CAR-NK是否优于CAR-T细胞免疫疗法？

cantonchn

作者：疑夕
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  t$ h; C6 m0 x' Z8 Q+ i' m9 OOn 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) y1 F  l3 T' E

( ]0 U0 t& p# @$ a+ u4 E% WCAR-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?6 T& M: ?, B  q  \! d& u

7 u5 f5 |# W* U4 h# `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:8 V7 C4 t8 g# G: q2 o  E
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(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.' |) W3 r; e0 }& F

- \9 e: Y; A( V8 Q5 Y(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.- @! Z' h8 J* ?$ L% Y/ K
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(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./ E# A7 _! Z; t6 U5 L; \3 z# j

2 e) w& |# e; J, w, X  \8 c(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.9 X" q  u5 ?6 j8 f/ A

. u1 k# N: W+ u(5) CAR-NK cells can also be produced in large scaleunder GMP conditions. Moerover, it may be used in the setting of allogeneic transplantation.5 }6 f8 E) e$ G7 w1 ?
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Naturally, 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.9 H& Q) ~1 G0 m6 l+ B! l

5 O  d2 _4 u7 M; Q- C; W2 h3 jNatural 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].5 U3 v8 {4 w5 k4 t/ B7 r) H7 `
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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.' H9 [  b: Y2 p& D, J* Z! K
[2] Leukemia. 2014, 28(4), 917-927. 0 d6 }; Z5 y3 a. [3 h, ~6 w# `& F

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: S' {" ]9 @9 e1 {; @7 S, J外周血中的NK数量应该没有10%这么多，正常在4%~6%之间。