WikiPathologica

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CAR-T; Cellular immunotherapy using chimeric antigen receptor-expressing T-cells

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¤·¤«¤·, ¤¬¤óÆÃ°ÛÀ­¤Î¤Ê¤¤TºÙ˦¤òºÆÃíÆþ¤·¤Æ¤âÎ×¾²¸ú²Ì¤Ï¤Ê¤«¤Ã¤¿. ¥Û¥ë¥Þ¥ê¥ó¸ÇÄê¥Ñ¥é¥Õ¥£¥óÊñËäÁÈ¿¥¤«¤é¡Ö¤¬¤ó¹³¸¶¡×¤È¾Î¤¹¤ë¤â¤Î¤ò¼è¤ê½Ð¤·, ¤½¤ì¤ÇÌȱÖÉê³è¤·¤¿TºÙ˦¤òºÆÃíÆþ¤¹¤ë¼£ÎŤâ, °ìÉô¤ÎÎã³°¤ò½ü¤¤¤Æ¤Ï¸ú²Ì¤¬³Îǧ¤Ç¤­¤Ê¤«¤Ã¤¿.
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°ìÉô¤ÎÎã³°¤È¤·¤Æ¤Ï, °­À­¹õ¿§¼ð(melanoma)¤Ë¤ª¤¤¤Æ, ¤¬¤ó¹³¸¶ÆÃ°ÛŪ¤Ê¥¨¥Õ¥§¥¯¥¿¡¼TºÙ˦¤ò´Þ¤àºÙ˦½¸ÃĤÎÃíÆþ¤Ç¼£ÎŸú²Ì¤ò¼¨¤¹¾ÉÎ㤬Êó¹ð¤µ¤ì¤Æ¤¤¤ë. (TIL; tumor-infiltrating lymphocyte).
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CAR-TÎÅË¡*1

¤¬¤óÆÃ°ÛÀ­¤ò¤â¤¿¤Ê¤¤TºÙ˦¤Ë°äÅÁ»ÒÁàºî¤Ë¤è¤ë²þÊѤò²Ã¤¨¤Æ, Ëö¾¿·ì¤«¤é, ¤¬¤óÆÃ°ÛÀ­¤ò³ÍÆÀ¤·¤¿¥¨¥Õ¥§¥¯¥¿¡¼TºÙ˦¤òÂçÎ̤Ë, ³Î¼Â¤ËºîÀ®¤¹¤ëµ»½Ñ(°äÅÁ»Ò²þÊÑ·¿TºÙ˦ÎÅË¡)¤òÍѤ¤¤ë¼¡À¤Âå¤ÎÍÜ»ÒÌȱÖÎÅË¡¤Î¤Ò¤È¤Ä¡£

 
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chimeric antigen receptor(CAR)¤Îʬ»Ò¹½Â¤¤Ï, ¼ðáçºÙ˦ɽÌ̹³¸¶¤òǧ¼±¤¹¤ë¥â¥Î¥¯¥í¥Ê¡¼¥ë¹³ÂÎͳÍè¤ÎLº¿¤ÈHº¿¤Î²ÄÊÑÎΰè(VL, VH)¤òľÎó¤Ë·ë¹ç¤µ¤»¤¿°ìËܺ¿¹³ÂÎ(single chain variable fragment: scFv)¤ÈTºÙ˦¼õÍÆÂΤÎCD3 ¦Æº¿¤ò·ë¹ç¤µ¤»¤¿¥­¥á¥é¥¿¥ó¥Ñ¥¯¼Á.

°ìËܺ¿¹³ÂΤÈCD3¦Æº¿¤Î´Ö¤Ë¤ÏºÙ˦³°¥Ò¥ó¥¸¥É¥á¥¤¥ó, Ëì´ÓḀ̈ɥᥤ¥ó, TºÙ˦³èÀ­²½¤ËɬÍפʺÙ˦Æâ¥·¥°¥Ê¥ëÅÁã¥É¥á¥¤¥ó¤¬ÁȤ߹þ¤Þ¤ì¤Æ¤¤¤ë.

¹³ÂΤòÁȤ߹þ¤ó¤À¥­¥á¥é¥¿¥ó¥Ñ¥¯¼Á¤Ë¤è¤Ã¤ÆTºÙ˦¤Ë¹³¸¶ÆÃ°ÛÀ­¤òÉÕÍ¿¤¹¤ë¹Í¤¨¤Ï1989ǯ¥¤¥¹¥é¥¨¥ë¤Î¥°¥ë¡¼¥×¤Ë¤è¤êÄ󾧤µ¤ì¤¿.*2

CAR¤ÎºÙ˦³°¥Ò¥ó¥¸¥É¥á¥¤¥ó¤äËì´ÓḀ̈ɥᥤ¥ó¤Ë¤ÏCD8¦Á¤äCD28¤Ê¤É¼ï¡¹¤Îʬ»ÒͳÍèÇÛÎ󤬻Ȥï¤ì, ¤½¤Î¥Ç¥¶¥¤¥ó¤Ë¤è¤êCAR¤Îȯ¸½¸úΨ¤äµ¡Ç½¤¬º¸±¦¤µ¤ì¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.

CARʬ»Ò¤ÏºÙ˦Æâ¥·¥°¥Ê¥ëÅÁã¥É¥á¥¤¥ó¤Î¹½Â¤¤Ë¤è¤êÂè°ì¤«¤éÂè»°À¤Âå¤Þ¤Ç¤ËʬÎव¤ì, Âè°ìÀ¤Âå¤ÏCD3¦Æº¿¤Î¤ß, ÂèÆóÀ¤Âå¤ÏCD3¦Æº¿¤Ë, CD28¤Þ¤¿¤ÏCD137¤ÎTºÙ˦¶¦»É·ãʬ»Ò¥·¥°¥Ê¥ë¥É¥á¥¤¥ó¤ò²Ã¤¨¤¿¹½Â¤¤Ë¤Ê¤Ã¤Æ¤¤¤ë. Âè»°À¤Âå¤Îʬ»Ò¤Ï°Û¤Ê¤ë¶¦»É·ãʬ»Ò¤òÊ£¿ôÁȤ߹þ¤ó¤Ç¤¤¤ë.

ÂèÆó,Âè»°À¤Âå¤ÎCAR-TºÙ˦¤ÏÂè°ìÀ¤Âå¤ËÈæ³Ó¤·¤ÆÁý¿£Ç½, ¥µ¥¤¥È¥«¥¤¥ó»ºÀ¸Ç½, ºÙ˦¾ã³²³èÀ­¤¬¶¯¤¯, À¸ÂÎÆâ¤ÇĹ´ü¤ËÀ¸Â¸¤¹¤ë¤³¤È¤¬¼¨¤µ¤ì¤Æ¤¤¤ë. *3*4*5

CD137¤ò´Þ¤àºÙ˦Æâ¥·¥°¥Ê¥ëÅÁã¥É¥á¥¤¥ó¤Ï, CAR-TºÙ˦¤ÎÌȱÖÈèÊÀ¤òËɤ®, ¥»¥ó¥È¥é¥ë¥á¥â¥ê¡¼TºÙ˦¤Ø¤Îʬ²½¤ò²ð¤·¤ÆCAR-TºÙ˦¤ÎĹ´üÀ¸Â¸¤òͶƳ¤¹¤ëÅÀ¤Ç, CD28¤è¤ê¤âÍ¥¤ì¤Æ¤¤¤ë¤è¤¦¤Ç¤¢¤ë. *6*7
CAR-TºÙ˦ÎÅË¡¤Î¸ú²Ì¤ä°ÂÁ´À­¤Î¤¿¤á, ºÇŬ¤ÊCARʬ»Ò¹½Â¤¤Î³«È¯¤¬É¬ÍפǤ¢¤ë.

 
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CD137(4-1BB/ 4-1BB¥ê¥¬¥ó¥É ¥ì¥»¥×¥¿¡¼)

TºÙ˦¤ËÆÃ°ÛŪ¤Ê°äÅÁ»Ò¤òõº÷¤¹¤ë²áÄø¤Ç, ºÙ˦¾ã³²À­TºÙ˦¤È¥Ø¥ë¥Ñ¡¼TºÙ˦¤Ë¤ª¤¤¤Æcon A¤äTºÙ˦¥ì¥»¥×¥¿¡¼¹³ÂΤÇͶƳ¤µ¤ì¤Æ¤¯¤ëʬ»Ò¤Î°ì¤Ä¤È¤·¤ÆÃ±Î¥¤µ¤ì¤¿.
³èÀ­²½TºÙ˦¤ÎÁý¿£¤òÂ¥¿Ê¤¹¤ë¥ê¥ó¥Õ¥©¥È¥­¥·¥óÍͤÎ4-1BB¥ê¥¬¥ó¥É¤Î¥ì¥»¥×¥¿¡¼(¥µ¥¤¥È¥«¥¤¥ó¥ì¥»¥×¥¿¡¼)¤Ç¤¢¤ë.

ʬ»ÒÎÌ30-40kDa¤ÎËì·ë¹ç¥¿¥ó¥Ñ¥¯¤Ç238aa. NËöü¦169»Ä´ð¤ÏºÙ˦³°Îΰè¤Ç, 3¸Ä¤ÎTumor necrosis factor receptor(TNFR)¥É¥á¥¤¥ó¤ò´Þ¤à. TNFR¥É¥á¥¤¥ó¤ò¤â¤Äreceptor family¤Ë¤Ï, CD27, CD30, CD40, CD95(Fas), CD120a(p55TNFR, TNFR1),CD120b(p75TNFR, TNFR­¶), TNF receptor-related protein(TNF-RP), CD134(OX-40)¤Ê¤É¤¬Â°¤·¤Æ¤¤¤ë.

CD137¤Ï, ÇÝÍܺÙ˦¤Ç¤Ï, ³èÀ­²½¤ò¼õ¤±¤¿TºÙ˦¤À¤±¤Ç¤Ê¤¯, ³èÀ­²½¤µ¤ì¤¿BºÙ˦¤äñµå¤ÇͶƳ¤µ¤ì¤ë. 磤ǤÏ35-45%¤ÎTºÙ˦¤¬¹±¾ïŪ¤ËCD137¤òȯ¸½¤·¤Æ¤¤¤ë.

CD137Ligand(4-1BBL)¤Ïtype­¶·¿¤ÎË쥿¥ó¥Ñ¥¯¼Á¤Ç¥ê¥ó¥Õ¥©¥È¥­¥·¥óTNF¤ÈÁêÆ±À­¤ò¤â¤Ä. 4-1BBL¤ÏÀ®½ÏBºÙ˦¤ä¥Þ¥¯¥í¥Õ¥¡¡¼¥¸, ¹³CD3¹³ÂΤdzèÀ­²½¤µ¤ì¤¿ÆÃÄê¤ÎTºÙ˦, Á°¶îBºÙ˦¤ä̤½Ï¥Þ¥¯¥í¥Õ¥¡¡¼¥¸¤ËÄ㤤¥ì¥Ù¥ë¤Ç¸ºß¤¹¤ë.

CD137¤Ï³èÀ­²½TºÙ˦¤Ë¤ª¤¤¤Æ, CD80¤ÈƱÍͤʶ¦»É·ã¤òÍ¿¤¨¤ë¤³¤È¤Ë¤è¤êÁý¿£¤ä¥µ¥¤¥È¥«¥¤¥ó»ºÀ¸¤òÁý¶¯¤¹¤ëƯ¤­¤ò¤â¤Ã¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.

CAR-TºÙ˦ÎÅË¡¤ÎÎ×¾²»î¸³

1. CD19¤ò¥¿¡¼¥²¥Ã¥È¤Ë¤·¤¿CAR-TÎÅË¡¤Ç¤ÏÂè­¶Áê»î¸³(-->»²¹Í:¼£¸³wikipedia)¤¬¿Ê¹Ô¤·¤Æ¤¤¤ë.

  • Èó¥Û¥¸¥­¥ó¥ê¥ó¥Ñ¼ð, ALL, CLL¤Ê¤É¤ÎBºÙ˦·Ï°­À­¼ðáç¤ËCD28¤Þ¤¿¤Ï, CD137¤ò»È¤Ã¤¿ÂèÆóÀ¤Âå¤ÎCD19ɸŪCAR-TºÙ˦¤¬»ÈÍѤµ¤ì¤Æ¤¤¤ë.*8
     
  • ¾®»ù¡¦¼ãǯ¼Ô¤ÎºÆÈ¯Æñ¼£À­CD19+ALL´µ¼Ô¤µ¤ó¤òÂоݤȤ·¤¿ÂèI, Âè­¶ÁêÎ×¾²»î¸³¤Ç¤Ï, 36/39(92%)¤È¤¤¤¦¹â¤¤´°Á´´²²òΨ¤¬ÆÀ¤é¤ì¤Æ¤ª¤ê, ºÇ½é¤Î´µ¼Ô¤µ¤ó¤Ï2ǯ°Ê¾å¤ÎĹ´ü´²²ò¤ò°Ý»ý¤·¤Æ¤¤¤ë.*9
     
  • CD19ɸŪCAR-TÎÅË¡¤Ç¤Ï, ¼ðáçºÙ˦¤À¤±¤Ç¤Ï¤Ê¤¯, CD19+¤ÎÀµ¾ïBºÙ˦¤ò¹¶·â¤·BºÙ˦¤Î¾Ã¼º¤¬¤ª¤³¤ë.( on-target off-tumor toxicity¤È¤è¤Ö). ¤³¤ì¤ÏÍ­³²»ö¾Ý¤ÎÂåɽ¤Ç¤¢¤ë¤¬, ÀºÀ½immunoglobulinÅêÍ¿¤Ë¤è¤ê¤·¤Î¤°¤³¤È¤¬²Äǽ¤Ç¤¢¤ê¸½»þÅÀ¤Ç¤Ï½ÅÆÆ¤Ê´¶À÷¾É¤ÎÊó¹ð¤Ï¤Ê¤¤.
     
  • ¤¿¤À¤·on-target off-tumor toxicity¤ÏCD19ɸŪCAR-TÎÅË¡¤ÎÎ×¾²ÅªÌäÂêÅÀ¤Ç¤¢¤ê, ´²²ò¤òĹ´ü°Ý»ý¤¹¤ë¤¿¤á¤Ë¤É¤ì¤¯¤é¤¤¤Î´ü´ÖCAR-TºÙ˦¤òÀ¸ÂÎÆâ¤Ç°Ý»ý¤¹¤ëɬÍפ¬¤¢¤ë¤Î¤«¤Ï¤Þ¤ÀÌÀ¤é¤«¤Ç¤Ï¤Ê¤¤.
     
  • ɸŪ¤¬¤óºÙ˦¤ÎCD19ɽÌ̹³¸¶¾Ã¼º¤ä, ÁªÂòŪ¥¹¥×¥é¥¤¥·¥ó¥°¤Ë¤è¤ëÊѰۤÇCAR-T¤Îǧ¼±¤ò²óÈò¤¹¤ë¤³¤È¤¬Êó¹ð¤µ¤ì¤Æ¤¤¤ë.*10

2. Hodgkin lymphoma¤ÎCD30¤òɸŪ¤È¤¹¤ëCAR-T*11

3. CLL¤äMantle cell lymphoma¤Ê¤É¼ï¡¹¤Î¤¬¤óºÙ˦¤Ëȯ¸½¤¹¤ëROR1(receptor thyrosine kinase-like orphan receptor 1)ɸŪCAR-T*11. ROR1¤Ï°­À­BºÙ˦¤ËÆÃ°ÛŪ¤Ëȯ¸½¤¹¤ë¤³¤È¤«¤éÀµ¾ïBºÙ˦¤ËÂФ¹¤ëon-target off-tumor toxicity¤¬¤Ê¤¤¤È¤µ¤ì¤Æ¤¤¤ë.

4. Èó¥Û¥¸¥­¥ó¥ê¥ó¥Ñ¼ð¤ä¿ȯ¹ü¿ñ¼ð, CLL¤ÎIgG kappa ·Úº¿¤òɸŪ¤Ë¤¹¤ëCAR-T*11

5. AML¤Ë¤Ä¤¤¤Æ¤ÏÀµ¾ï´´ºÙ˦¤Ëȯ¸½¤»¤º, ¼ðáçºÙ˦ÆÃ°ÛŪ¤Ê¹³¸¶¤ÎÁªÂò¤¬ÆñÌä¤Ç¤¢¤ë¤¬, IL-3R¦Á/CD123, CD33, Lewis-Y¤Ê¤É¤ÎCAR-T¤ÎɸŪʬ»Ò¤¬¸¡Æ¤¤µ¤ì¤Æ¤¤¤ë.

6. Multiple Myeloma¤Ë¤Ä¤¤¤Æ¤Ï, Lewis-Y, IgG kappa¤òɸŪ¤È¤·¤¿Î×¾²»î¸³¤Ë²Ã¤¨¤Æ, CD138, BCMA(B cell mutation antigen),CS1(CD319/SLAMF7)¤òɸŪ¤ÎCAR-T¤¬¸¡Æ¤¤µ¤ì¤Æ¤¤¤ë.


*1  ¶ÌÅĹ̼£ ¥­¥á¥é¹³¸¶¼õÍÆÂΰäÅÁ»ÒƳÆþTºÙ˦ÎÅË¡(CAR-TºÙ˦ÎÅË¡) ¼Â¸³°å³Ø 2016; 34(12): 173-178
*2  Gross G et al. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10024-8.
*3  Savoldo B, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011 May;121(5):1822-6.
*4  Milone MC, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009 Aug;17(8):1453-64.
*5  Carpenito C, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3360-5.
*6  Long AH, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015 Jun;21(6):581-90.
*7  Kawalekar OU,et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. 2016 Feb 16;44(2):380-90.
*8  Frey NV, Porter DL. CAR T-cells merge into the fast lane of cancer care. Am J Hematol. 2016 Jan;91(1):146-50
*9  Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17.
*10  Sotillo E, et al. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015 Dec;5(12):1282-95. doi: 10.1158/2159-8290.CD-15-1020. Epub 2015 Oct 29.
*11  Ramos CA, et al. CAR-T Cell Therapy for Lymphoma. Annu Rev Med. 2016;67:165-83.

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Last-modified: 2019-02-21 (ÌÚ) 20:13:03 (703d)