title: Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma.
abstract: Successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time. We hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. We describe the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy. Cells were obtained and adequately expanded in all patients with anti-CD3/CD28 beads plus interleukin-2, and a median of 9.5 × 10(8) MILs were infused. Factors indicative of response to MIL ACT included (i) the presence of measurable myeloma-specific activity of the ex vivo expanded product, (ii) low endogenous bone marrow T cell interferon-γ production at baseline, (iii) a CD8(+) central memory phenotype at baseline, and (iv) the generation and persistence of myeloma-specific immunity in the bone marrow at 1 year after ACT. Achieving at least a 90% reduction in disease burden significantly increased the progression-free survival (25.1 months versus 11.8 months; P = 0.01). This study demonstrates the feasibility and efficacy of MILs as a form of ACT with applicability across many hematologic malignancies and possibly solid tumors infiltrating the bone marrow.
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Noonan
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Huff
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Davis
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: M Victor
authors.initials: MV
authors.lastname: Lemas
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fiorino
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bitzan
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferguson
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Emerling
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Powell
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Ephraim
authors.initials: E
authors.lastname: Fuchs
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Epstein
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rudraraju
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.affiliation: Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD 21231, USA. iborrell@jhmi.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
mesh_terms: D000328:Adult; D000368:Aged; D015142:Baltimore; D001853:Bone Marrow / Q000276:immunology*; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D019653:Myeloablative Agonists / Q000627:therapeutic use; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D016896:Treatment Outcome; D059016:Tumor Microenvironment
chemical_list: D019653:Myeloablative Agonists