TY - JOUR
T1 - Phase I trial of adoptive cell transfer with mixed-profile type-I/type-II allogeneic T cells for metastatic breast cancer
AU - Hardy, Nancy M.
AU - Mossoba, Miriam E.
AU - Steinberg, Seth M.
AU - Fellowes, Vicki
AU - Yan, Xiao Yi
AU - Hakim, Frances T.
AU - Babb, Rebecca R.
AU - Avila, Daniele
AU - Gea-Banacloche, Juan
AU - Sportés, Claude
AU - Levine, Bruce L.
AU - June, Carl H.
AU - Khuu, Hahn M.
AU - Carpenter, Ashley E.
AU - Krumlauf, Michael C.
AU - Dwyer, Andrew J.
AU - Gress, Ronald E.
AU - Fowler, Daniel H.
AU - Bishop, Michael R.
PY - 2011/11/1
Y1 - 2011/11/1
N2 - 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 graftversus- 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-IICD4 + 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.
AB - 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 graftversus- 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-IICD4 + 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.
UR - http://www.scopus.com/inward/record.url?scp=80455162303&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80455162303&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-1579
DO - 10.1158/1078-0432.CCR-11-1579
M3 - Article
C2 - 21948234
AN - SCOPUS:80455162303
SN - 1078-0432
VL - 17
SP - 6878
EP - 6887
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -