Stem cell transplantation is frequently used as a consolidation or salvage treatment for many patients with poor prognosis hematological malignancies. However, disease recurrence remains the major cause of treatment failure after autologous SCT, as the graft-versus-tumor (GVT) effects mediated by the donor-derived immune components infused with an allograft are lacking. Hence development of non-toxic """"""""consolidation treatments"""""""" after transplant remains a highly desirable objective and the adoptive transfer of antigen/tumor-specific cytotoxic T lymphocytes (CTLs) is one promising approach. The introduction of chimeric antigen receptors (CARs) into T cells allows the rapid generation of effector cells specific for virtually any surface molecule and has significantly increased the clinical applicability of adoptive transfer of tumor-specific CTLs. Our central hypothesis is that y combining ASCT with tumor directed CAR+ T cells it should be possible to retain the superior safety of autologous SCT, whilst adding an effective GVT component. We propose to test this hypothesis in patients with CD30+ malignancies (including HL and ALCL) undergoing ASCT and at high risk of relapse, as we have a novel CAR targeting the CD30 molecule and new immune-based approaches are urged to prevent the diseases recurrence after ASCT in these patients. In the proposed phase I study we will address if combining CAR-based therapies with ASCT will reduce the risk of toxicities associated with high tumor burden, tumor immune evasion of this cell therapy, and if T cells grafted with our novel CAR and expended in IL-15 will have enhance persistence, expansion and in vivo activity. On completion of this first-in-man study we will know whether the infusion of CAR+ T cells is safe, and whether the cells persist and have in vivo functionality. All components to execute the study are in place and we have sufficient individual and institutional experience to ensure the study will be opened, completed and analyzed as planned, providing valuable information about the use of T cell immunotherapy after SCT.
We have had success in treating patients with hematological malignancies by using their own immune cells modified with a chimeric molecule that eliminates tumor cells. In this project we intend test in a Phase I clinical trial the safety, persistence andin vivo functionality of these cells as adjuvant therapy for patients who have received a stem cell transplant for relapsed/refractory disease and are at high risk of relapse.
|Landoni, Elisa; Savoldo, Barbara (2018) Treating hematological malignancies with cell therapy: where are we now? Expert Opin Biol Ther 18:65-75|
|Ramos, Carlos A; Ballard, Brandon; Zhang, Huimin et al. (2017) Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest 127:3462-3471|
|Sun, Chuang; Dotti, Gianpietro; Savoldo, Barbara (2016) Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies. Blood 127:3350-9|
|Xu, Yang; Chaudhury, Arindam; Zhang, Ming et al. (2016) Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J Clin Invest 126:2678-88|
|Arber, Caroline; Feng, Xiang; Abhyankar, Harshal et al. (2015) Survivin-specific T cell receptor targets tumor but not T cells. J Clin Invest 125:157-68|
|Ramos, Carlos A; Savoldo, Barbara; Dotti, Gianpietro (2014) CD19-CAR trials. Cancer J 20:112-8|
|Perna, Serena K; Pagliara, Daria; Mahendravada, Aruna et al. (2014) Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. Clin Cancer Res 20:131-9|
|Xu, Yang; Zhang, Ming; Ramos, Carlos A et al. (2014) Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123:3750-9|
|Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara et al. (2014) Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev 257:107-26|
|Savoldo, Barbara; Dotti, Gianpietro (2013) Chimeric antigen receptors (CARs) from bench-to-bedside. Immunol Lett 155:40-2|