A Novel Method Using Blinatumomab for Efficient, Clinical-Grade Expansion of Polyclonal T Cells for Adoptive Immunotherapy

Abstract

Current treatment of chronic lymphocytic leukemia (CLL) patients often results in life-threatening immunosuppression. Furthermore, CLL is still an incurable disease due to the persistence of residual leukemic cells. These patients may therefore benefit from immunotherapy approaches aimed at immunoreconstitution and/or the elimination of residual disease following chemotherapy. For these purposes, we designed a simple GMP-compliant protocol for ex vivo expansion of normal T cells from CLL patients’ peripheral blood for adoptive therapy, using bispecific Ab blinatumomab (CD3 × CD19), acting both as T cell stimulator and CLL depletion agent, and human rIL-2. Starting from only 10 ml CLL peripheral blood, a mean 515 × 106 CD3+ T cells were expanded in 3 wk. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ and mostly effector and central memory cells. The Th1 subset was slightly prevalent over Th2, whereas Th17 and T regulatory cells were <1%. CMV-specific clones were detected in equivalent proportion before and after expansion. Interestingly, BET cells had normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were cytotoxic against CD19+ targets in presence of blinatumomab in vitro. In support of their functional capacity, we observed that BET, in combination with blinatumomab, had significant therapeutic activity in a systemic human diffuse large B lymphoma model in NOD-SCID mice. We propose BET as a therapeutic tool for immunoreconstitution of heavily immunosuppressed CLL patients and, in combination with bispecific Ab, as antitumor immunotherapy.

Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia

“…This bispecific antibody fragment has a molecular weight of 54.1 kDa, approximately one-third of the size of a traditional monoclonal antibody (mAb). As CD19 is an attractive target, CD19 mAb has been widely studied for therapies of lymphoma, leukemia, and autoimmune disorders, such as anti-B4-bR, SAR3419 (huB4-DM4), and BiTE [ 38 – 40 , 52 ]. Blinatumomab can potentiate unstimulated T cells and induce direct cytotoxicity against CD19+ cells [ 42 ].…”

“…BiTE antibodies against other antigens (e.g., CD33, CD 79b) are under active clinical studies for myeloid leukemia and lymphoma [ 81 , 82 ]. Since blinatumomab was shown to activate effector T cells [ 52 , 58 ], it would be interesting to study the potential of using blinatumomab for effector T cell expansion for cancer immunotherapy.…”

Phase II Study of Sequential Infusion of Donor Lymphocyte Infusion and Cytokine-Induced Killer Cells for Patients Relapsed after Allogeneic Hematopoietic Stem Cell Transplantation

“…Similarly, the strategy may benefit from a pre-emptive administration of the cells in selected categories of patients at high risk of relapse [37,38]. Furthermore, CIK cells may represent an ideal platform to genetically modify the cells by chimeric antigen receptor (CART) transduction or by "arming" the cells by ex vivo or in vivo co-administration with bispecific antibodies, as already published by our group [39][40][41]. Indeed, CIK cells are mostly CD8 positive T memory lymphocytes, and this may represent an advantage with respect to unselected CART transduced cells populations used so far, which contain significant amounts of CD4 T cells, an element that may maximally contribute to the dramatic cytokine storms observed in vivo [36].…”

Anti-CD19 monoclonal antibodies in acute lymphoblastic leukemia in children

“…Таким образом, BET могут быть определены в качестве терапевтического инструмента для иммунной реконституции в случаях сильно имму-носупрессированных пациентов с ХЛЛ и в комбинации с блинатумомабом могут рассматриваться в качестве противоопухолевой иммунотерапии [59]. У пациентов после начала инфузии блинатумомаба было описано быстрое падение количества периферических Т-кле-ток, а также экспансия выше базового количества в процессе терапии.…”