Turning live cancer cells into drugs

Cancer drugs come in many forms: small molecules, proteins such as cytokines and antibodies, bacteria, and viruses to name a few. Some cancer vaccines utilise irradiated and therefore non-proliferative cancer cell lines. However an emerging concept is the use of a patient’s live proliferating cancer cells as vectors to activate the immune system or deliver drugs to the tumour mass.

In a recent study of a mouse xenograft model of cancer the injection of live cancer cells expressing tumour necrosis factor alpha (TNF) reduced the tumour volume of primary tumours and metastases composed of the same cells as the TNF vector cells [1]. This is thought to be due to the phenomenon of “tumour cell seeding” – circulating tumour cells returning to their site of origin [2]. The clinical extension of this study would be to extract circulating tumour cells from a patient’s blood (not simple for solid tumours) or take a biopsy if possible from the primary tumour, transfect/ transduce with TNF and return the cells to the blood stream.

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Figure 1: Immunofluorescence microscopy image of a group of killer T cells (green and red) surrounding a cancer cell (blue, center). Credit: Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths, National Institutes of Health. No changes were made. Creative Commons Attribution 2.0 Generic.

In a model of murine acute lymphoblastic leukaemia (ALL) it was found that administering mouse ALL cells transduced to express IL-12, an immune system activating cytokine, resulted in an immune response and clearing of the ALL [3]. Importantly in mouse models of squamous cell carcinoma, osteosarcoma, prostate cancer and Lewis lung carcinoma administering cancer cells transduced with IL-12 also resulted in immune system activation and elimination of the tumours [4]. Figure 1 depicts a cancer cell surrounded by activated T-cells. The image is unrelated to study [4]. The effectiveness of live cell vaccines may be related both to their ability to amplify the immune stimulatory signal through initial proliferation and their ability to physically target their tumour of origin. The biotech AvroBio is taking the concept forward into clinical trials for acute myeloid leukemia [5].

Refs

  1. Dondossola, Eleonora, Andrey S. Dobroff, Serena Marchiò, Marina Cardó-Vila, Hitomi Hosoya, Steven K. Libutti, Angelo Corti, Richard L. Sidman, Wadih Arap, and Renata Pasqualini. ‘Self-Targeting of TNF-Releasing Cancer Cells in Preclinical Models of Primary and Metastatic Tumors’. Proceedings of the National Academy of Sciences, 8 February 2016, 201525697. doi:10.1073/pnas.1525697113.
  2. Kim, Mi-Young, Thordur Oskarsson, Swarnali Acharyya, Don X. Nguyen, Xiang H.-F. Zhang, Larry Norton, and Joan Massagué. ‘Tumor Self-Seeding by Circulating Cancer Cells’. Cell 139, no. 7 (December 2009): 1315–26. doi:10.1016/j.cell.2009.11.025.
  3. Labbe, Alain, Megan Nelles, Jagdeep Walia, Lintao Jia, Caren Furlonger, Takahiro Nonaka, Jeffrey A. Medin, and Christopher J. Paige. ‘IL-12 Immunotherapy of Murine Leukaemia: Comparison of Systemic versus Gene Modified Cell Therapy’. Journal of Cellular and Molecular Medicine 13, no. 8b (2 August 2009): 1962–76. doi:10.1111/j.1582-4934.2008.00412.x.
  4. Wei, Louis Z., Yixin Xu, Megan E. Nelles, Caren Furlonger, James C.M. Wang, Marco A. Di Grappa, Rama Khokha, Jeffrey A. Medin, and Christopher J. Paige. ‘Localized Interleukin-12 Delivery for Immunotherapy of Solid Tumours’. Journal of Cellular and Molecular Medicine 17, no. 11 (November 2013): 1465–74. doi:10.1111/jcmm.12121.
  5. ‘Cancer Immunotherapy | AvroBio’. Accessed 22 February 2016. http://www.avrobio.com/technology/cancer-immunotherapy/.
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