PF435 A FLEXIBLE THERAPEUTIC STRATEGY FOR LEUKEMIA USING EX‐VIVO EXPANDED T CELLS COMBINED WITH BISPECIFIC ANTIBODIES

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Background: Cytokine induced killer cells (CIK) are an advanced therapeutic medicinal product (ATMP) composed of activated, mostly CD8+, T cells with anti‐tumor but little graft versus host disease (GvHD) activity, even in an allogeneic setting. In our recent phase II clinical trial, 73 leukemia/lymphoma patients, relapsed after allogeneic hematopoietic stem cell transplantation, were treated with a low dose of donor lymphocyte infusion (DLI) followed by 3 infusions of donor‐derived CIK cells. The results suggested that CIK have therapeutic activity against low burden disease and confirmed their limited GvHD potential. Aims: In order to increase the specificity and efficacy of CIK, we have investigated the possibility of combining them with CD3xCD19 bispecific T cell engager (BiTE) antibody blinatumomab to better control CD19+ tumors. Methods: CIK cells were expanded in vitro from peripheral blood (PB) or cord blood (CB) mononuclear cells by stimulation with interferon‐gamma (IFN‐ɣ), anti‐CD3 antibody and recombinant interleukin‐2 (rhIL‐2). They were tested in vitro and in vivo for their capacity to degranulate (CD107a induction), proliferate (cell count, 7‐AAD staining, CSFE assays) and induce killing of CD19 targets in presence or absence of blinatumomab (calcein‐AM release assays). The efficacy of CIK and blinatumomab was also tested in vivo in a mouse model of acute lymphoblastic leukemia (ALL‐2, patient‐derived model). Results: We show that CIK cells can be efficiently redirected against leukemic targets in presence of blinatumomab, both in vitro and in vivo. Target cells were killed in vitro up to 40–80% in presence of blinatumomab at 1:1 and 1:10 effector target ratios, respectively, compared to 2–33% in the absence of blinatumomab. More detailed analysis of cell cultures showed that, in vitro, CIK degranulate at 2–4 hours, and in part die at 48 hours but then very rapidly proliferate at days 4–7 following exposure to CD19+ targets, blinatumomab and rhIL‐2. In vivo in mice CIK had significantly enhanced therapeutic activity in presence compared to absence of blinatumomab (mean survival time of 62 days compared to 46 days, p < 0.01). Also human CIK could still be detected in the bone marrow and spleen of animals up to 4 weeks after infusion. Summary/Conclusion: Our data are summarized in Fig.1 and suggest that blinatumomab has the strong capacity to signal CIK to proliferate and become cytotoxic against CD19+ tumor targets, both in vitro and in vivo. This is reminiscent of what is observed using CAR19‐modified T cells. We suggest that CIK, combined with blinatumomab, offer a novel and effective immunotherapy approach for the treatment of CD19+ tumors. This approach is flexible, allowing to taper the BsAb in case of toxicity and, in the future, to use different T cell engaging antibodies for blinatumomab‐refractory, CD19 negative tumors (Fig.1). We propose to perform a Phase I clinical trial to test the safety of the combination of in vitro expanded T cells and blinatumomab. image

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