Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes - 05/05/16

Doi : 10.1016/j.jaci.2015.12.1311

Swati Naik, MD ^a,^b,^{∗
These authors contributed equally to this work.}, Sarah K. Nicholas, MD ^c,^n,^{∗
These authors contributed equally to this work.}, Caridad A. Martinez, MD ^a,^b, Ann M. Leen, PhD ^a, Patrick J. Hanley, PhD ^d,^e, Steven M. Gottschalk, MD ^b, Cliona M. Rooney, PhD ^a, I. Celine Hanson, MD, PhD ^c, Robert A. Krance, MD ^b, Elizabeth J. Shpall, MD ^p, Conrad R. Cruz, MD, PhD ^f, Persis Amrolia, MD ^g, Giovanna Lucchini, MD ^g, Nancy Bunin, MD ^h, Jennifer Heimall, MD ⁱ, Orly R. Klein, MD ^j, Andrew R. Gennery, MD ^k, Mary A. Slatter, MD ^k, Mark A. Vickers, MD ^l,^m, Jordan S. Orange, MD, PhD ^c,ⁿ, Helen E. Heslop, MD, PhD ^a,^b, Catherine M. Bollard, MD ^d,^e, Michael D. Keller, MD ^d,^o,^⁎
^a Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Tex
^b Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Tex
^c Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, Tex
^d Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC
^e Division of Blood and Marrow Transplantation, Children's National Medical Center, Washington, DC
^f Sheikh Zayed Institute, Children's National Medical Center, Washington, DC
^g Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, United Kingdom
^h Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pa
ⁱ Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa
^j Department of Oncology, Division of Pediatric Hematology/Oncology, Johns Hopkins University School of Medicine, Baltimore, Md
^k Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
^l Scottish National Blood Transfusion Service, Aberdeen, United Kingdom
^m University of Aberdeen, Aberdeen, United Kingdom
ⁿ Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex
^o Division of Allergy and Immunology, Children's National Medical Center, Washington, DC
^p Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Tex

^∗Corresponding author: Michael D. Keller, MD, Children's National Medical Center, 111 Michigan Ave NW, M7745A, Washington, DC 20010.Children's National Medical Center111 Michigan Ave NW, M7745AWashington, DC20010

Abstract

Background

Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers.

Objective

We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs.

Methods

Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared.

Results

Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive.

Conclusion

VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs.

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Key words : Primary immunodeficiency, immunotherapy, cytotoxic T lymphocytes, antiviral therapy

Abbreviations used : ADV, CMV, EBV-LPD, GVHD, HHV6, HSCT, PID, SCID, VST

Plan

Methods

Results

Patient demographics

VST production and infusion

Viral infections and response

Overall survival and adverse events after VST infusion

Discussion

This research was funded by grants from the National Institutes of Health (RO1CA061384 to C.M.R., P50CA126752 to H.E.H., and U54 HL081007 to C.M.R. and H.E.H.); the National Cancer Institute (PO1 CA148600e02 to C.M.B. and E.J.S.); a SPORE 5P50CA126752 (to H.E.H.); an SCOR from the Leukemia and Lymphoma Society (to H.E.H.); the Production Assistance for Cellular Therapies (PACT) program (NHLBI contract no. HHSN268201000007C); the Clinical Research Center at Texas Children's Hospital; the Dan L. Duncan Institute for Clinical and Translational Research at Baylor College of Medicine; the Amy Strelzer Manasevit Scholar Award (to C.M.B. and A.M.L.); the Clinical Immunology Society (to S.K.N.); a Jeffrey Modell Diagnostic and Research Center Grant (to J.S.O.), the American Academy of Allergy, Asthma & Immunology (to S.K.N.); American College of Allergy, Asthma & Immunology (to M.D.K.); the Clinical and Translational Science Institute at Children's National (to M.D.K.); and a Translational Research Grant from the Jeffrey Modell Foundation (to M.D.K.).

Disclosure of potential conflict of interest: A. M. Leen received research funding from the National Institute of Health (NIH) and royalties from Celegene. M. A. Vickers receives payments for lectures from Hartley Taylor Medical Communications. J. S. Orange serves as a consultant form ADMA Biologics, CSL Behring, Baxalta, ASD Healthcare, and Walgreens/Optioncare; receives research funding from CSL Behring; received payments for lectures from Baxalta; and received royalties from UpToDate. H. E. Heslop receives research funding from the NIH, serves as a consultant for Chimerix, receives payments for lectures, and hold patents with Cell Medica and is the founder of Veracyte. C. M. Bollard receives research funding from the Modell Foundation and the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 137 - N° 5

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Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes - 05/05/16

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