Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells

Abstract

Purpose: 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.

Experimental design: 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.

Conflict of interest statement

Conflict of Interest Statement: A.P. Rapoport (corresponding author) has no conflicts of interest to declare. E.A. Stadtmauer has no conflicts of interest to declare. N.Aqui has no conflicts of interest to declare. D. Vogl has no conflicts of interest to declare. A. Chew has no conflicts of interest to declare. H-B. Fang has no conflicts of interest to declare. S. Janofsky has no conflicts of interest to declare. K. Yager has no conflicts of interest to declare. E. Veloso has no conflicts of interest to declare. Z. Zheng has no conflicts of interest to declare. T. Milliron has no conflicts of interest to declare. S. Westphal has no conflicts of interest to declare. J. Cotte has no conflicts of interest to declare. H. Huynh has no conflicts of interest to declare. A. Cannon has no conflicts of interest to declare. S. Yanovich has no conflicts of interest to declare. G. Akpek has no conflicts of interest to declare. M. Tan has no conflicts of interest to declare. K. Virts has no conflicts of interest to declare. K. Ruehle has no conflicts of interest to declare. C. Harris has no conflicts of interest to declare. R.H. Vonderheide declares a potential financial conflict of interest related to inventorship on a patent regarding hTERT as a tumor-associated antigen for cancer immunotherapy. B.L. Levine has no conflicts of interest to declare. C.H. June has no conflicts of interest to declare.

Figures

Figure 1

Flow diagram for new myeloma trial.

Figure 2

A: Statistically modeled absolute lymphocyte count (ALC) vs time following stem cell transplantation for all myeloma study patients (black line) with 95% confidence interval. Dashed orange and blue lines show the upper and lower limits of normal lymphocyte counts (for healthy adults) for reference. B: Shown is the ALC curve for a single patient (MD05) who exhibited the most dramatic lymphocyte recovery. Dashed yellow and blue lines show the upper and lower limits of normal lymphocyte counts for reference. C: Mean CD4+ T cell counts for current trial (red triangles) plus standard error bars vs. previous trial (blue diamonds = day +12, green squares = day +100); P

Figure 3

A: CT scan of abdomen showing thickened bowel wall (MD11). B: Crypt cell apoptosis (MD11). C: Features of GVHD including crypt lysis (red arrow) and neuroendocrine cell hyperplasia (black arrow) (MD11). D: Intraepithelial CD3+ T cells (MD11).

Figure 4

A: Grade III GVHD of gut (MD30) showing apoptotic crypt cells (thin arrows) and complete crypt dropout (thick arrow). B: Grade II GVHD of skin (MD30) with apoptotic keratinocytes (black arrow) and basal vacuolization and degeneration. C: Intraepidermal & intradermal CD3+ T cells (MD30).

Figure 5

% Change in mean serum cytokine levels at various timepoints after stem cell transplantation. P = 0.03 for day +14 vs enrollment for IL-6; P = 0.03 for day +14 vs enrollment for IFN-gamma; P