Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.
OBJECTIVE
Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.


METHODS
In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).


RESULTS
The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).


CONCLUSIONS
Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.
Rapoport
Aaron P
AP
University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA. Arapoport@umm.edu
Stadtmauer
Edward A
EA
Aqui
Nicole
N
Vogl
Dan
D
Chew
Anne
A
Fang
Hong-Bin
HB
Janofsky
Stephen
S
Yager
Kelly
K
Veloso
Elizabeth
E
Zheng
Zhaohui
Z
Milliron
Todd
T
Westphal
Sandra
S
Cotte
Julio
J
Huynh
Hong
H
Cannon
Andrea
A
Yanovich
Saul
S
Akpek
Gorgun
G
Tan
Ming
M
Virts
Kristen
K
Ruehle
Kathleen
K
Harris
Carolynn
C
Philip
Sunita
S
Vonderheide
Robert H
RH
Levine
Bruce L
BL
June
Carl H
CH
D000328:Adult; D000368:Aged; D000465:Algorithms; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000534:rehabilitation*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D019653:Myeloablative Agonists / Q000627:therapeutic use; D020127:Recovery of Function / Q000276:immunology*; D013577:Syndrome; D013601:T-Lymphocytes / Q000637:transplantation*; D014182:Transplantation, Autologous
D015789:HLA-A2 Antigen; D019653:Myeloablative Agonists; D008558:Melphalan