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Advantages and applications of CAR-expressing natural killer cells.

Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, Grez M, Kloess S, Arseniev L, Koehl U - Front Pharmacol (2015)

Bottom Line: In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD).These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance.Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Therapeutics Integrated Research and Treatment Center Transplantation, Hannover Medical School Hannover, Germany.

ABSTRACT
In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

No MeSH data available.


Related in: MedlinePlus

GMP-conform manufacturing of chimeric antigen receptor expressing natural killer cells with/without suicide genes for safety improvement. One major technical obstacle for the wide spread application of CAR expressing NK cells in cancer is the complexity of the GMP-conform manufacturing process of these CAR-ATMPs. The development of this process comprises not only the set-up of GMP-conform protocols for isolation, activation, engineering and expansion of the cells but also the final formulation, definition of product specifications and release quality control. In order to enter a clinical phase I/II trial the corresponding SOPs will be generated, validation runs will be performed and the application for manufacturing licenses has to be submitted. Due to the maturation status of the NK cells suicide genes might be necessary to improve safety in the use of CAR-engineered NK cells. CAR, chimeric antigen receptor; ATMP, advanced therapy medicinal products; depl., depletion; sel., selection; SOP, standard operation protocol; IMP, investigational medicinal product; IMPD, investigational medicinal product dossier; CMC, chemical manufacturing and control.
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Figure 1: GMP-conform manufacturing of chimeric antigen receptor expressing natural killer cells with/without suicide genes for safety improvement. One major technical obstacle for the wide spread application of CAR expressing NK cells in cancer is the complexity of the GMP-conform manufacturing process of these CAR-ATMPs. The development of this process comprises not only the set-up of GMP-conform protocols for isolation, activation, engineering and expansion of the cells but also the final formulation, definition of product specifications and release quality control. In order to enter a clinical phase I/II trial the corresponding SOPs will be generated, validation runs will be performed and the application for manufacturing licenses has to be submitted. Due to the maturation status of the NK cells suicide genes might be necessary to improve safety in the use of CAR-engineered NK cells. CAR, chimeric antigen receptor; ATMP, advanced therapy medicinal products; depl., depletion; sel., selection; SOP, standard operation protocol; IMP, investigational medicinal product; IMPD, investigational medicinal product dossier; CMC, chemical manufacturing and control.

Mentions: For successful clinical translation of gene modified NK cells, the preclinical and clinical development (Figure 1) will have to focus on the transduction efficacy, as well as on the safety and efficacy of the CAR and/ or the suicide constructs introduced. Therefore quality aspects related to CTMP and GTMP as defined in guidelines [CPMP/BWP/3088/99; EMEA/CHMP/410869/2006; Ph. Eur. 0784: Ph. Eur. 5.14] will apply to the identity, potency, and activity including the conditional suicidality, purity, and safety of vectors and genetically modified product. The establishment of correspondingly adequate in-process and quality controls as well as of process target values and product specifications will have to take into account the variability of the primary effector cell as the starting material (Schule et al., 2010).


Advantages and applications of CAR-expressing natural killer cells.

Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, Grez M, Kloess S, Arseniev L, Koehl U - Front Pharmacol (2015)

GMP-conform manufacturing of chimeric antigen receptor expressing natural killer cells with/without suicide genes for safety improvement. One major technical obstacle for the wide spread application of CAR expressing NK cells in cancer is the complexity of the GMP-conform manufacturing process of these CAR-ATMPs. The development of this process comprises not only the set-up of GMP-conform protocols for isolation, activation, engineering and expansion of the cells but also the final formulation, definition of product specifications and release quality control. In order to enter a clinical phase I/II trial the corresponding SOPs will be generated, validation runs will be performed and the application for manufacturing licenses has to be submitted. Due to the maturation status of the NK cells suicide genes might be necessary to improve safety in the use of CAR-engineered NK cells. CAR, chimeric antigen receptor; ATMP, advanced therapy medicinal products; depl., depletion; sel., selection; SOP, standard operation protocol; IMP, investigational medicinal product; IMPD, investigational medicinal product dossier; CMC, chemical manufacturing and control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325659&req=5

Figure 1: GMP-conform manufacturing of chimeric antigen receptor expressing natural killer cells with/without suicide genes for safety improvement. One major technical obstacle for the wide spread application of CAR expressing NK cells in cancer is the complexity of the GMP-conform manufacturing process of these CAR-ATMPs. The development of this process comprises not only the set-up of GMP-conform protocols for isolation, activation, engineering and expansion of the cells but also the final formulation, definition of product specifications and release quality control. In order to enter a clinical phase I/II trial the corresponding SOPs will be generated, validation runs will be performed and the application for manufacturing licenses has to be submitted. Due to the maturation status of the NK cells suicide genes might be necessary to improve safety in the use of CAR-engineered NK cells. CAR, chimeric antigen receptor; ATMP, advanced therapy medicinal products; depl., depletion; sel., selection; SOP, standard operation protocol; IMP, investigational medicinal product; IMPD, investigational medicinal product dossier; CMC, chemical manufacturing and control.
Mentions: For successful clinical translation of gene modified NK cells, the preclinical and clinical development (Figure 1) will have to focus on the transduction efficacy, as well as on the safety and efficacy of the CAR and/ or the suicide constructs introduced. Therefore quality aspects related to CTMP and GTMP as defined in guidelines [CPMP/BWP/3088/99; EMEA/CHMP/410869/2006; Ph. Eur. 0784: Ph. Eur. 5.14] will apply to the identity, potency, and activity including the conditional suicidality, purity, and safety of vectors and genetically modified product. The establishment of correspondingly adequate in-process and quality controls as well as of process target values and product specifications will have to take into account the variability of the primary effector cell as the starting material (Schule et al., 2010).

Bottom Line: In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD).These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance.Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Therapeutics Integrated Research and Treatment Center Transplantation, Hannover Medical School Hannover, Germany.

ABSTRACT
In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

No MeSH data available.


Related in: MedlinePlus