Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Abstract

Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cellmediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.

A phase I/II trial of interleukin-15–stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors

“…The administration of CsA was tapered as soon as possible. NK cell activity after stem cell transplantation has been shown to have potential activity against leukemia but also Ewing sarcoma [38,39]. Previous reports demonstrate that NK cells cultured in the presence of CsA retained their cytotoxic capabilities [40e44].…”

In vitro immunotherapy potency assays using real-time cell analysis

“…In summary, the real-time impedance-based platform and reagents described in this paper provides a sensitive, robust and reproducible assay system that can be used for quantitative assessment of different immunotherapy approaches in vitro [ 38 – 41 ]. Despite the fact that various groups have already incorporated this technology for assessment of BiTEs and bispecific antibodies [ 25 , 26 ] oncolytic viruses [ 42 , 43 ], NK-mediated cytolysis [ 44 , 45 ] and for assessment of engineered T cells such as CAR-T [ 10 , 46 , 47 ], the new adaptation to suspension cancer cells and the companion immunotherapy analysis software promises to further extend and accelerate the adoption of the technology for immunotherapy approaches. While the assay can be used during the research and development phases of different immunotherapies, it can also be incorporated as part of the manufacturing process for batch release of different types of immunotherapy reagents.…”

Donor lymphocyte infusions in adolescents and young adults for control of advanced pediatric sarcoma

“…We hypothesize that allo-SCT does not constitute an endpoint but a starting point of immunotherapy in a subgroup of patients yet to be defined. Several reports such as the use of adjuvant tumor lysate-pulsed dendritic cell vaccination in patients after standard antineoplastic treatment [ 18 ] as well as the use of natural killer (NK) cells raise hope that ES may become targetable with immunotherapy [ 19 , 20 ]. In the present analysis, 4 out of 8 patients responded to treatments including DLI.…”

“…Eliciting a pro-inflammatory environment using allo-SCT may lead to enhanced phagocytic, NK cell as well as T cell activity [ 22 ]. In this regard, there is supporting evidence that alloreactive NK cells play a role in controlling minimal residual disease (MRD) in leukemia and solid pediatric tumors and are discussed to prolong survival after haploidentical allo-SCT compared to a HLA-matched setting [ 19 ]. A recent analysis showed even lower rates of chronic GvHD rates and similar survival outcomes of haploidentical allo-SCT compared to matched sibling or unrelated donor transplants by implementing post-transplantation cyclophosphamide [ 23 ].…”