Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation

Abstract

Donor lymphocyte infusion (DLI), a standard relapse treatment after allogeneic stem cell transplantation (AlloSCT), has limited efficacy and often triggers GVHD. We hypothesized that after AlloSCT tumor-infiltrating donor lymphocytes could be costimulated ex vivo to preferentially activate/expand antitumor effectors. We tested the feasibility and safety of costimulated, tumor-derived donor lymphocyte (TDL) infusion in a phase 1 trial. Tumor was resected from 8 patients with B-cell malignancy progression post-AlloSCT; tumor cell suspensions were costimulated with anti-CD3/anti-CD28 Ab-coated magnetic beads and cultured to generate TDL products for each patient. Costimulation yielded increased proportions of T-bet(+)FoxP3(-) type 1 effector donor T cells. A median of 2.04 × 10(7) TDL/kg was infused; TDLs were well tolerated, notably without GVHD. Two transient positron emission tomography (PET) responses and 2 mixed responses were observed in these refractory tumors. TDL are a feasible, tolerable, and novel donor cell therapy alternative for relapse after AlloSCT.

Trial registration: ClinicalTrials.gov NCT00445666.

Figures

Figure 1

18FDG-PET responses. (A) 18FDG-PET before and at 4 and 8 weeks after TDL. PN6, a 36-year-old with primary-refractory HL with unabated disease progression following myeloablative conditioning and a 6 of 6 HLA-matched sibling-donor AlloSCT with posttransplantation in vivo T-cell depletion with cyclophosphamide. Transient responses followed radiation and gemcitabine, vinorelbine, and liposomal doxorubicin therapies. Twenty-eight months post-AlloSCT, TDL were generated from a right axillary tumor harvest and 26.3 × 106 TDL/kg were infused. Moderate pain and tenderness at sites of chest wall tumor and worsening of pleural effusions developed 1 week after infusion. At restaging, 18FDG-PET-CT demonstrated decreasing standardize uptake values (SUV) in all lesions over 3 consecutive months. By 4 months, however, PET showed increasing SUV in prior sites of disease, which correlated with clinical progression. Shown are coronal maximum intensity projection (MIP) images with a cutoff intensity of 2.5 SUV. (B) Transverse 18FDG-PET-CT fusion images demonstrate decreased SUV in PN8, a 35-year-old with relapsed HL, whose disease progressed from best partial response 6 months after reduced-intensity conditioning and a T-cell replete, 6 of 6 HLA-matched sibling-donor AlloSCT. The patient was treated with vinblastine and subsequently with 3 cycles of dose-adjusted EPOCH (etoposide, vincristine, adriamycin, prednisone, and cyclophosphamide) plus DLI. Seventy months from AlloSCT, TDL were generated from a right axillary tumor harvest, and 91.2 × 106 TDL/kg were infused. Grade 2 cytokine release syndrome (culture-negative fevers to 39.5°C, mild hypotension, and tachycardia) was observed from 4 to 24 hours after infusion. 18FDG-PET-CT was stable at 4 weeks, then demonstrated decrease in SUV in multiple sites of disease at 2 months; tumor size was stable by CT. At 4 months, although PET-CT did not show clear progression, the patient developed severe radicular pain associated with tumor-involved cervical lymph nodes requiring additional therapy.