A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug–loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fiorina, P., Shapiro, A.M., Ricordi, C. & Secchi, A. The clinical impact of islet transplantation. Am. J. Transplant. 8, 1990–1997 (2008).
Alison, M.R., Islam, S. & Lim, S.M. Cell therapy for liver disease. Curr. Opin. Mol. Ther. 11, 364–374 (2009).
Alper, J. Geron gets green light for human trial of ES cell–derived product. Nat. Biotechnol. 27, 213–214 (2009).
Dimos, J.T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons 321, 1218–1221 (2008).
Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
Hunder, N.N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).
Mackinnon, S., Thomson, K., Verfuerth, S., Peggs, K. & Lowdell, M. Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol. Dis. 40, 63–67 (2008).
Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005).
Wallace, A. et al. Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T cell therapy of established solid cancers. Clin. Cancer Res. 14, 3966–3974 (2008).
Trowbridge, J.J., Xenocostas, A., Moon, R.T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 12, 89–98 (2006).
Berger, C. et al. Safety and immunological effects of IL-15 administration in nonhuman primates. Blood 114, 2417–2426 (2009).
Thompson, J.A. et al. Recombinant interleukin 2 toxicity, pharmacokinetics and immunomodulatory effects in a phase I trial. Cancer Res. 47, 4202–4207 (1987).
Treisman, J. et al. Interleukin-2–transduced lymphocytes grow in an autocrine fashion and remain responsive to antigen. Blood 85, 139–145 (1995).
Sahaf, B., Heydari, K., Herzenberg, L.A. & Herzenberg, L.A. Lymphocyte surface thiol levels. Proc. Natl. Acad. Sci. USA 100, 4001–4005 (2003).
Bernstein, I.D., Boyd, R.L. & van den Brink, M.R. Clinical strategies to enhance posttransplant immune reconstitution. Biol. Blood Marrow Transplant. 14, 94–99 (2008).
Jain, R.K. A new target for tumor therapy. N. Engl. J. Med. 360, 2669–2671 (2009).
Overwijk, W.W. et al. gp100/pmel 17 is a murine tumor rejection antigen: induction of 'self'-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J. Exp. Med. 188, 277–286 (1998).
Rubinstein, M.P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl. Acad. Sci. USA 103, 9166–9171 (2006).
Lu, J. et al. Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin. Cancer Res. 8, 3877–3884 (2002).
Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).
Dinauer, N. et al. Selective targeting of antibody-conjugated nanoparticles to leukemic cells and primary T lymphocytes. Biomaterials 26, 5898–5906 (2005).
Davis, M.E., Chen, Z.G. & Shin, D.M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7, 771–782 (2008).
Prescher, J.A., Dube, D.H. & Bertozzi, C.R. Chemical remodelling of cell surfaces in living animals. Nature 430, 873–877 (2004).
Reddy, S.T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159–1164 (2007).
Woodrow, K.A. et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat. Mater. 8, 526–533 (2009).
Bin Na, H., Song, I.C. & Hyeon, T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 21, 2133–2148 (2009).
Tong, R. et al. Nanopolymeric therapeutics. MRS Bull. 34, 422–431 (2009).
Bartlett, D.W., Su, H., Hildebrandt, I.J., Weber, W.A. & Davis, M.E. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. USA 104, 15549–15554 (2007).
Weissleder, R., Kelly, K., Sun, E.Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23, 1418–1423 (2005).
Dhar, S., Gu, F.X., Langer, R., Farokhzad, O.C. & Lippard, S.J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc. Natl. Acad. Sci. USA 105, 17356–17361 (2008).
Kirpotin, D.B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006).
Reichardt, W. et al. Impact of mammalian target of rapamycin inhibition on lymphoid homing and tolerogenic function of nanoparticle-labeled dendritic cells following allogeneic hematopoietic cell transplantation. J. Immunol. 181, 4770–4779 (2008).
This work was supported in part by the US National Institutes of Health (CA140476), the US National Science Foundation (Materials Research Science and Engineering Center award DMR-02-13282), Cancer Center Support (core) grant P30-CA14051 from the US National Cancer Institute and a gift to the Koch Institute by Curtis and Cathy Marble. D.J.I. is an investigator of the Howard Hughes Medical Institute. We thank M. Sadelain (Memorial Sloan-Kettering Cancer Center) for extG-luc and M. van den Brink (Memorial Sloan-Kettering Cancer Center) for F-luc–transgenic mice.
The authors declare no competing financial interests.
Supplementary Figures 1–17 and Supplementary Methods (PDF 4409 kb)
Maleimide-bearing NPs are not internalized after cell surface conjugation. CD8+ T cells were surface-conjugated with fluorescent DiD-tagged NPs (Fig. 1c). Sequences of single confocal z-sections acquired at 0.4 1m intervals throughout the T cells are shown here and in Supplementary Movie 2. (MOV 642 kb)
Maleimide-bearing NPs are not internalized after cell surface conjugation. CD8+ T cells were surface-conjugated with fluorescent DiD-tagged NPs (Fig. 1c). Sequences of single confocal z-sections acquired at 0.4 1m intervals throughout the T cells are here and in Supplementary Movie 1. (MOV 713 kb)
Membrane-tethered NPs are retained on the cell surface of tumor homing T lymphocytes. Explanted cross-sectioned EG7-OVA tumors 2 d after T cell injection (Fig 3c). CellTracker green–labeled OT-1 T cells and rhodamine lipid–coated NPs (magenta) were visualized by confocal microscopy. Sequences of single confocal z-sections acquired at 0.4-1m intervals throughout the T cells are shown here and in Supplementary Movie 4. Scale bar, 1.5 1m. (MOV 670 kb)
Membrane-tethered NPs are retained on the cell surface of tumor homing T lymphocytes. Explanted cross-sectioned EG7-OVA tumors 2 d after T cell injection (Fig 3c). CellTracker green–labeled OT-1 T cells and rhodamine lipid–coated NPs (magenta) were visualized by confocal microscopy. Sequences of single confocal z-sections acquired at 0.4-1m intervals throughout the T cells are shown here and in Supplementary Movie 3. Scale bar, 1.5 1m. (MOV 1140 kb)
About this article
Labeling Of Pk-15 Cell Line with Nanoparticles of Hadolinium Orthovanadate: Influence of time and Incubation Conditions
Ukraïnsʹkij žurnal medicini, bìologìï ta sportu (2019)
Cell membrane engineering with synthetic materials: Applications in cell spheroids, cellular glues and microtissue formation
Acta Biomaterialia (2019)
Advanced Therapeutics (2019)
Applied Materials Today (2019)