Phase I trial of adoptive cell transfer with mixed-profile type-I/type-II allogeneic T cells for metastatic breast cancer

Abstract

Purpose: Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, type-II-polarized T cells promote engraftment and modulate GVHD, whereas type-I-polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This phase I translational study evaluated adoptive transfer of ex vivo costimulated type-I/type-II (T1/T2) donor T cells with T-cell-depleted (TCD) allogeneic stem cell transplantation (AlloSCT) for MBC.

Experimental design: Patients had received anthracycline, taxane, and antibody therapies, and been treated for metastatic disease and a human leukocyte antigen (HLA)-identical-sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody-coated magnetic beads in interleukin (IL)-2/IL-4-supplemented media. Patients received reduced intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD, and tumor response; results were compared with historical controls, identically treated except for T1/T2 product infusions.

Results: Mixed type-I/type-II CD4(+) T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at dose level 1 (5 × 10(6) cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD.

Conclusion: Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses.

Trial registration: ClinicalTrials.gov NCT00082953.

Conflict of interest statement

Conflict of Interest Statement: CH June has royalties from US Government owned patents and patent applications in the field of adoptive immunotherapy. This arrangement is under compliance with the policies of the University of Pennsylvania.

©2011 AACR

Figures

Figure 1. Study Design

Abbreviations: CD4: CD4+-T cell; µl: microliter; mg/m2: milligram per square meter; µg/kg: micrograms per kilogram; HLA: human leukocyte antigen; DLI: donor lymphocyte infusion.

Figure 2. Functional Phenotype of Donor T1/T2 Products and Post-infusion Recipient PBL at Two Weeks

T1/T2 products were evaluated for CD4+ and CD8+ subsets and, samples permitting, for transcription factor and cytokine expression by cell-surface and intracellular flow cytometry, respectively. Two weeks after donor PBSC and T1/T2 cell infusions, recipient PBL CD4+ and CD8+-T cells were assessed for secretion of Type-I and Type-II cytokines using MACS® Cytokine Secretion Assay detection kits.

Figure 3. In-vivo Effects of Donor T1/T2 Cell Infusion

A. Percent-change in sum-of-product tumor measurements from baseline (per RECIST) for T1/T2 cell recipients (top) and historical controls (bottom). Black bars denote patients with a tumor response at Day +28; gray bars denote patients with stable or progressive disease at Day +28. The day relative to donor T1/T2 cell infusion is shown on the horizontal axis for both graphs (middle). B. Eosinophilia, a Type-II inflammatory response, was observed in most patients. The relative percent-change in absolute eosinophil counts (AEC) from baseline at peak are shown for each patient using the left vertical axis: black columns identify patients who received steroids on or before Day +42, gray columns represent patients who did not. Using the right vertical axis, each patient’s peak AEC is shown (♦); the horizontal axis identifies the Patient Number and day of peak relative to donor T1/T2 cell infusion. The horizontal dotted line indicates the upper limit of normal (ULN) for the AEC. C. In PN14, the rise in eosinophils coincided with early tumor response and the peak with onset of acute GVHD (Day +42). The line graph depicts absolute eosinophil counts; the bar graph shows percent-change in sum-of-product tumor measurements from baseline at each time-point; the ULN is shown by the horizontal dotted line; the vertical dashed line indicates when systemic steroids were initiated (Day +46).