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Retroviral Vectors for Cancer Gene Therapy

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Current Strategies in Cancer Gene Therapy

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 209))

Abstract

Advances in molecular technologies have led to the discovery of many disease-related genetic mutations as well as elucidation of aberrant gene and protein expression patterns in several human diseases, including cancer. This information has driven the development of novel therapeutic strategies, such as the utilization of small molecules to target specific cellular pathways and the use of retroviral vectors to retarget immune cells to recognize and eliminate tumor cells. Retroviral-mediated gene transfer has allowed efficient production of T cells engineered with chimeric antigen receptors (CARs), which have demonstrated marked success in the treatment of hematological malignancies. As a safety point, these modified cells can be outfitted with suicide genes. Customized gene editing tools, such as clustered regularly interspaced short palindromic repeats–CRISPR-associated nucleases (CRISPR-Cas9), zinc-finger nucleases (ZFNs), or TAL-effector nucleases (TALENs), may also be combined with retroviral delivery to specifically delete oncogenes, inactivate oncogenic signaling pathways, or deliver wild-type genes. Additionally, the feasibility of retroviral gene transfer strategies to protect the hematopoietic stem cells (HSC) from the dose-limiting toxic effects of chemotherapy and radiotherapy was demonstrated. While some of these approaches have yet to be translated into clinical application, the potential implications for improved cellular replacement therapies to enhance and/or support the current treatment modalities are enormous.

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Abbreviations

aGVHD:

Acute graft-versus-host disease

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

AraC:

Cytarabine

CARs:

Chimeric antigen receptors (CARs)

CLL:

Chronic lymphocytic leukemia

CRISPR-Cas9:

Clustered regularly interspaced short palindromic repeats–CRISPR-associated nucleases

CTLA-4:

Cytotoxic T lymphocyte-associated antigen 4

DLBCL:

Diffuse large-cell lymphoma

DNA:

Deoxyribonucleic acid

EGFP:

Enhanced green fluorescent protein

EGFR:

Epidermal growth factor receptor

FL:

Follicular lymphoma

HDR:

Homology-directed repair

HLA:

Human leukocyte antigen

HSC:

Hematopoietic stem cells

HSPC:

HSC and progenitor cells

HSV-tk:

Herpes simplex virus thymidine kinase

IFN:

Interferon

iPSC:

Induced pluripotent stem cells

LTRs:

Long-terminal repeats

MCL:

Mantle cell lymphoma

MDR1:

Multidrug resistance gene 1

MDS:

Myelodysplastic syndrome

MGMT:

O-6-methylguanine DNA methyltransferase

MPP:

Multipotent progenitor

NB:

Neuroblastoma

NHEJ:

Nonhomologous end-joining

NSG:

NOD.cgPrkdcscidIL2rgtm/Wjl/Sz

PD-1:

Programmed death-1

preTs:

T cell-committed progenitors

RD114/TR:

Modified feline endogenous retrovirus envelope glycoprotein

RECIST:

Response Evaluation Criteria in Solid Tumors

scFv:

Single-chain variable fragment

SIN:

Self-inactivating

TAA:

Tumor-associated antigens

TALENs:

TAL-effector nucleases

TCRs:

T cell receptors

TERT:

Telomerase

Thbd:

Thrombomodulin

TNF:

Tumor necrosis factor

ZFNs:

Zinc-finger nucleases

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Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft [SFB738, Cluster of Excellence REBIRTH (EXC 62/1)], the Bundesministerium für Bildung und Forschung (BMBF, Joint Research Project IFB-Tx, PID-NET), CRISPR Therapeutics and the European Union (FP7 projects PERSIST, CELLPID and Horizon 2020 project SCIDNET).

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Authors and Affiliations

  1. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany

    Axel Schambach & Michael Morgan

  2. REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany

    Axel Schambach & Michael Morgan

  3. Division of Hematology/Oncology, Boston Children’s Hospital Harvard Medical School, Boston, MA, USA

    Axel Schambach

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  1. Axel Schambach
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  2. Michael Morgan
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Correspondence to Axel Schambach or Michael Morgan .

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  1. Department of Translational Oncology, Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Berlin, Germany

    Wolfgang Walther

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Schambach, A., Morgan, M. (2016). Retroviral Vectors for Cancer Gene Therapy. In: Walther, W. (eds) Current Strategies in Cancer Gene Therapy. Recent Results in Cancer Research, vol 209. Springer, Cham. https://doi.org/10.1007/978-3-319-42934-2_2

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  • DOI: https://doi.org/10.1007/978-3-319-42934-2_2

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