Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation

Abstract

The primary objective of this clinical trial was to evaluate the safety, feasibility, and biologic effects of administering costimulated, interleukin (IL)-4 polarized donor CD4(+) T cells in the setting of HLA-matched sibling, T cell-replete allogeneic hematopoietic cell transplantation (HCT). Forty-seven subjects with hematologic malignancy received granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic cell transplants and cyclosporine graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning. Initial subjects received no additional cells (n = 19); subsequent subjects received additional donor CD4(+) T cells generated ex vivo by CD3/CD28 costimulation in medium containing IL-4 and IL-2 (administered day 1 after HCT at 5, 25, or 125 x 10(6) cells/kg). Studies after HCT included measurement of monocyte IL-1alpha and tumor necrosis factor alpha, detection of T cells with antitumor specificity, and characterization of T cell cytokine phenotype. The culture method generated donor CD4(+) T cells that secreted increased T helper 2 (Th2) cytokines and decreased T helper 1 (Th1) cytokines. Such Th2-like cells were administered without infusional or dose-limiting toxicity. The Th2 cohort had accelerated lymphocyte reconstitution; both cohorts had rapid hematopoietic recovery and alloengraftment. Acute GVHD and overall survival were similar in the Th2 and non-Th2 cohorts. Th2 cell recipients tended to have increased monocyte IL-1alpha and had increased tumor necrosis factor alpha secretion. CD8(+) T cells with antitumor specificity were observed in Th2 and non-Th2 cohorts. Post-transplantation T cells from Th2 cell recipients secreted IL-4 and IL-10 (Th2 cytokines) and IL-2 and interferon gamma (Th1 cytokines). Allograft augmentation with costimulated, IL-4-polarized donor CD4(+) T cells resulted in activated Th1, Th2, and inflammatory cytokine pathways without an apparent increase in GVHD.

Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation

“…In a previous report where the same conditioning regimen was used 37% developed acute pulmonary toxicities. 29 After dose reduction to 600 mg/m 2 /day was applied for the remaining 30 patients we did not observe major acute noninfectious pulmonary problems. For this cohort the TRM rate at day þ 100 and 1 year was acceptable at 10 and 23%, respectively.…”

Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation

“…To modulate GVHD after NST, Fowler et al 96 infused ex vivo-expanded Th2 cells. They found that Th2 cell infusions resulted in enhanced lymphocyte recovery without an apparent increase in GVHD.…”

Adoptive T-cell therapy for malignant disorders

“…In terms of cell function, the expanded cells retain a highly diverse TCR repertoire and, by varying the culture conditions, can be induced to secrete cytokines characteristic of T helper 1 (Th1) or T helper 2 (Th2) cells. 5 One important advantage of this bead-based system is that it does not cross-react with CTLA4 and, therefore, provides unopposed CD28 stimulation for more efficient expansion of T cells. Another, unanticipated discovery was that crosslinking of CD3 and CD28 with bead-immobilized antibody renders CD4 + T lymphocytes highly resistant to HIV infection.…”

“…Moreover, these cells have been injected into humans as part of a tumor vaccine, signifying that these cells can be used in a GMP manner. Bead or cell-based aAPCs have also been developed that are optimized for Th2 cells, 5 and for T-regulatory cells.…”