CAR T-cell therapy: the latest weapon in the fight against cancer
¾ÏÀº °¡Àå ¿À·¡µÇ°í Ä¡¸íÀûÀÎ Áúº´À¸·Î, 3,500³â Àü ÀÌÁýÆ®ÀÇ ÀÇÇÐ ¼ÀûÀÎ Edwin Smith Papyrus¿¡¼ óÀ½ ¼Ò°³µÇ¾úÀ¸³ª ¾ÆÁ÷±îÁö Ä¡·á¹ýÀÌ °³¹ßµÇÁö ¾Ê¾Ò´Ù. ¼öõ³â µ¿¾È ¾Ï¼¼Æ÷¸¦ Ç¥Àû Á¦°ÅÇϱâ À§ÇØ ¿Ü°úÀû ¼ö¼ú, ¹æ»ç´É Ä¡·á,
ÈÇÐ ¿ä¹ýÀ» ÁøÇàÇÏ¿© È¿°ú¸¦ È®ÀÎÇÏ¿´À¸³ª, °á°úÀûÀ¸·Î »ó´çÇÑ ½Åü ¼Õ»óÀÌ À¯¹ßµÇ°í ¾Ï À¯Çü¿¡ µû¶ó¼µµ ±× Ä¡·á È¿°ú°¡ ´Ù¸£°Ô ³ªÅ¸³µ´Ù. ÀÌ·¯ÇÑ Ä¡·á ÀÌÈÄ¿¡µµ ¾ÏÀÌ Áö¼ÓµÇ°Å³ª ¾ÏÀÌ Àç¹ßÇÏ´Â °æ¿ì¿¡´Â ¿¹ÈÄ ¶ÇÇÑ ÁÁÁö ¾Ê¾Ò´Ù.
¹éÇ÷º´À̳ª ¸²ÇÁÁ¾°ú °°Àº Ç÷¾×¾ÏÀÌ ¹ß»ýÇÏ¸é ¹éÇ÷±¸°¡ ÅëÁ¦ ºÒ°¡´ÉÇÒ Á¤µµ·Î ºÐ¿ÇÏ°í, °ñ¼ö³ª ¸²ÇÁÀý¿¡¼ ´Ù¸¥ Ç÷¾× ¼¼Æ÷µéÀº ¹Ð·Á³ª¿À°Ô µÈ´Ù. ÀϹÝÀûÀ¸·Î´Â ºü¸£°Ô ºÐ¿ÇÏ´Â ¾Ï¼¼Æ÷¸¦ Ç¥ÀûÀ¸·Î »ç¸êÇÏ´Â ¼¼Æ÷ µ¶¼º ¾à¹°À» ÀÌ¿ëÇÑ ¸²ÇÁ±¸ Á¦°Å
ÈÇпä¹ý (lymphodepletion chemotherapy)À» 1Â÷ Ä¡·á·Î ÁøÇàÇÑ´Ù. ±×·¯³ª ÀÌ Ä¡·á¹ýÀº ¾Ï¼¼Æ÷ »Ó ¾Æ´Ï¶ó Á¶Ç÷¸ð¼¼Æ÷ (blood-forming hematopoietic stem cells, HSCs)³ª ¸ð³¶ ¹× À§Àå°ü ¼¼Æ÷ µî¿¡µµ ¿µÇâÀ» ¹ÌÃÄ, Å»¸ð³ª ¸Þ½º²¨¿ò, ÀÎÁö/±â¾ï Àå¾Ö,
°¨°¢ º¯È (ƯÈ÷ ÈÄ°¢, ¹Ì°¢), ¸é¿ª ü°èÀÇ ÀÌ»óÀÌ ¹ß»ýÇÒ ¼ö ÀÖÀ¸¸ç »ý¸í¿¡ Ä¡¸íÀûÀÎ À§ÇùÀ» À¯¹ßÇÒ ¼ö ÀÖ´Ù. 1Â÷ Ä¡·á°¡ ¼º°øÀûÀ¸·Î ÁøÇàµÇ¸é ȯÀÚ´Â ÀûÀýÇÑ °ø¿©ÀڷκÎÅÍ HSC¸¦ ÀÌ½Ä ¹ÞÀ½À¸·Î½á ¿ÏÄ¡µÉ ¼ö ÀÖÀ¸³ª, ÀÌ½ÄµÈ ¸é¿ª¼¼Æ÷ÀÇ °ÅºÎ¹ÝÀÀÀ¸·Î
ÀÌ½Ä Æí´ë ¼÷ÁÖº´(Graft versus host disease, GVHD)°ú °°Àº ÇÕº´ÁõÀÌ ¹ß»ýÇÒ ¼ö ÀÖ´Ù.
ÃÖ±Ù ¿¬±¸µÇ´Â CAR-T Ä¡·á (Chimeric antigen receptor T-cell therapy)¶ó´Â ½Å±â¼úÀº Ç÷¾×¾Ï ȯÀÚÀÇ T ¼¼Æ÷°¡ ¾Ï¼¼Æ÷¸¦ °ø°ÝÇÏ°Ô ¸¸µêÀ¸·Î½á, Á¶Ç÷¸ð¼¼Æ÷ À̽ÄÀ̳ª ¹Ýº¹ÀûÀÎ ÈÇÐ ¿ä¹ýÀ¸·Î ÀÎÇÑ ºÎÀÛ¿ë ¾øÀ̵µ ¾ÏÀ» Ä¡·áÇÒ ¼ö ÀÖÀ» °ÍÀ¸·Î º¸ÀδÙ.
´ÙÄ«¶ó¹ÙÀÌ¿À´Â CAR-T ¼¼Æ÷ Ä¡·á¸¦ ¼º°øÀûÀ¸·Î ¿¬±¸ÇÒ ¼ö ÀÖµµ·Ï ´Ù¾çÇÑ Á¦Ç°À» Áö¿øÇÏ°í ÀÖ´Ù.
Weaponizing the patient¡¯s immune system
±âÁ¸ÀÇ Ç×¾ÏÁ¦¸¦ ÀÌ¿ëÇÑ Ä¡·á¹ý°ú ´Þ¸®, CAR-T Ä¡·á¹ýÀÇ °Á¡Àº T ¼¼Æ÷ ÀÚüÀÇ ¹æ¾î ±âÀüÀ» ÀÌ¿ëÇÏ´Â °Í¿¡ ÀÖ´Ù. ÀϹÝÀûÀÎ ¸é¿ª ¹ÝÀÀ¿¡¼ °¨¿°µÈ ¼÷ÁÖ ¼¼Æ÷´Â Á¶Á÷ ÀûÇÕ¼º º¹ÇÕü (Major Histocompatibility Complex, MHC)¸¦ ÀÌ¿ëÇØ ¼¼Æ÷ Ç¥¸é¿¡
¿ÜÀμº Ç׿øÀ» ³ªÅ¸³½´Ù. T ¼¼Æ÷´Â ƯÁ¤ TCR (T-cell Receptor)¸¦ ÀÌ¿ëÇØ MHC/Ç׿ø º¹ÇÕü¿¡ °áÇÕÇÏ¿©, ¼¼Æ÷°¡ ³ªÅ¸³»´Â Ç׿øÀÌ ³»ÀμºÀÎÁö ¿ÜÀμºÀÎÁö¸¦ ÆǺ°ÇÑ´Ù. ³»Àμº Ç׿øÀÇ °æ¿ì T ¼¼Æ÷¿¡¼ ¸é¿ª¹ÝÀÀÀÌ ÀϾÁö ¾ÊÀ¸³ª, ¿ÜÀμº Ç׿øÀ»
ÀνÄÇÏ´Â °æ¿ì T ¼¼Æ÷°¡ ¼¼Æ÷ µ¶¼º ¸Å°³Ã¼¸¦ °¨¿° ¼¼Æ÷¿¡ Á÷Á¢ Àü´ÞÇÏ¿© ¼¼Æ÷ »ç¸êÀ» À¯¹ßÇÑ´Ù.
ÀÌ ¸é¿ª ¹ÝÀÀÀÌ ¾Ï°ú ¾î¶»°Ô °ü·ÃµÇ¾î ÀÖ´ÂÁö »ìÆì º¸¸é, ±Þ¼º ¸²ÇÁ±¸¼º ¹éÇ÷º´ (Acute Lymphocytic Leukemia, ALL)À̳ª °Å´ë B ¼¼Æ÷ ¸²ÇÁÁ¾ (Diffuse Large B-Cell Lymphoma, DBLCL)°ú °°Àº B ¼¼Æ÷ ¾ÏÀÇ °æ¿ì, À¯ÀüÀû ¹× ÈļºÀû º¯È·Î ÀÎÇØ Á¤»ó B ¼¼Æ÷°¡
¾Ï¼¼Æ÷·Î º¯ÈÇÏ°Ô µÈ´Ù. T ¼¼Æ÷´Â ÀÌ·¸°Ô º¯ÇüµÈ ´ÜÀÏ B ¼¼Æ÷ÀÇ Ç׿ø ¼ö¿ëü ÀϺθ¦ ÀνÄÇÏ¿© Á¾¾ç ƯÀÌÀû Ç׿øÀ¸·Î ÀνÄÇÑ´Ù. CD19´Â B ¼¼Æ÷¿¡¼ ƯÀÌÀûÀ¸·Î ¹ßÇöÇÏ´Â signal ´Ü¹éÁú·Î½á ¾Ç¼º B ¼¼Æ÷¿¡¼ ³ô°Ô ¹ßÇöÇÏ°í, Á¶Ç÷¸ð Áٱ⼼Æ÷¿¡¼
³·Àº ¹ßÇöÀ» º¸À̱⠶§¹®¿¡, À̸¦ Ÿ°ÙÇϵµ·Ï T ¼¼Æ÷¸¦ Á¶ÀÛÇϸé Áß¿äÇÑ Á¶Ç÷¸ð¼¼Æ÷ÀÇ ¼Õ»ó ¾øÀÌ Ä¡·á°¡ °¡´ÉÇÏ´Ù.
CAR-T ¼¼Æ÷´Â ÀÌ ÀÛ¿ë ±âÀüÀ» ÀÌ¿ëÇÏ¿©, ƯÈ÷ ¾Ç¼º¼¼Æ÷¸¦ »ç¸êÇϵµ·Ï Á¶À۵Ǹç, 1) CD19¿Í °°Àº ƯÁ¤ ¾Ï Ç׿øÀ» ÀνÄÇϰųª 2) TCR¿¡¼ º¸ÀÌ´Â ¼¼Æ÷ µ¶¼º ¼ººÐÀ» °áÇÕÇÏ¿© Á¦À۵ȴÙ. CAR-T Ä¡·á¹ýÀº ¾Ï Ç׿øÀ» ÀνÄÇÒ ¼ö ÀÖµµ·Ï ¸²ÇÁ±¸¿¡ TCR À¯ÀüÀÚ¸¦ µµÀÔÇÏ°í,
¸²ÇÁ±¸ Á¦°Å ÈÇпä¹ýÀ» ÁøÇàÇÑ È¯ÀÚ¿¡°Ô ´Ù½Ã ÁÖÀÔÇÔÀ¸·Î½á »õ·Î¿î ¸²ÇÁ±¸°¡ ¾Ï ¼¼Æ÷¸¦ ÀνÄÇÏ°Ô ÇÏ°í, ¸é¿ª¹ÝÀÀÀ» ÅëÇØ Á¦°ÅÇÏ´Â °úÁ¤À¸·Î ÁøÇàµÈ´Ù (
±×¸² 1).
¸¸¼º ¸²ÇÁ±¸¼º ¹éÇ÷º´ (Chronic Lymphocytic Leukemia, CLL) ȯÀÚ¸¦ ´ë»óÀ¸·Î ÇÑ ¿¬±¸¿¡¼ CAR-T Ä¡·á¹ýÀº ±âÁ¸ÀÇ Á¶Ç÷¸ð¼¼Æ÷ ÀÌ½Ä Ä¡·á¹ý¿¡ ºñÇØ ¸î¸î ÀåÁ¡À» °¡Áø´Ù. ½ÇÁ¦ ȯÀÚÀÇ ¼¼Æ÷¸¦ ±×´ë·Î ÀÌ¿ëÇ߱⠶§¹®¿¡ GVHD·Î ÀÎÇÑ ºÎÀÛ¿ëÀ» ¹æÁöÇÒ ¼ö ÀÖ¾úÀ» »Ó
¾Æ´Ï¶ó, CAR-T ¼¼Æ÷¸¦ 4¹è·Î È®´ë ¹è¾çÇÒ ¼ö ÀÖ¾ú°í, 6°³¿ù ÀÌ»ó ¼¼Æ÷°¡ À¯ÁöµÇ´Â ÀåÁ¡À» º¼ ¼ö ÀÖ¾ú´Ù (Kalos 2016). ÀÌ ¿¬±¸¸¦ ÅëÇØ ¸î¸î ȯÀÚµéÀº ¿ÏÄ¡µÇ¾úÀ¸³ª ÀϺΠºÎÀÛ¿ëµµ È®ÀεǾú´Ù.
±×¸² 1. T-cellÀ» ÀÌ¿ëÇÑ Ä¡·á °úÁ¤
CAR T-cell therapy involves removing a leukemia or lymphoma patient's T cells by leukapheresis (Step 1), modifying and expanding the T cells ex vivo so they express a chimeric antigen receptor that recognizes cancerous B cells (Steps 2 and 3), and then reinfusing the CAR T cells back into the same patient (Step 4). Several commercially available products (encompassing the aforementioned process) take the autologous approach (cells come from and are infused back into the same patient, avoiding GVHD), while several companies are developing therapies that use Steps 1-3 of the workflow but can be used to treat thousands of patients (allogeneic approach).
CAR T-cell therapies on the battlefield
ÇöÀç, B ¼¼Æ÷ ¾ÏÀÌ Àç¹ßÇϰųª ÈÇÐ ¿ä¹ý¿¡ ³»¼ºÀÌ ÀÖ´ø ¸î¸î ȯÀÚ¿¡¼´Â µÎ Á¾·ùÀÇ CAR-T Ä¡·á¹ýÀÌ Àû¿ëµÇ°í ÀÖ´Ù. KTE-C19 / axicabtagene ciloleucel (axi-cel)Àº DLBCL Ä¡·á¸¦ À§ÇØ Ã³À½À¸·Î 2017³â¿¡ FDA ½ÂÀÎÀ» ¹ÞÀº CAR T ¼¼Æ÷ Ä¡·áÁ¦´Ù. 2018³â 5¿ù¿¡µµ Àç¹ß¼º/ºÒÀÀ¼ºÀÇ DLBCL »Ó¸¸ ¾Æ´Ï¶ó Àç»ý¼º/ºÒÀÀ¼ºÀÇ B ¼¼Æ÷ Àü±¸Ã¼ ALLÀÇ Ä¡·á¿¡ Àû¿ë °¡´ÉÇÑ tisagenlecleucelÀÌ FDA ½ÂÀÎÀ» ¹Þ¾Ò´Ù. ³î¶ø°Ôµµ ÀÓ»ó 2»ó¿¡¼ tisagenlecleucel·Î Ä¡·áÇÑ ALL ȯÀÚ 53¸í Áß 83%°¡ ¿ÏÄ¡µÇ¾ú´Ù. ¶ÇÇÑ DLBCL ȯÀÚ 81¸í Áß 53%´Â ¿ÏÄ¡µÇ¾úÀ¸¸ç, ¿ÏÄ¡µÈ ȯÀÚÀÇ 74%´Â 6°³¿ù ÈÄ¿¡µµ ¾ÏÀÌ Àç¹ßµÇÁö ¾Ê¾Ò´Ù (Ogba
et al. 2018).
ÀÌ·¸°Ô ÁÁÀº °á°ú°¡ ÀÖ¾úÀ½¿¡µµ ºÒ±¸ÇÏ°í, ¾ÆÁ÷ CAR T ¼¼Æ÷ Ä¡·áÁ¦´Â ºÎÀÛ¿ëÀ» µ¿¹ÝÇÑ´Ù. »çÀÌÅäÄ«ÀÎ ¹æÃâ ÁõÈıº (Cytokine release syndrome, CRS)Àº ¿, ½Ä¿å ºÎÁø, ÅëÁõ°ú °°Àº Áõ»óÀ» µ¿¹ÝÇϸç, ºü¸¥ ½É¹Úµ¿À̳ª ¹ßÀÛ, ÀúÇ÷¾Ð, È£Èí °ï¶õ µî »ý¸íÀ» À§ÇùÇÒ ¼öµµ ÀÖ´Ù (Brudno and Kochenderfer 2016). ÀÌ Ä¡·á¹ýÀº ³úº´Áõ, ¹ßÀÛ, ¶³¸²°ú °°Àº ½Å°æÇÐÀû ÇÕº´ÁõÀÌ ¹ß»ýµÉ ¼ö ÀÖÁö¸¸ ´ëºÎºÐ °¡¿ªÀûÀ̾ú´Ù.
The future of cancer warfare
±×·³¿¡µµ ºÒ±¸ÇÏ°í CAR T ¼¼Æ÷ Ä¡·áÁ¦´Â ¹«ÇÑÇÑ °¡´É¼ºÀ» °¡Áö°í ÀÖ¾î, ¿¬±¸ÀÚµéÀº CAR T ¼¼Æ÷ Ä¡·áÁ¦ ±â¼úÀ» ¹ßÀü½ÃÄÑ ºÎÀÛ¿ëÀ̳ª off-target È¿°ú¸¦ ÃÖ¼ÒÈÇÏ´Â ¹æ¹ý (reviewed in Bonifant
et al. 2016) ¿Ü¿¡µµ Ç¥Àû ¼¼Æ÷ÀÇ µ¶¼º°ú »çÀÌÅäÄ«ÀÎ »ý»ê, T ¼¼Æ÷ Áõ½Ä ¹× »ýÁ¸À» °³¼±ÇÏ°í ÀÖ´Ù (
±×¸² 2). °Ô´Ù°¡ ÇöÀç FDA¿¡¼ ½ÂÀÎµÈ Ä¡·á¹ýÀÌ CD19¸¦ Ÿ°ÙÀ¸·Î ÇÏ´Â ¹Ý¸é, CD20, CD22, CD23, ROR1 µî°ú °°ÀÌ ´Ù¸¥ B ¼¼Æ÷ Ç׿øÀ» Ÿ°ÙÀ¸·Î ÇÏ´Â Ä¡·áÁ¦ÀÇ ÀÓ»ó Å×½ºÆ®µµ ÁøÇà Áß¿¡ ÀÖ´Ù (D¡¯Aloia
et al. 2018).
±×¸² 2. CAR T ¼¼Æ÷ ±¸Á¶ÀÇ ÁøÈ
Building on the original CAR T-cell technology, later generations have incorporated additional elements to aid in T-cell persistence, proliferation, cytokine production, and survival. Fourth-generation CAR T cells (termed "armored CARs") use modified second-generation CAR T cells engineered to express and secrete cytokines to improve efficacy. Image: Monica Casucci and Attilio Bondanza / Public Domain.
[¿ø¹®] CAR T-cell therapy: the latest weapon in the fight against cancer
[Âü°í¹®Çå]
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