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Mol Ther. 2018 Jun 6;26(6):1482-1493. doi: 10.1016/j.ymthe.2018.04.015. Epub 2018 Apr 13.

Self-Delivering RNAi Targeting PD-1 Improves Tumor-Specific T Cell Functionality for Adoptive Cell Therapy of Malignant Melanoma.

Author information

1
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm 17176, Sweden.
2
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm 17176, Sweden. Electronic address: yagopico@gmail.com.
3
Advirna LLC, Worcester, MA 01605, USA.
4
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm 17176, Sweden; Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8510, Japan.
5
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm 17176, Sweden; Charles University, 2(nd) Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; Sotio A.S., 170 00 Prague, Czech Republic.
6
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm 17176, Sweden; Clinical Research Center, Guizhou Medical University Hospital, Guiyang 550025, People's Republic of China.
7
RXi Pharmaceuticals, Marlborough, MA 01752, USA.

Abstract

Adoptive cell therapy (ACT) is becoming a prominent alternative therapeutic treatment for cancer patients relapsing on traditional therapies. In parallel, antibodies targeting immune checkpoint molecules, such as cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and cell death protein 1 pathway (PD-1), are rapidly being approved for multiple cancer types, including as first line therapy for PD-L1-expressing non-small-cell lung cancer. The combination of ACT and checkpoint blockade could substantially boost the efficacy of ACT. In this study, we generated a novel self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor-infiltrating lymphocytes (TIL). We have developed an alternative chemical modification of RNA backbone for improved stability and increased efficacy. Our results show that T cells treated with sdRNA specific for PD-1 had increased interferon γ (IFN-γ) secreting capacity and that this modality of gene expression interference could be utilized in our rapid expansion protocol for production of TIL for therapy. TIL expanded in the presence of PD-1-specific sdRNA performed with increased functionality against autologous tumor as compared to control TIL. This method of introducing RNAi into T cells to modify the expression of proteins could easily be adopted into any ACT protocol and will lead to the exploration of new combination therapies.

KEYWORDS:

PD-1; RNA interference; adoptive cell therapy; checkpoint blockade; rapid expansion protocol; sd-rxRNA; sdRNA

PMID:
29735366
PMCID:
PMC5986970
DOI:
10.1016/j.ymthe.2018.04.015
[Indexed for MEDLINE]
Free PMC Article

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