Administering Leukemia-Directed Donor Lymphocytes to Patients with AML or MDS to Prevent or Treat Post-Allogeneic HSCT Relapse

Abstract

Allogeneic HSCT (alloHSCT) can be curative for AML, but >40% of patients relapse, and then have a median OS of To date we have made 25 lines, which were polyclonal [CD4+ (35.1±0.2%) and CD8+ (41.03%±0.23)], enriched for tumor-directed clonotypes based on deep sequencing and confirmed to be LAA-reactive as determined by IFNg ELIspot [PRAME: mean 123 SFC/105, range 0-770; WT1: 57, 0-561; Survivin: 11, 0-90; NYESO1: 3, range 0-284)]. Importantly, none of the lines manifest alloreactivity against patient PHA blasts, (2±3.6% specific lysis at E:T 20:1, n=25). We have now infused 19 pts with adverse-risk AML/MDS (12 on Arm A and 7 on Arm B) at cell doses ranging from 0.5-2 × 107 cells/m2 with no immediate toxicities. All 12 pts infused as adjuvant remained in CCR at the 4 week disease assessment but 4 later relapsed (at 4, 8, 9 and 10mths post-infusion). Of these 4, 1 subsequently entered a CR with additional mLAA-T cells, 2 (with CNS relapse) were successfully treated with intrathecal chemotherapy, and the patient with bone marrow relapse was treated with systemic chemotherapy and another alloHSCT. Thus, 11/12 pts infused as adjuvant therapy are currently alive and in CR [median 12mths] while 1 pt died in CR from influenza 12 mths post-infusion. On the active disease arm all 7 pts infused had relapsed AML and were resistant to a median of 3 lines of prior therapies. One achieved a durable CR, 1 achieved a PR (enabling a second alloHSCT), and 2 patients derived transient benefit - 1 had an improvement in ANC (0 pre-T cells to >500 at wk8) with concomitant decline in blood and platelet transfusions while another had clearance of peripheral blasts (56% to 0%) with a Clinical responses correlated with the emergence and persistence (>9mths) of line-exclusive tumor-reactive T cells, as assessed by longitudinal clonotype tracking using deep sequencing. The expansion of product-derived clones was higher in patients who responded as compared with those that progressed post-infusion as confirmed by both ELIspot and deep sequencing. Notably, no patient had infusion-related CRS, neurotoxicity or GVHD. Thus, mLAA-targeted T cells directed to PRAME, WT1, NYESO1 and Survivin can be safely administered to patients with AML/MDS, in whom they can subsequently be detected long-term and produce sustained responses.