Abstract SSY01-05: Therapeutic cell engineering using surface-conjugated synthetic nanoparticles
Authors: Matthias Stephan, James J. Moon, Soong Ho Um, Anna Bershteyn, Darrell J. Irvine
Journal: Cancer Research (2010)

Abstract Cell therapy is a rapidly expanding field in translational medicine as a targeted cancer treatment modality. While allogeneic bone marrow transplantations have been in clinical practice for decades to treat hematological malignancies, a plethora of new cell-based cancer treatment formats are in early clinical trials infusing large numbers of autologous T lymphocytes with high avidity for tumor antigens (1). Notably, following cell transfer, therapeutic cells often rely on the co-delivery of adjuvant drugs. These agents are designed to maximize donor cell efficacy and in vivo persistence, offset suppressive and adverse molecules at cell homing sites, or promote the differentiation of transferred cells into a therapeutically desirable cellular phenotype. Examples include administration of γc receptor cytokines, including interleukin (IL-) 2, IL-7, IL-21 and IL-15 in adoptive T-cell therapy (2), the blockade of immunosuppressive transforming growth factor-beta (TGF-β) in the tumor microenvironment (3), or the use of small-molecule drugs to boost immune reconstitution following HSC transplants (4). However, these agents often require high and sustained systemic doses to achieve the desired therapeutic effect, leading to dose-limiting toxicities due to the generally pleiotropic nature of these drugs, which has restricted their clinical use. One approach to focus adjuvant drug action on the transferred cell population is to genetically engineer donor cells to secrete their own supporting factors. However, regulatory and cost barriers of large-scale clinical grade vector production and safety testing, costly and lengthy cell culture, and technical challenges of high gene transfer hinder the implementation of clinical gene transfer protocols. More importantly, several emerging adjuvant therapies are based on small-molecule drugs that cannot be genetically encoded. We present a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles directly onto the plasma membrane of therapeutic cells. Using this method to provide sustained pseudo-autocrine stimulation to donor cells, we elicited dramatic enhancements in tumor elimination in a model of adoptive T-cell therapy for cancer and increased the in vivo repopulation rate of hematopoietic stem cell grafts, using very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a facile and generalizable strategy to augment cytoreagents while minimizing systemic side effects of adjuvant drugs. Based on the wealth of available NP-formulations tailored to deliver small molecule drugs, proteins, or siRNA, the range of therapeutic or diagnostic cargos that can be attached to therapeutic cells extends far beyond the small molecules and recombinant proteins tested in our studies. In addition, our results suggest therapeutic cells are promising vectors for actively targeted drug delivery. References 1. Morgan, R.A., et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126-129 (2006). 2. June, C.H. Adoptive T cell therapy for cancer in the clinic. The Journal of clinical investigation 117, 1466-1476 (2007). 3. Wallace, A., et al. Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clin Cancer Res 14, 3966-3974 (2008). 4. Trowbridge, J.J., Xenocostas, A., Moon, R.T. &amp; Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 12, 89-98 (2006). Citation Format: Matthias Stephan, James J. Moon, Soong Ho Um, Anna Bershteyn, Darrell J. Irvine. Therapeutic cell engineering using surface-conjugated synthetic nanoparticles [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SSY01-05