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CAR T cells generated in vivo

16 / 2018

In August 2018, two CAR T cell therapeutics obtained marketing authorization from the European Commission. They provide efficacious treatment options for patients suffering from certain forms of leukemia and who have not responded to other treatment options. However, manu­facturing CAR-T cells that are composed of genetically engineered patient immune cells is laborious: the cells are taken from the patient, genetically modified with the CAR, multiplied and then reinfused into the same patient. Researchers of the Paul-Ehrlich-Institut (PEI) succeeded in animal experiments to engineer CAR T cells directly in the living organism. EMBO Molecular Medicine reports on the research results in its online issue of Monday, 17 September 2018.

Cancer cells often escape the immune system unrecognized. A new form of cancer therapy aims at tackling this by retargeting immune cells against the cancer cells. CAR T cells belong to this cancer immunotherapies. This involves removing certain immune cells (T cells) from the patient, equipping them outside the body with a chimeric (synthetic) antigen receptor (CAR), amplification and retransplantation into the patient. The antigen receptor recognizes distinct surface structures, in case of the authorized products, the CD19 antigen on cancer cells. Being equipped with the chimeric antigen receptor, the immune cells can recognize and kill cancer cells.

This therapy resulted in some patients, who had not profited from standard care, in the complete elimination of cancer cells and their absence over many years. Manufacturing such products is however laborious: The cells have to be harvested from the patient, must be genetically modified outside the body and then reinfused. Moreover, the distinct steps of this process can inadvertently alter the immune cells and their activities.

Researchers led by Prof. Christian Buchholz at the Paul-Ehrlich-Institut, head of the research group "Molecular Biotechnology and Gene Therapy" of the Paul-Ehrlich-Institut, succeeded within a research project funded by the German Cancer Aid together with collaboration partners, in achieving this genetic modification of human T cells directly in vivo, i.e in the living organism. The key factor for this success were specifically modified lentiviral vector particles transferring the CAR gene selectively into those T cell subtypes being responsible for cancer attack. For their proof-of-principle demonstration, the researchers used mice that had been equipped with human blood cells. A single intravenous injection of the vector particles was sufficient to generate sufficient numbers of CAR T cells that became detectable in blood and lymphatic organs. These in vivo generated CAR T cells proliferated upon antigen contact and eliminated CD19-positive cells. As observed in clinical applications, some animals experienced cytokine release syndrome and neurotoxicity.

This is the first proof-of-concept demonstration that human cytotoxic T cells can be reprogrammed into CAR T cells and kill target cells. The implications of these results are plentifold: The animal model will facilitate research into the side-effects caused by CAR T cell therapy. The technology of genetically modifying T cells in vivo will be potentially applied in other fields of immunotherapy. Finally, the results form the basis to transform the CAR T cell therapy from an individualized into an universally applicable therapy. This could impact the economic feasibility of this therapy enormously, but, requires, however, a series of preclinical studies first.

Diagram of CAR-T cell generation. On the left, manufactured CAR-T cells are injected. On the right, a gene shuttle selectively introduces the genetic information for CAR into T-cells. Diagram of CAR-T cell generation. On the left, manufactured CAR-T cells are injected. On the right, a gene shuttle selectively introduces the genetic information for CAR into T-cells. Source: EMBO Mol Med

Original publication

Pfeiffer A, Thalheimer FB, Hartmann S, Frank AM, Bender RR, Danisch S, Costa C, Wels WS, Modlich U, Stripecke R, Verhoeyen E, Buchholz CJ (2018): In vivo generation of human CD19-CAR T cells results in B cell depletion and signs of cytokine release syndrome.
EMBO Mol Med 10: e9158.
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Updated: 17.09.2018