Blinatumomab Expanded T-cells (BET) in Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia

Overview

Non-Hodgkin CD20 + Indolent Lymphoma (iNHL) and Chronic Lymphatic Leukemia (CLL) are the most frequent neoplasms of B lymphocytes. They include various histologies (follicular NHL, marginal zone NHL and Lymphocytic NHL/ CLL) characterized by a chronic course and prolonged survival, but while patients with a limited disease could be cured, those with advanced disease or relapsed after localized radiation therapy are generally considered untreatable through standard treatments. The options for first-line therapy include the use of the FCR scheme, based on Fludarabine, Cyclophosphamide and Rituximab or the BR, with Bendamustine and Rituximab. Despite good results, treatment with these two regimens (FCR or BR) is associated with severe immunosuppression which worsens the immunological dysfunction already present at diagnosis in several patients. It has been shown previously that the adoptive transfer of ex vivo anti-CD3/CD28 co-stimulated autologous T cells can successfully accelerate a robust early recovery of T cells after autologous transplantation in multiple myeloma. These CD3/CD28 expanded T cells cannot however be used in NHLi and CLL due to the presence of contaminating tumor cells in the preparation. Polyclonal T cells can also be expanded in vitro in presence of Blinatumomab and recombinant human IL2 (rhIL2) and have been called BET (Blinatumomab-expanded T cells). They are a product of Advanced Therapeutic Medicinal Product (ATMP) composed of polyclonal CD8 and CD4 T cells that are still functional and devoid of contaminating CD19+ neoplastic cells. Based on these data, it was hypothesized that infusion of BET in patients with iNHL/CLL, after the first treatment line (with FCR or BR), could induce adequate immunological recovery.

* Indolent non-Hodgkin lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) are among the most frequent B-cell neoplasms. They include different histologies (i.e. follicular NHL, marginal zone NHL and lymphocytic NHL/CLL) characterized by chronic course and prolonged survival. While some patients with limited stage disease may be cured, those presenting with advance stage or relapsing after local radiotherapy are generally considered not curable with standard treatments. * First-line treatment of CLL/LL is currently based on the biologic profile of the disease. Excluding high risk patients harboring the del(17p) and/or TP53 mutations, first line chemoimmunotherapy options includes the use of either fludarabine, cyclophosphamide and rituximab (FCR) or BR. Despite the good results, treatment with FCR or BR regimens is associated with severe immunosuppression that worsens the immune dysfunctions already present at diagnosis in several patients. In the CLL phase III trial, high frequency of grade 3/4 infections was reported in FCR and BR, being observed in 39% and 25% of the patients, respectively. In iNHL, infections have been observed in 37-55% of the patients treated with BR, with grade 3/4 events in 7-12% of the cases. * Blinatumomab-expanded T cells (BET) are an Advanced Therapeutic Medicinal Product (ATMP) composed of autologous polyclonal activated T cells expanded in vitro using blinatumomab and rhIL-2, to be used for somatic cell therapy in an autologous setting. Indeed the investigators have developed a method using blinatumomab and rhIL2 to expand and activate ex vivo the T lymphocytes present in the peripheral blood from CLL and iNHL patients, while at the same time eliminating contaminating CD19+ neoplastic cells. The resulting polyclonal T cells can be used for immuno-reconstitution purposes. The Cell Factory "Centro di Terapia Cellulare G. Lanzani" showed the functionality of BET in a mouse B-cell NHL xenograft model. Upon in vivo inoculation, BET retain functional activity: upon engagement with blinatumomab in vivo, BET were able to efficiently kill the B-cell NHL cells. Importantly, BET did not showed any toxicity in animals, even at high doses and in presence of blinatumomab. * About clinical experience, it has been previously shown that adoptive transfer of ex vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells can successfully accelerate a robust T-cell recovery early after autologous transplant for multiple myeloma. However, the invariable presence of clonal disease in cell product of iNHL/CLL patients hampered this possibility up to now. In contrast BET cell expansion leads to lysis of contaminating neoplastic cells. BET can therefore be expanded from CLL patients peripheral blood in GMP (Good Manufacturing Practice) conditions for adoptive therapy. Starting from only 10 mL of peripheral blood, a mean 5.15x108 CD3+ cells can be expanded in 3 weeks with a rapid clearance of CLL contamination. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ T cells and mostly effector and central memory cells. They showed a normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were functionally active, showing cytotoxicity against CD19+ targets in presence of Blinatumomab in vitro and in vivo. * On the basis of these data the investigators hypothesize that BET infusion after first-line treatment of iNHL/CLL with either FCR or BR could lead to an adequate immune recovery.