Engineered tumor-specific T cells using immunostimulatory photothermal nanoparticles

Elizabeth E. Sweeney, George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA. Electronic address: lizie@gwu.edu.
Palak Sekhri, George Washington Cancer Center, Department of Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Deepti Telaraja, George Washington Cancer Center, Department of Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Jie Chen, George Washington Cancer Center, Department of Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Samantha J. Chin, The Institute for Biomedical Sciences, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Katherine B. Chiappinelli, George Washington Cancer Center, Department of Microbiology, Immunology, and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Carlos E. Sanchez, George Washington Cancer Center, Department of Neurosurgery, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
C Russell Cruz, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA. Electronic address: ccruz@childrensnational.org.
Rohan Fernandes, George Washington Cancer Center, Department of Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA; The Institute for Biomedical Sciences, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA. Electronic address: rfernandes@gwu.edu.

Document Type

Journal Article

Publication Date

7-1-2023

Journal

Cytotherapy

Volume

25

Issue

7

DOI

10.1016/j.jcyt.2023.03.014

Keywords

adoptive cell therapy; ex vivo T cell manufacture; immunotherapy; nanoparticle-mediated photothermal therapy; thermal and immunogenic cell death; tumor-specific T cells

Abstract

BACKGROUND: Adoptive T cell therapy (ATCT) has been successful in treating hematological malignancies and is currently under investigation for solid-tumor therapy. In contrast to existing chimeric antigen receptor (CAR) T cell and/or antigen-specific T cell approaches, which require known targets, and responsive to the need for targeting a broad repertoire of antigens in solid tumors, we describe the first use of immunostimulatory photothermal nanoparticles to generate tumor-specific T cells. METHODS: Specifically, we subject whole tumor cells to Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) before culturing with dendritic cells (DCs), and subsequent stimulation of T cells. This strategy differs from previous approaches using tumor cell lysates because we use nanoparticles to mediate thermal and immunogenic cell death in tumor cells, rendering them enhanced antigen sources. RESULTS: In proof-of-concept studies using two glioblastoma (GBM) tumor cell lines, we first demonstrated that when PBNP-PTT was administered at a "thermal dose" targeted to induce the immunogenicity of U87 GBM cells, we effectively expanded U87-specific T cells. Further, we found that DCs cultured ex vivo with PBNP-PTT-treated U87 cells enabled 9- to 30-fold expansion of CD4+ and CD8+ T cells. Upon co-culture with target U87 cells, these T cells secreted interferon-ɣ in a tumor-specific and dose-dependent manner (up to 647-fold over controls). Furthermore, T cells manufactured using PBNP-PTT ex vivo expansion elicited specific cytolytic activity against target U87 cells (donor-dependent 32-93% killing at an effector to target cell (E:T) ratio of 20:1) while sparing normal human astrocytes and peripheral blood mononuclear cells from the same donors. In contrast, T cells generated using U87 cell lysates expanded only 6- to 24-fold and killed 2- to 3-fold less U87 target cells at matched E:T ratios compared with T cell products expanded using the PBNP-PTT approach. These results were reproducible even when a different GBM cell line (SNB19) was used, wherein the PBNP-PTT-mediated approach resulted in a 7- to 39-fold expansion of T cells, which elicited 25-66% killing of the SNB19 cells at an E:T ratio of 20:1, depending on the donor. CONCLUSIONS: These findings provide proof-of-concept data supporting the use of PBNP-PTT to stimulate and expand tumor-specific T cells ex vivo for potential use as an adoptive T cell therapy approach for the treatment of patients with solid tumors.

Department

Biochemistry and Molecular Medicine

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