Advertisement

Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells

  • Ahmet F. Atik
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Carter M. Suryadevara
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States

    Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Ryan M. Schweller
    Affiliations
    Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States

    Regeneration Next, Duke University, Durham, NC 27710, United States
    Search for articles by this author
  • Jennifer L. West
    Affiliations
    Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States
    Search for articles by this author
  • Patrick Healy
    Affiliations
    Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, United States
    Search for articles by this author
  • James E. Herndon II
    Affiliations
    Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, United States
    Search for articles by this author
  • Kendra L. Congdon
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Luis Sanchez-Perez
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Roger E. McLendon
    Affiliations
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Gerald E. Archer
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • Peter Fecci
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States

    Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author
  • John H. Sampson
    Correspondence
    Corresponding author at: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC 27710, United States.
    Affiliations
    Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States

    The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States

    Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States
    Search for articles by this author

      Highlights

      • Obstacles for CED of CAR T cells are sedimentation, tube clogging, low viability.
      • LV Hydrogel is a biodegradable hyaluronic acid based biomaterial.
      • LV Hydrogel provides 20-fold increase in the delivery rate of CAR T cells.
      • Migration capacity and cytotoxicity of CAR T cells remain the same after infusion.
      • LV hydrogel has no toxic effect on rodent brain and fully disintegrated after 2 weeks.

      Abstract

      Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension. In this study, we evaluated whether LVHydrogel can effectively act as a carrier for the CED of tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells were resuspended in saline or LVHydrogel carriers, loaded into syringes, and passed through the CED system for 5 h. CAR T cells submitted to CED were counted and the efficiency of delivery was determined. In addition to delivery, the ability of CAR T cells to migrate and induce cytotoxicity was evaluated. Our studies demonstrate that LVHydrogel is a superior carrier for CED in comparison to saline. The efficiency of cell delivery in saline carrier was only ∼3–5% of the total cells whereas delivery by the LVHydrogel carrier was much higher, reaching ∼45–75%. Migration and Cytotoxicity was similar in both carriers in non-infused samples but we found superior cytotoxicity in LVHydrogel group post-infusion. We demonstrate that LVHydrogel, a biodegradable biomaterial which does not cause acute toxicity on preclinical animal models, prevents cellular sedimentation during CED and presents itself as a superior carrier to the current carrier, saline, for the CED of CAR T cells.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Clinical Neuroscience
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kanu O.O.
        • Mehta A.
        • Di C.
        • Lin N.
        • Bortoff K.
        • Bigner D.D.
        • et al.
        Glioblastoma multiforme: a review of therapeutic targets.
        Expert Opin Ther Targets. 2009; 13: 701-718
        • Imperato J.P.
        • Paleologos N.A.
        • Vick N.A.
        Effects of treatment on long-term survivors with malignant astrocytomas.
        Ann Neurol. 1990; 28: 818-822
        • Misra A.
        • Ganesh S.
        • Shahiwala A.
        • Shah S.P.
        Drug delivery to the central nervous system: a review.
        J Pharm Pharm Sci. 2003; 6: 252-273
        • Raghavan R.
        • Brady M.L.
        • Rodriguez-Ponce M.I.
        • Hartlep A.
        • Pedain C.
        • Sampson J.H.
        Convection-enhanced delivery of therapeutics for brain disease, and its optimization.
        Neurosurg Focus. 2006; 20: E12
        • Chaichana K.L.
        • Pinheiro L.
        • Brem H.
        Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas.
        Ther Deliv. 2015; 6: 353-369
        • Ashby L.S.
        • Smith K.A.
        • Stea B.
        Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review.
        World J Surg Oncol. 2016; 14: 225
        • Riccione K.
        • Suryadevara C.M.
        • Snyder D.
        • Cui X.
        • Sampson J.H.
        • Sanchez-Perez L.
        Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care.
        J Vis Exp. 2015;
        • Miao H.
        • Choi B.D.
        • Suryadevara C.M.
        • Sanchez-Perez L.
        • Yang S.
        • De Leon G.
        • et al.
        EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.
        PLoS One. 2014; 9: e94281
        • Sampson J.H.
        • Choi B.D.
        • Sanchez-Perez L.
        • Suryadevara C.M.
        • Snyder D.J.
        • Flores C.T.
        • et al.
        EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.
        Clin Cancer Res. 2014; 20: 972-984
        • Choi B.D.
        • Suryadevara C.M.
        • Gedeon P.C.
        • Herndon 2nd, J.E.
        • Sanchez-Perez L.
        • Bigner D.D.
        • et al.
        Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma.
        J Clin Neurosci. 2014; 21: 189-190
        • Prins R.M.
        • Shu C.J.
        • Radu C.G.
        • Vo D.D.
        • Khan-Farooqi H.
        • Soto H.
        • et al.
        Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain.
        Cancer Immunol Immunother. 2008; 57: 1279-1289
        • Fisher B.
        • Packard B.S.
        • Read E.J.
        • Carrasquillo J.A.
        • Carter C.S.
        • Topalian S.L.
        • et al.
        Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma.
        J Clin Oncol. 1989; 7: 250-261
        • Balyasnikova I.V.
        • Wainwright D.A.
        • Solomaha E.
        • Lee G.
        • Han Y.
        • Thaci B.
        • et al.
        Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor alpha2.
        J Biol Chem. 2012; 287: 30215-30227
        • Han J.
        • Chu J.
        • Keung Chan W.
        • Zhang J.
        • Wang Y.
        • Cohen J.B.
        • et al.
        CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells.
        Sci Rep. 2015; 5: 11483
        • Brown C.E.
        • Alizadeh D.
        • Starr R.
        • Weng L.
        • Wagner J.R.
        • Naranjo A.
        • et al.
        Regression of glioblastoma after chimeric antigen receptor T-cell therapy.
        N Engl J Med. 2016; 375: 2561-2569
        • Nishikawa R.
        • Ji X.D.
        • Harmon R.C.
        • Lazar C.S.
        • Gill G.N.
        • Cavenee W.K.
        • et al.
        A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity.
        Proc Natl Acad Sci USA. 1994; 91: 7727-7731
        • Kauer T.M.
        • Figueiredo J.L.
        • Hingtgen S.
        • Shah K.
        Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas.
        Nat Neurosci. 2011; 15: 197-204
        • Ransohoff R.M.
        • Kivisakk P.
        • Kidd G.
        Three or more routes for leukocyte migration into the central nervous system.
        Nat Rev Immunol. 2003; 3: 569-581
        • Muller M.
        • Carter S.
        • Hofer M.J.
        • Campbell I.L.
        Review: the chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity – a tale of conflict and conundrum.
        Neuropathol Appl Neurobiol. 2010; 36: 368-387
        • Aleksandrov A.A.
        • Dzhuraeva E.V.
        • Utenkov V.F.
        Viscosity of aqueous solutions of sodium chloride.
        High Temp. 2012; 50: 354-358
        • Korson L.
        • Drost-Hansen W.
        • Millero F.J.
        Viscosity of water at various temperatures.
        J Phys Chem. 1969; 73: 34-39
        • Almdal K.
        • Dyre J.
        • Hvidt S.
        • Kramer O.
        Towards a phenomenological definition of the term ‘gel’.
        Polym Gels Networks. 1993; 1: 5-17
        • Park H.
        • Temenoff J.S.
        • Tabata Y.
        • Caplan A.I.
        • Mikos A.G.
        Injectable biodegradable hydrogel composites for rabbit marrow mesenchymal stem cell and growth factor delivery for cartilage tissue engineering.
        Biomaterials. 2007; 28: 3217-3227
        • Yu L.
        • Ding J.
        Injectable hydrogels as unique biomedical materials.
        Chem Soc Rev. 2008; 37: 1473-1481
        • Tsao C.T.
        • Kievit F.M.
        • Ravanpay A.
        • Erickson A.E.
        • Jensen M.C.
        • Ellenbogen R.G.
        • et al.
        Thermoreversible poly(ethylene glycol)-g-chitosan hydrogel as a therapeutic T lymphocyte depot for localized glioblastoma immunotherapy.
        Biomacromolecules. 2014; 15: 2656-2662