [12,13,29,30], we used unmanipulated grafts and included ATG in the conditioning. Although the tumor progressed after haploSCT, regimen-related short-term toxicity was manageable, complete donor chimerism was successfully achieved, and acute GVHD was mild in the present study.…”

“…The graft-versus-leukemia (GVL) effect is a widely accepted major component of alloSCT in leukemia [10], and there is emerging evidence for a GVT effect in solid tumors [11]. A GVT effect has been also demonstrated in patients with advanced NB who received alloSCT [12][13][14][15]. However, regimen-related mortality following standard alloSCT with an intensive conditioning regimen may be extremely high in patients who have been already heavily treated [16][17][18].…”

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

“…Another study also suggests the feasibility of using haplo-SCT in the pediatric population with advanced neuroblastomas/sarcomas. 12 However, the utility of haploidentical HSCT for the treatment of RCC have not been yet evaluated in the clinical studies. Here, we report the efficacy of haplo-SCT in RCC-bearing recipients in murine models.…”