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作者：疑夕
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/ c- a6 M- z& y' E9 J- q, N4 |On December 15, 2014, Patrick Soon Shiong, the richest physician in the world, acquired 19.9% of Sorrento Therapeutics (NASDAQ: SRNE)’s equity at $5.80 per share (about 41.7 million). Four days later, Sorrento and Conkwest announced an agreement to co-develop CAR-NK immunotherapy. Sorrento’s stock price reached a high of $11.38 on January 15, 2015.( J" h3 J% u1 E6 O
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CAR-T cell immunotherapy has been regarded as one of the most compelling breakthroughs in cancer treatment in recent years. Companies working on CAR-T (e.g., JUNO, KITE, BLCM, BLUE, ZIOP) are red hot at present. Sorrento/Conkwest is developing CAR-expressing NK cells rather than T cells to kill cancer cells. How about CAR-TNK compares to CAR-T?
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Here is a comparison published in OncoImmunology[1]. The author, Hans Klingemann, is the inventor of the NK-92 cell line and co-founded ZelleRx in 2002, which was renamed Conkwest in 2010. CAR-NK has many several advantages over CAR-T:1 u8 b% y" ]' ^/ Y% @
' p* |1 A3 y% B7 M' F(1) CAR-NK cells don’t produce IL-6 which is associated with the cytokine release syndrome. A series of patient deaths in the trials of CAR-T were linked to unusually high levels of IL-6.
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) y7 F8 c- A( z1 K. i(2) CAR-NK cells disappear relatively rapidly from the circulation owing to their limited lifespan. There is no concern about persisting CAR-associated side effects. Whereas Juno Therapeutics has to insert EGFRt gene into the CAR-T cells to control them.
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7 L- Y$ D. W3 @) e( c$ T& u- O$ E$ B(3) NK cells are known as serial killers which diligently moves from one target to the next one, killing on as many as 7-10 cells.
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(4) The transfection efficiency of NK-92 cells is about 50%, even with non-viral methods. Avoiding viral vectors eliminates the risks of oncogene activation and insertional mutagenesis.- W5 y5 |, @( I5 Z$ C0 d
, M# w6 @) v3 x0 g(5) CAR-NK cells can also be produced in large scaleunder GMP conditions. Moerover, it may be used in the setting of allogeneic transplantation.
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2 c, R; C! n) Z! u g5 G" UNaturally, only about 10% of circulating lymphocytes are NK cells. The activation of NK cells is determined by the balance of inhibitory and activating receptor stimulation. MHC class I molecules in normal cells inhibit the activation of NK cells.$ X6 n: b5 l( s9 @" l) A
8 K8 U% `, U6 d7 x0 DNatural NK cells do not express antigen specific receptors. Can CAR-NK cells equipped with an antigen specific receptor kill cancer cells as effectively as CAR-T cells? Hard to say.
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Preclinical studies in leukemia, lymphoma, and multiple myeloma have been reported. For instance, treatment with anti-CS1 CAR-NK cells prolonged the survival of multiple myeloma mice from 40 days to 50 days[2].6 G. b+ v# X# D5 G
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Sorrento intends to develop anti-CD19, anti-PDL1, anti-PSMA, and anti-CD123 CAR-NK cells. It is expected to initiate Phase I trials in 2016.
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[1] Oncoimmunology. 2014, 3, e28147. doi: 10.4161/onci.28147.. V4 n7 K8 i2 y
[2] Leukemia. 2014, 28(4), 917-927. % \5 ?; |& Z1 D; q6 S6 J9 p
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发表于 2015-11-11 10:59
