Demonstration of clinical responses to adoptive cellular therapy using allogeneic T cells in metastatic breast cancer

Category: Cell-Based Therapy

Authors: M. R. Bishop, D. Marchigiani, S. Grasmeder, S. Steinberg, C. Kasten-Sportes, C. Chow, M. Tamari, R. Dean, R. Gress, D. Fowler; National Cancer Institute/NIH, Bethesda, MD; National Insitutes of Health, Bethesda, MD

Abstract: There are anecdotal reports of tumor regression after allogeneic stem cell transplantation (alloSCT) in metastatic breast cancer (MBC). However, a clinical graft-versus-tumor (GVT) effect could not be distinguished from the cytotoxic effects of the transplant conditioning regimen. To determine if a GVT effect occurs against MBC, a clinical trial was designed using allogeneic T cells as adoptive cellular therapy after T cell depleted (TCD), reduced-intensity alloSCT from HLA-matched siblings. Eligibility was measurable MBC that had progressed after an anthracycline, a taxane, and a hormonal agent and/or Trastuzumab if tumors expressed estrogen receptors or HER2, respectively. There have been 21 pts enrolled; 13 pts have received alloSCT. Median age was 43 yrs (32-56). Median number of metastatic sites was 3 (1-5); median number of prior therapies for MBC was 4 (2-8). The conditioning regimen consisted of cyclophosphamide 4.8 gm/m² and fludarabine 120 mg/m². Allografts were TCD with CD34+ selection and antibodies against CD2, CD6, and CD7. Cyclosporine was started day -1, tapered, and discontinued by day +42. Pts received dose-escalated (1 x 10⁶ - 1 x 10⁷ CD3+ cells/kg) donor T cell infusions on days +42, +70, +98 post-alloSCT to provide a chemotherapy-independent anti-tumor effect. All evaluable pts (n = 12) had donor engraftment by day +14 post-alloSCT. Grade II-IV acute graft-versus-host disease (GVHD) developed in 8/12 pts. Best response post-alloSCT was partial response (PR) = 4, minor response (MR; 25-49% reduction) = 3, stable disease = 3, and progressive disease (PD) = 2. Four (PR = 2; MR = 2) of 7 responses were from a GVT effect (response occurred ≥ day +42). A GVT effect occurred at a median of 6 months (1.5-12), was not observed until complete donor lymphoid engraftment occurred, and was observed in pts with PD after chemotherapy. A GVT effect was associated with GVHD and was diminished with GVHD treatment. Median progression-free and overall survival was 3.2 and 10.6 months, respectively. These results indicate that a GVT effect can occur in MBC and provide rationale for further study of allogeneic T cells in a multimodality approach to MBC.