Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease.

Purpose: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (T _N ) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of T _N -depletion of peripheral blood stem-cell (PBSC) grafts.
Methods: One hundred thirty-eight patients with acute leukemia received T _N -depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of T _N . Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD.
Results: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years.
Conclusion: Depletion of T _N from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.
Competing Interests: Marie BleakleyStock and Other Ownership Interests: HighPass BioConsulting or Advisory Role: HighPass Bio, Orca BioResearch Funding: HighPass BioPatents, Royalties, Other Intellectual Property: TCRs specific for minor histocompatibility antigen HA-1 and uses thereof US20190211076A1 and international. Patent issued January 21, 2020. US10,538,574. Inventor on patent. Held by Fred Hutchinson Cancer Research CenterOther Relationship: Miltenyi Biotec Alison SehgalSpeakers' Bureau: OncLiveResearch Funding: Kite/Gilead, Juno Therapeutics Melinda A. BiernackiEmployment: Outpace Bio (I), Lyell Immunopharma (I)Stock and Other Ownership Interests: Lyell Immunopharma (I), Outpace Bio (I)Patents, Royalties, Other Intellectual Property: My partner receives royalties from a patent held by the Fred Hutchinson Cancer Research Center pertaining to nanomaterials for mRNA delivery. There is no relationship between the research in the current publication and the technology in the patent (I) Elizabeth F. KrakowResearch Funding: HighPass Bio (Inst) Ann DahlbergResearch Funding: Jazz Pharmaceuticals, Atara Biotherapeutics Paul J. MartinStock and Other Ownership Interests: Procter & GambleHonoraria: Janssen/Pharmacyclics, TherakosConsulting or Advisory Role: Pfizer, Mesoblast, Rigel, Talaris, MalinckrodtResearch Funding: AltruBio (Inst) Paul A. CarpenterHonoraria: Johnson and Johnson CorporationConsulting or Advisory Role: Janssen Scientific AffairsResearch Funding: Pharmacyclics, Janssen, Incyte Mary E. FlowersHonoraria: Astellas Pharma, MallinckrodtResearch Funding: Pharmacyclics, Incyte Theodore A. GooleyConsulting or Advisory Role: Kiadis Pharma, Pharmacyclics, Regimmune Brent L. WoodHonoraria: Amgen, Seattle Genetics, AbbVie, Janssen, Amgen, Astellas Pharma, Roche Diagnostics, Beckman CoulterConsulting or Advisory Role: SysmexResearch Funding: Amgen (Inst), Seattle Genetics (Inst), Pfizer (Inst), Juno Therapeutics (Inst), BiolineRx (Inst), Biosight (Inst), Stemline Therapeutics (Inst), Janssen Oncology (Inst), Novartis, Kite, a Gilead Company (Inst), Macrogenics (Inst)Travel, Accommodations, Expenses: Amgen Stanley R. RiddellEmployment: Lyell ImmunopharmaLeadership: Lyell ImmunopharmaStock and Other Ownership Interests: Lyell Immunopharma (Inst), Adaptive BiotechnologiesConsulting or Advisory Role: Lyell ImmunopharmaResearch Funding: Lyell ImmunopharmaPatents, Royalties, Other Intellectual Property: Patents, licensing fees, and royalties from Bristol Myers Squibb, Lyell, and Deverra. Patents, licensing fees, and royalties from Bristol Myers Squibb, Lyell, and Deverra (Inst) Warren D. ShlomchikEmployment: Bluesphere BioStock and Other Ownership Interests: Bluesphere BioConsulting or Advisory Role: Bluesphere BioResearch Funding: Bluesphere BioPatents, Royalties, Other Intellectual Property: T-cell receptorsNo other potential conflicts of interest were reported.