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Chimeric antigen receptor T-cell therapies for multiple myeloma

Lekha Mikkilineni and James N. Kochenderfer

Article Figures & Data

Figures

  • Figure 1.

    A diagram of a CAR is shown. The antigen-binding domain of a CAR is attached to intracellular T-cell signaling moieties by an extracellular hinge domain and a transmembrane region. The CAR antigen-binding domain is usually a scFv derived from a monoclonal antibody. Examples of costimulatory domains are CD28 and 4-1BB. The T-cell activation domain is usually from the CD3Zeta molecule. Professional illustration by Patrick Lane, ScEYEnce Studios.

  • Figure 2.

    A representation of the CAR-T therapy process is shown. Cells are harvested from patients by apheresis. T cells are activated and genetically modified with a CAR gene that will lead to expression of a CAR protein on the T cells. Genetic modification is carried out with a gene-therapy vector such as a γ-retrovirus or a lentivirus. CAR-expressing T cells proliferate ex vivo. Patients often receive a chemotherapy conditioning regimen to deplete endogenous leukocytes with a goal of enhancing CAR-T activity. After completion of the conditioning chemotherapy regimen, CAR-Ts are infused. Professional illustration by Patrick Lane, ScEYEnce Studios.

Tables

  • Table 1.

    Target antigens that have been considered for CAR-T therapies of MM

    AntigenExpression in nonmalignant cellsExpression in MMClinical trial of CAR-Ts in myelomaReferences
    CD44v6Activated T cells, activated monocytes, keratinocytesReported to be expressed by 43% of advanced MM casesNo62, 63
    CD70Activated lymphoid cellsOnly a portion of the myeloma cells express CD70 in most casesNo64, 66
    CD56NK cells, T cells, neuronal cellsStrongly expressed in 70% of patients with myelomaNo67, 68, 70
    CD38Precursor B cells, plasma cells, T cells, NK cells, myeloid precursors, prostate cells, nervous system, osteoclasts, muscle cellsStrong, uniform expression on myeloma cellsNo72, 78, 79
    CD138Plasma cells, salivary glands, liver, skinExpressed on MM cellsYes36, 81, 82
    CD19B cellsMinimal expression of CD19 on myeloma plasma cell surface. CD19+ cells may represent cancer stem cell in MMYes10, 35, 59, 84
    Immunoglobulin κ light chainMature B cellsPotential target on B cells that represent MM stem cells and that express surface immunoglobulinsYes21, 85
    SLAMF7Plasma cells, NK cells, CD8+ cells, activated monocytes and B cells, dendritic cellsStrongly expressed by MM cellsNo88, 89
    BCMAPlasma cells, small subset of B cellsExpressed on MM cellsYes9, 20, 37, 95, 96, 102, 103
    • BCMA, B-cell maturation antigen; NK, natural killer; SLAMF7, signaling lymphocyte–activating molecule F7.

  • Table 2.

    Clinical trials of CAR-Ts for MM with published results

    TargetInstitutionCAR constructConditioning chemotherapyResponseReference
    CD138Chinese People's Liberation Army General HospitalLentivirus; CD28 costimulatory molecule; murine scFvVaried, all patients received some type of chemotherapy shortly before cell infusion5 patients treated; best responses: 4 SD, 1 PD36
    CD19University of PennsylvaniaLentivirus 4-1BB costimulatory molecule; murine scFvMelphalan 140-200 mg/m2 prior to ASCT10 patients treated; median PFS 185 d (range, 42-479 d)10, 35
    Immunoglobulin κ light chainBaylor College of Medicineγ- retrovirus; CD28 costimulatory molecule; murine scFvSalvage chemotherapy by referring physician (3 patients) or 12.5 mg/kg cyclophosphamide 4 days prior to CAR-T infusion (4 patients)7 patients treated: 4 SD, 3 no response21
    BCMANational Cancer Instituteγ-retrovirus; CD28 costimulatory molecule; murine scFv3 doses of 300 mg/m2 cyclophosphamide and 3 doses of 30 mg/m2 fludarabine12 patients treated; best responses: 1 sCR; 2 VGPR; 1 PR; 8 SD9
    BCMAMulticenter; Bluebird BioLentivirus; 4-1BB costimulatory molecule; murine scFv3 doses of 300 mg/m2 cyclophosphamide and 3 doses of 30 mg/m2 fludarabineAmong 18 patients with at least 2 mo follow-up, currently, best responses are 4 CR, 7 VGPR, 5 PR, 2 SD102
    BCMAUniversity of PennsylvaniaLentivirus; 4-1BB costimulatory molecule; human scFvNone6 patients treated; 1 sCR; 1 VGPR; 4 with minimal or no response37
    BCMAThe Second Affiliated Hospital of Xi’an Jiaotong UniversityNot publishedNot publishedAmong 19 patients there was a 100% response rate with 18 patients obtaining sCR or VGPR103