Early Results Using Donor-Derived Marrow Infiltrating Lymphocytes (ddMILs) for Relapsed Disease after Allografting with Post-Transplant Cyclophosphamide (PTCy)
2019
Since the bone marrow is both the site of disease in most hematologic malignancies and a reservoir of tumor specific T cells, we hypothesized that MILs collected after alloBMT in patients treated with PTCy could be a source of tumor-specific T cells for adoptive immunotherapy. We report results of a first-in-human study of ddMILs, i.e., engrafted allogeneic T cells harvested from the patients’ marrow. The primary objectives of this study is to determine feasibility of expanding ddMILs from patients relapsing after alloBMT and the incidence of ddMILs induced grade III-IV acute GVHD. Engrafted patients with relapse after HLA-matched or haploBMT with PTCy as GVHD prophylaxis; at least 6 months post-transplant and without active grade GVHD were eligible. BM was harvested (200 ml) from relapsed patients under ambulatory conscious sedation. Dose-escalated ddMILs were expanded ex-vivo and infused following salvage chemotherapy using pre-determined dosing schedules. A total of 17 patients were harvested and expanded (AML (5), MM (8), CLL (3) and CML (1)) with anti-CD3/CD28 magnetic beads for 10 days. Patients had a medium 22.3 (1.8-104.3)-fold expansion, except the initial 3 AML patients with a high blast counts and low lymphocyte contents which prompted a modification to enrollment criteria requiring 500/µl. Following this modification, we effectively expanded all subsequent patient products. 14 patients received ddMILs: 4 HLA-matched patients (3 patients received 1 × 10 7 CD3 + cells/kg and 1 patent was treated at escalated dose of 5 × 10 7 ) and 10 HLA-haploBMT (5 at 1 × 10 6 , 3 at 5 × 10 6 and 2 at 1 × 10 7 CD3 + T cells/kg). The median time post-transplant at time of MILs infusion was 28 months. Following salvage chemotherapy and MILs infusion, absolute neutropenia (ANC 500 was 7 days. For patients who initially responded and then progressed, intra-patient dose-escalation was done upon retreatment. Overall, no cases of GVHD were observed. Two patients with MM sustained a PR for 9 months at lower doses of ddMILs and 1 MM patient who received 5 × 10 6 HLA-mismatched ddMILs is in CR >12 months post-infusion (overall response of 30%). One haplo AML patient treated initially with 1 × 10 6 CD3 + T cells/kg progressed and was retreated with 5 × 10 6 CD3 + T cells/kg after salvage chemotherapy. This patient achieved a second CR lasting 9 months. Three patients with relapsed CLL after alloBMT were put on ibrutinib with minimal response and then received ddMILs: two patients are showing no signs of disease progression. In this ongoing phase 1 study, ddMILs has shown promising efficacy in adult patients with relapsed malignancies after alloBMT. The excellent safety profile, the absence of GVHD, and early evidence of clinical activity at low doses suggests a potentially more active, less toxic alternative to the traditional DLI.
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