Abstract
Abstract 521
Ex-vivo culture of murine donor CD4+ T cells using rapamycin, co-stimulation, and IL-4 yielded a defined T cell population (T-rapa cells) that favorably modulated the balance between GVHD, graft rejection, and GVT effects. To translate these findings, we conducted a multi-center clinical trial (NCT0074490) to evaluate T-rapa cell therapy after allogeneic HCT. T-rapa cells were manufactured by ex vivo culture of donor CD4+ T cells using CD3/CD28 co-stimulation in media containing IL-4, IL-2, and rapamycin. T-rapa cells had a mixed Th2/Th1 phenotype with minimal Treg content (intra-cellular flow, n=48 products; median transcription factor expression: 11.5% [GATA-3], 5.1% [T-bet], and 0.1% [FoxP3]). Median T-rapa cell cytokine secretion (pg/ml; re-stimulation at harvest) was 1.3 [IL-4], 20.6 [IL-5], 9.7 [IL-10], 23.7 [IL-13], 34.7 [IFN-g], and 17.1 [IL-2]. Patients received an HLA-matched sibling, T cell-replete, G-CSF mobilized allograft, and GVHD prophylaxis of cyclosporine plus short-course sirolimus (to d14 post-HCT). Two protocol arms evaluated T-rapa cell therapy after induction chemotherapy and outpatient, low-intensity preparative chemotherapy (Table I). First, patients (n=25) were accrued to arm A to evaluate T-rapa infusion at d +14 post-HCT; subsequently, accrual was initiated to arm B (n=25) to evaluate T-rapa infusion on d0 of HCT. Arm A was then expanded to n=40 patients. Patients accrued to arms A and B were similar for recipient age, high-risk malignancy diagnosis, chemotherapy refractoriness, and prior regimen number (Table I). Most recipients were not in remission at the time of HCT. High-risk NHL was the most frequent diagnosis (25/65 patients), followed by non-high-risk NHL (11/65), AML/MDS (8/65), myeloma (7/65), CLL (6/65), Hodgkin's disease (5/65), and CML (3/65). Arm A and B recipients had similar mean donor myeloid cell chimerism at d +14, +28, and +100 (arm A, 43%, 74%, and 89%; arm B, 50%, 62%, and 84%). At d +14, arm A and B recipients also had mixed donor T cell chimerism (mean values, 60% in each arm; Table I). At d +28 and +100, T cell chimerism increased in arm A to 80% and 89%; in arm B, these values increased to only 67% and 69%. Four recipients on arm B had < 10% donor T cell chimerism at d +100; in contrast, the lowest donor T cell chimerism value observed at d +100 on arm A was 36%. T-rapa therapy on arm A was relatively safe as there was: no engraftment syndrome, a 10% rate of acute grade II to IV GVHD, a 67% incidence of chronic GVHD, and no transplant-related mortality (Table I). On arm A, 37.5% (15/40) of recipients are in sustained complete remission, with a median survival probability of 63.6% at 24 months post-HCT. Therefore, pre-emptive donor lymphocyte infusion with ex-vivo manufactured T-rapa cells that express a balanced Th2/Th1 effector phenotype represents a novel approach to safely accelerate alloengraftment and harness allogeneic GVT effects after low-intensity conditioning.
. | Arm A . | Arm B . | ||||
---|---|---|---|---|---|---|
Low-Intensity Regimen | ||||||
Induction Chemotherapy | 1EPOCH-FR | EPOCH-FR | ||||
2Terminal Chemotherapy | 3Flu (120 mg/m2) | EPOCH-FR | ||||
Cy (1200 mg/m2) | ||||||
T-Rapa Cell Timing | D +14 post-HCT | D 0 of HCT | ||||
Patient Characteristics | ||||||
& of Patients Accrued | 40 | 25 | ||||
Age (median, range) | 55 (25–67) | 51 (32–66) | ||||
& of Prior Regimens | 3 (1–6) | 3 (1–8) | ||||
High-Risk Malignancy | 65% (26/40) | 52% (13/25) | ||||
Chemotherapy Refractory | 50% (20/40) | 48% (12/25) | ||||
CR (at time of HCT) | 25% (10/40) | 8% (2/25) | ||||
% Donor T Cell Chimerism | Mean Median (Range) | Mean Median (Range) | ||||
Day 14 post-HCT | 60 | 61 | (8–97) | 60 | 60 | (4–100) |
Day 28 post-HCT | 80 | 89 | (27–100) | 67 | 73 | (10–100) |
Day 100 post-HCT | 89 | 93 | (36–100) | 69 | 82 | (0–100) |
Clinical Results | ||||||
Engraftment Syndrome | 0% (0/40) | 0% (0/25) | ||||
Acute GVHD | 10% (4/40) | 23% (5/22) | ||||
Chronic GVHD | 67% (22/33) | 75% (15/20) | ||||
Complete Remission | 38% (15/40) | 28% (7/25) | ||||
Transplant-related Mortality | 0% (0/40) | 0% (0/25) | ||||
Percent Survival | 65% (26/40) | 40% (10/25) | ||||
Median Survival | 27.5 mo | 11.2 mo | ||||
Survival Prob. at 24 mo | 63.6% | 44.0% |
. | Arm A . | Arm B . | ||||
---|---|---|---|---|---|---|
Low-Intensity Regimen | ||||||
Induction Chemotherapy | 1EPOCH-FR | EPOCH-FR | ||||
2Terminal Chemotherapy | 3Flu (120 mg/m2) | EPOCH-FR | ||||
Cy (1200 mg/m2) | ||||||
T-Rapa Cell Timing | D +14 post-HCT | D 0 of HCT | ||||
Patient Characteristics | ||||||
& of Patients Accrued | 40 | 25 | ||||
Age (median, range) | 55 (25–67) | 51 (32–66) | ||||
& of Prior Regimens | 3 (1–6) | 3 (1–8) | ||||
High-Risk Malignancy | 65% (26/40) | 52% (13/25) | ||||
Chemotherapy Refractory | 50% (20/40) | 48% (12/25) | ||||
CR (at time of HCT) | 25% (10/40) | 8% (2/25) | ||||
% Donor T Cell Chimerism | Mean Median (Range) | Mean Median (Range) | ||||
Day 14 post-HCT | 60 | 61 | (8–97) | 60 | 60 | (4–100) |
Day 28 post-HCT | 80 | 89 | (27–100) | 67 | 73 | (10–100) |
Day 100 post-HCT | 89 | 93 | (36–100) | 69 | 82 | (0–100) |
Clinical Results | ||||||
Engraftment Syndrome | 0% (0/40) | 0% (0/25) | ||||
Acute GVHD | 10% (4/40) | 23% (5/22) | ||||
Chronic GVHD | 67% (22/33) | 75% (15/20) | ||||
Complete Remission | 38% (15/40) | 28% (7/25) | ||||
Transplant-related Mortality | 0% (0/40) | 0% (0/25) | ||||
Percent Survival | 65% (26/40) | 40% (10/25) | ||||
Median Survival | 27.5 mo | 11.2 mo | ||||
Survival Prob. at 24 mo | 63.6% | 44.0% |
EPOCH-FR, EPOCH with fludarabine (Flu) and rituximab.
Terminal (preparative) chemotherapy administered one week prior to HCT.
Flu/Cy [cyclophosphamide] doses are total doses, given over 4 days (Cy dose is 75% lower than 4800 mg/m2 “reduced-intensity” Cy dose).
No relevant conflicts of interest to declare.
![](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/116/21/10.1182_blood.v116.21.521.521/1/m_permbld2009abs02.jpeg?Expires=1726677190&Signature=IgzyBvc~FLQeGsO3U~qE71itFCKoVPUlOQyICL2sOFlVE~P85IBirqSjGXtR8OFRMAKQtQcw7MhWr-3LR7D09ee47bybdu0P0wNggPz~zZgmN9erTPqBkmhavpDFQj8a9jYMfoBLK~tAKxaZLWfs5n3Q3EeAGn1FXh2Qcr9SZolDPoIdGAtcHIH6c1wYr8yF7Fm9XDLYD-uERsAg5Uza3NycfM4CwquEXsTxHfoQynXYXKEzy7Mzk7S57n3EglgbljMqaguwOdxSkeF1u1C2drNhsASWlPPKfbZUkZzwzoq1XexgiIkqOncZkfeqeS~Y0ApataGJfkFE9LhNI3P9Tg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
This icon denotes an abstract that is clinically relevant.
Author notes
Asterisk with author names denotes non-ASH members.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal