Table 3.
Selected studies using allodepletion, alloanergy induction, and other immune modulation to facilitate T cell addback after haploidentical HSCT.
| Underlying disease | Transplant protocol | Study cohort | Method for generating T cell therapy product | T cell dose/time of infusion | Outcome | References |
|---|---|---|---|---|---|---|
| Malignant and non-malignant diseases | CD34+ selected graft, myeloablative conditioning, ATG. No post-transplant immunosuppression | Infants or young children (n = 15) | Anti-CD25 immunotoxin-mediated allo-depletion using non-donor parent PBMC as alllo-stimulators | 1–8 × 105/kg in dose-escalating cohorts; 15–47 days after HSCT |
CD4 count ≥200/μL after 13 weeks (median) in 10 evaluable patients; massive expansion of T cells within 4 weeks of T cell infusion in three patients with CMV infection; aGVHD II-IV in 0/15 patients. | Andre-Schmutz et al. (73)* |
| Malignant and non-malignant diseases | CD34+ selected graft, myeloablative and non-myeloablative-conditioning, alemtuzumab. 7/16 patients received tacrolimus/CSA | Children (n = 14) Adults (n = 2) |
Anti-CD25 immunotoxin-mediated allo-depletion using recipient EBV-LCL as allo-stimulators | Two dose levels: Level 1: 104/kg (n = 8), Level 2: 105/kg (n = 8); Days +30, +60 and +90 after HSCT |
Dose level 2 significantly accelerated reconstitution of both CD4 and CD8 T cells, with CMV and EBV-specific responses observed in 4 of 6 evaluable patients at 2–4 months after HSCT; aGVHD II-IV in 2/16 patients | Amrolia et al. (74) |
| Malignant diseases | CD34+ selected graft, myeloablative conditioning, ATG. No post-transplant immunosuppression | Adults (n = 19) | Photodepletion with TH9402 using recipient PBMC as allo-stimulators | Phase I dose-finding study: 1 × 104/kg−5 × 106/kg; 28–40 days after HSCT | aGVHD I–II in 5/19 patients No aGVHD III–IV | Roy et al. (75) |
| High-risk AML and ALL | CD34+ selected graft, myeloablative conditioning, ATG. | Adults (n = 23) | Photodepletion with TH9402 using recipient PBMC as allo-stimulators | Phase II study: 2 × 106/kg; 28 days (median) after HSCT |
aGVHD I–II in 22 %; 1 year TRM: 32% | Roy et al. (76) (Abstract) |
| Malignant and non-malignant diseases | Allo-anergized bone marrow with post-transplant CSA/MTX | Children (n = 9) Young adults (n = 3) |
CTLA-4-Ig mediated alloanergy induction, using recipient PBMC as allo-stimulators | 1.6–5.5 × 107/kg (contained in BM graft) on Day 0 of HSCT | CD4 count ≥400/μL by 6 months and CD4/CD8 ratio ≥ 1.4 by 7 months in all five surviving patients; Gut aGVHD in 3/11 patients; DFS at last follow-up: 5/12 patients | Guinan et al. (77) |
| High-risk acute leukemia or MDS | CD34+ selected graft, myeloablative conditioning, ATG. No post-transplant immunosuppression | Children (n = 5) Adults (n = 11) |
Anti-B7.1-mediated alloanergy induction using PBMC from recipient or a second haploidentical donor as allo-stimulators | Escalating dose levels: Level 1: 103/kg, Level 2: 104/kg, Level 3: 105/kg; 35–42 days after HSCT |
Functional virus-specific CD4 T cells detectable at a median of 9, 3, and 2.5 months and CD8 T cells at median of 9, 4, and 3 months in dose level 1/no DLI, dose level 2, and dose level 3, respectively; aGVHD II-IV in 5/16 patients; DFS at last follow-up: 4/16 patients | Davies et al. (78) |
| High-risk AML, ALL, lymphoma | CD34+ selected graft, myeloablative conditioning. No ATG or other serotherapy. No post-transplant immunosuppression. | Adults (n = 26) | Fresh Tregs (G-CSF mobilized) isolated by CD25-immuno-magnetic selection on Day (– 4), CD34+ selected stem cells and Tcon on Day 0. | Two dose levels: Level 1: Treg 2 × 106/kg + Tcon 0.5–1 × 106/kg (n = 21); Level 2: Treg 4 × 106/kg + Tcon 2 × 106/kg (n = 5) |
CD4 count ≥100/μL and ≥ 200/μL at median of 42 (28–135) and 67 (40–146) days after HSCT, respectively; CD8 count ≥100/μL and ≥200/μL at median of 38 (19–95) and 48 (21–95) days, respectively; aGVHD II-IV in 2/26 patients; 12-month DFS: 46% | Di Ianni et al. (79) |
| High-risk AML and ALL | CD34+ selected graft, myeloablative conditioning. No serotherapy (n = 25), ATG or alemtuzumab (n = 18). No post-transplant immunosuppression. | Adults (n = 43) | As above | Treg 2.5 × 106/kg (mean) + Tcon 1.1 × 106/kg (mean) | CD4 count ≥100/μL and ≥200/μL at median of 40 (25–150) and 55 (45–160) days after HSCT, respectively; CD8 count ≥100/μL and ≥200/μL at median of 45 (18–100) and 60 (50–140) days, respectively; aGVHD II-IV in 15%; Relapse: 2/41 patients; 46-month DFS: 56% | Martelli et al. (17)† |
| AML, ALL or lymphoma | CD34+ selected graft, myeloablative conditioning. ATG. | Adults (n = 12) | IL-10 mediated alloanergy induction using recipient CD3-depleted peripheral blood cells as allo-stimulators | T cells dose of 3–5 × 105/kg; 28–64 days after HSCT | CD4 count >150/μL and CD8 count >100/μL at a median of 30 (15–102) days in the four long-term survivors; aGVHD II-III in 5/12 patients; DFS at last follow-up: 4/12 patients | Bacchetta et al. (80) |
aGVHD, acute graft- vs.-host disease; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; BM, bone marrow; CSA, cyclosporine; CTLA-4-Ig, cytotoxic T-lymphocyte-associated protein-4-immunoglobulin bound to human IgG1 constant region; DFS, disease-free survival; MDS, myelodysplastic syndrome; MM, multiple myeloma; MTX, methotrexate; OS, overall survival; PBMC, peripheral blood mononuclear cells; TRM, transplant related mortality.
*
This study included haploidentical HSCT (n = 13) and matched unrelated HSCT (n = 3), with one patient receiving two transplants.
†
Some of the patients (n = 24) in this study have been reported in the Di Ianni study (79).