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Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis

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Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis

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In the future, it is likely that rational decisions on the use of anti¡VPD-1/L1 antibody therapy alone or in combination will be based on the assessment of the presence or absence of tumor antigen¡Vspecific T cells that are inhibited by PD-L1 expression by cancer cells.

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PD-L1 positivity is only desirable in the context of treatment targeting the PD-1¡VPD-L1 interaction, as in the absence of this therapy it may be a mechanisms of immune escape that is only beneficial to the cancer cells.

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What does PD-L1 positive or negative mean?

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1. PD-1¬O§K¬ÌT²Ó­M¸Ìªº·Å©M¬£(¥D©M¤£¥D¾Ô¡A¥­±`¦b°ê¤º´N·|ªý¤î¥»°ê­x¤H(§K¬ÌT²Ó­M)§ðÀ»¥­¥Á(°·±d²Ó­M))¡A§K¬Ì²Ó­M¸Ì¤]¦³PD-L1

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Development History and FDA Approval Process for Tecentriq

Date Article

Apr 17, 2017 FDA Grants Genentech¡¦s Tecentriq (atezolizumab) Accelerated Approval as Initial Treatment for Certain People with Advanced Bladder Cancer

Oct 18, 2016 FDA Approves Genentech¡¦s Cancer Immunotherapy Tecentriq (Atezolizumab) for People with a Specific Type of Metastatic Lung Cancer

May 18, 2016 FDA Approves Tecentriq (atezolizumab) for Urothelial Carcinoma

Apr 10, 2016 FDA Grants Priority Review for Genentech¡¦s Cancer Immunotherapy Atezolizumab in Specific Type of Lung Cancer

Mar 14, 2016 FDA Grants Genentech¡¦s Cancer Immunotherapy Atezolizumab Priority Review for Advanced Bladder Cancer

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¦Ñ´­¤j±z¦n, °O±o±z´¿¸g»¡¹L, ¦Û¦³¸êª÷¤£Ä@·N³QÂê¤T¦~, ½Ð°Ý¬°¦ó«á¨Ó¦ü¥G§ë¤J°Ñ»P¨ì33.6/63µ¥¨p¶Ò»ù?

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MBE¤j¡AÁÂÁ§󥿡I¤£ºÞ¬O¬P¬PÁÙ¬O·à¤l¡AªÑ»ù©M¦Ñ´­³£¨S¦³Ãö«Y¤F¡I³o¼Ë¤À¨É°_¨Ó¤~¨S¦³À£¤O¡A¤£µM

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¦¨¥»¦Ü¹s¦¨¥»¡I§ë¸ê¾Þ§@¬O­Ó¤Hªº¨Æ¡A¦³¤H­n¶ú§ª®âÅB¦Ñ´­¤]¨S¿ìªk¡I

³ßÅw¬Ý¦Ñ´­ªº¤À¨É´N½Ð«ùÄòÃöª`¡A¤£³ßÅw¬Ýªº¤]¥i¥H¨Ó½|¨â¥y±·­Ó¤H³õ¡I

sunshine¤j¡B¥Í§Þ007¤j¡A¤£­n¦A²K¶Ã¤F¡I¦Ñ´­©M»«¹£³£¬O´²¤á¡A¨S¦³¨º»ò¤jªº¨{¤l¡I·í¤UªºªÑ»ù¤£¯à«æº¦¡A

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»aÃǤj¡A±zªº²Ä¤@­Ó°ÝÃD¦^µª¦p¤U

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed

in Patients With Argininosuccinate Synthetase 1¡VDeficient Thoracic Cancers

Journal of Clinical Oncology 2017 Beddowes, Emma et al

±q¤¤Â^¨údiscussionªº¤º¤å

Arginine suppression with the ADIPemCis triplet was more prolonged than that which was

observed previously with ADI-PEG 20 monotherapy. In the ADAM monotherapy study, arginine was

depleted to below 30% of baseline for 7 weeks, but by 9 weeks, arginine concentrations

had returned to pretreatment levels, with a corresponding fall in citrulline concentrations.

Arginine suppression was also detected for the first 8 weeks only, before reaching

baseline levels by week 12, in a recent phase 1 combination study of ADI-PEG20 combined

with docetaxel in solid tumors. In contrast, with the ADIPemCis regimen, arginine concentrations

remained depleted compared with baseline levels until the end of treatment,

and citrulline concentrations were persistently elevated. Anti¡VADI-PEG 20 antibodies increased

gradually, then seemed to reach a plateau at approximately 10-3¦¸¤è by 8 to 10 weeks.

Interestingly,this was in contrast to samples taken from patients treated in the monotherapy and

docetaxel combination study, in which anti¡VADI-PEG 20 antibodies increased rapidly and reached

10-3 by 9 weeks, followed by a continued increase in titers (10-5 to 10-6) before reaching

a plateau by 16 weeks. Prolonged arginine depletion may be caused by the suppression of neutralizing

anti¡VADI-PEG 20 antibodies by pemetrexed and cisplatin, especially cisplatin, and by the use of

concomitant corticosteroids as chemotherapy premedication.

·N«ä¬O¤°»ò©O¡H(¥m¾´¤]¬Ý¬Ý§a¡A¥H«eÃi±o¦^À³§A¡A³o½g¦b¬P¤Í¸s¦­´N°Q½×¹L¤F¡AÅý§A¨Ó¶Ã¤@¤U¶¶«K¬~¤@¬~«H¤ß¤£Ã­©wªº´²¤á¡I)

1. ADI³æ¤@¥ÎÃĪºADAM study(ªÍ¶¡¥ÖÀù)¡A±qbaseline¶}©l¥i¥Î­°¸ÑArg.¦Ü¤Ö©ó30%¥i¹F7wks, ¨ì9wks®É§Y«ì´_ªvÀø«eªºª¬ªp¡I

¬Û¹ïÀ³ªºcitrulline¤W¤É¥çµM¡I

2. ¦bADI+docetaxelªºÁp¦X¥ÎÃÄ¡A­°¸ÑArg.«h¹F¨ì8wks, ¨ì12wks®É§Y«ì´_ªvÀø«eªºª¬ªp¡I

3. ¦ý¬O¦bADI+Pem+Cis«o¦³¤jµo²{¡÷­°¸ÑArg.ª½¨ì¡´Àøµ{µ²§ô¡I¬Û¹ïÀ³ªºcitrulline¤W¤É¥çµM¡I

4. ¦Óanti-adi-peg20§ÜÅé¤]²£¥Íªº«Ü½wºC¡A¨ì8-10wks®É²£¥Í¦Ü10-3¦¸¤è´N¡´¤£¦A²£¥Í¡I¦Ó¦b³æ¤@¥ÎÃÄ©MADI+docetaxelÁp¦X¥ÎÃÄ

anti-adi-peg20§ÜÅé²£¥Íªº«D±`§Ö³t¡A¨ì9wks®É²£¥Í¦Ü10-3¦¸¤è¡A¨ì16wks®É²£¥Í¦Ü10-6¦¸¤è¤~°±¤î¡I

5. ©Ò¥HBeddowes»{¬°³o´N¬OPem+CisªºÃö«Y¡A¤×¨ä¬OCis¡A©MªvÀø«eª`®gªºÃþ©T¾J¥i¯à¤]¦³¤@ÂI¬ÛÃö©Ê¡I

¡´­«ÂI´N¬O¥_·¥¬P¦b³æ¤@¥ÎÃĸѪ¼¥¢±Ñ«á¡A¨³³t§ä¨ìÁpÃĪºÃöÁä¦]¯À¡AÁpÃĪvÀù¬OÁͶաI¬°¤°»ò¥xÆWªº¥Í§Þ¤½¥q«o¥u¦³¥_·¥¬P³o»ò¿n·¥

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»aÃǤj¡A±zªº²Ä¤G­Ó°ÝÃD¦^µª¦p¤U

¡´ADI-PEG20ªvÀø·|¦b24~48¤p®É¶¡¿Eµointerferon- alpha/betaªºÄÀ©ñ¡A»¤¾ÉASS1-negative ªºMPM²Ó­M®èªºPD-L1ªí¹F

(·N¸q¡÷ ¥¼¨ÓÁp¦X¥ÎÃĮɡA¥ýµ¹ADI«á²Ä¤G¤Ñ¦Aµ¹anti-PD1 ÃĪ«)

¡´³o­Ó³¡¤ÀADI+KeytrudaÀ³¸Ó´N¬O³o¼Ë°µªº¡÷ADI-PEG 20 (36 mg/m2) weekly in combination

with pembrolizumab (1 and 2 mg/kg or 200 mg) every three weeks¡÷²Ä¤@¤Ñ¥´ADI¡÷

²Ä2 ©Î 3¤Ñ¥´Keytruda¡÷²Ä8,15,22¤Ñ¦A¥´ADI¡÷²Ä23 or 24¤Ñ¥´Keytruda.......

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¥H¤W¥u¦³¾Ç³N¯Â°Q½×­È±o¬Ý¡A¨ä¥Lªº¯º¯º´N¦n¡A¤£¥i·í§@§ë¸ê¨Ì¾Ú¡I

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Received: 3 January 2017 Accepted: 13 July 2017

Published online: 12 Sem 2017

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