Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT.

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated the ability of this relatively safe transplant modality to eliminate autoimmune T-cell clones in the NOD mouse model which spontaneously develop T1DM. Our results demonstrate that using this approach, marked durable chimerism is attained, without any transplant-related mortality, and with a very high rate of diabetes prevention. TCR sequencing of transplanted mice showed profound changes in the T-cell repertoire and decrease in the prevalence of specific autoimmune T-cell clones directed against pancreatic antigens. This approach could be considered as strategy to treat people destined to develop T1DM but with residual beta cell function, or as a platform for prevention of beta cell destruction after transplantation of allogenic beta cells.

Case report: Robust response of metastatic clear cell sarcoma treated with cabozantinib and immunotherapy.

Clear Cell Sarcoma (CCS), also referred to as malignant melanoma of soft parts, is a rare and aggressive malignant tumor. It comprises 1% of all soft tissue sarcomas and is known to be radio- and chemotherapy resistant. CCS shares morphological and immunohistochemical features with malignant melanoma, including melanin biosynthesis and melanocytic markers. However, it is distinct for the presence of EWSR1-ATF1 translocation which activates MITF transcription factor. We report here of an aggressive case of CCS in a 9-year-old patient, which demonstrates the critical role of molecular analysis in the diagnosis and treatment of uncommon cancer variants in the era of personalized medicine. The EWSR1-ATF1 translocation induces pathological c-Met activation, and so, following unsuccessful CTLA4 and PD-1 blockade immunotherapy, the child received cabozantinib, a small molecule tyrosine kinase inhibitor, with the intent to block c-Met oncogenic effect. In parallel, active immunization, using hapten di-nitrophenyl modified autologous tumor cells was administered with monotherapy PD-1 inhibitor nivolumab. Under this "triplet" therapy, the patient attained an initial partial response and was progression-free for 2 years, in good performance status and resumed schooling. Based on our observation, cabozantinib can be used as an effective and potentially life-prolonging treatment in CCS. We suggest that priming the child's immune system using her autologous tumor and combating T cell exhaustion with PD-1 blockade may have synergized with the targeted therapy. Combining targeted and immunotherapy is a rapidly growing practice in solid tumors and provides a glimpse of hope in situations that previously lacked any treatment option.

Toward safer haploidnetical hematopoietic stem cell transplantation.

The use of haploidentical HSCT is gaining momentum using either megadose T-cell depleted (TCD) myeloablative HSCT, or T cell replete nonmyeloablative HSCT in conjunction with cyclophosphamide post-transplant (PTCY). However, the risks of myeloablative protocols in the former or prolonged immunosuppression in the later, adversely impacting GVL and anti-pathogen immunity are challenging. Recently, we demonstrated in a stringent BM allografting murine model, that combining megadose TCD HSCT with PTCY, enabled durable chimerism induction without GVHD in the absence of any immune suppression after CY. The outcome of this approach in one a patient with multiple myeloma and one with Hodgkin's disease indicate it might offer an attractive safe protocol for haploidentical HSCT. In addition, preclinical experiments show that donor type anti-third party central memory veto T cells that are administrated with a megadose TCD HSCT can potentially offer an editional tool for safer conditioning protocols. Moreover, proof of concept murine studies demonstrate that genetically manipulated veto cells armed with specific receptors against cancer cells, can survive for months in allogeneic recipients, laying the rational for the use of "off-the shelf " Veto-CAR T cells.