現行美國FDA核准之細胞與基因療法

基因治療導讀

目前美國食品藥物管理局(Food and Drug Administration, FDA)核可的細胞與基因療法共34項，應用於癌症、血液疾病、罕見疾病、和第一型糖尿病，以及作為細胞支架。首先，在癌症領域核可的基因療法共有9項。BREYANZI (lisocabtagene maraleucel)、YESCARTA(axicabtagene ciloleucel)、KYMRIAH (tisagenlecleucel)和TECARTUS (brexucabtagene autoleucel)均為CD19導向的基因改造自體(autologous) T細胞免疫療法。BREYANZI和YESCARTA適用於治療後復發(relapse)或難治(refractory)的大型B細胞淋巴瘤(large B-cell lymphoma, LBCL)患者；KYMRIAH適用於治療後復發或難治的濾泡型淋巴瘤(follicular lymphoma)；TECARTUS 則適用於復發或難治性的被套細胞淋巴瘤(Mantle cell lymphoma, MCL)和B細胞前驅急性淋巴細胞白血病(acute lymphoblastic leukemia, ALL)患者^1-4。ABECMA (idecabtagene vicleucel)和CARVYKTI (ciltacabtagene autoleucel)兩者均為B細胞成熟抗原(B-cell maturation antigen, BCMA)導向的基因修改自體T細胞免疫療法，適用於接受過包含免疫調節劑、蛋白酶體抑制劑和抗CD38單株抗體等四種以上的前線治療後，疾病復發或難治的多發性骨髓瘤(multiple myeloma)成人患者^5,6。ADSTILADRIN (nadofaragene firadenovec-vncg)是非複製型(non-replicating)的腺病毒載體基因治療，適用於對BCG疫苗不敏感的非肌肉侵襲性膀胱癌(on-muscle invasive bladder cancer, NMIBC)患者⁷。IMLYGIC (talimogene laherparepvec)為基因改造的腫瘤溶解(oncolytic)病毒療法，可作為黑色素瘤患者在初次手術後復發無法切除之表皮、皮下和淋巴結病灶的局部治療⁸。PROVENGE (sipuleucel-T)則為自體細胞免疫療法，適用於無症狀或症狀輕微的轉移性去勢抗性前列腺癌(castration-resistant prostate cancer, CRPC)⁹。

接著，共有9項核可的基因治療為臍帶血相關項目。ALLOCORD、CLEVECORD、Ducord、HEMACORD，以及來自University of Colorado、MD Anderson、LifeSouth、Bloodworks臍帶血銀行的臍帶血，上述8項均為異體(allogeneic)的臍帶血造血前驅細胞(hematopoietic progenitor cell)療法，適用於非親屬捐贈(unrelated donor)的造血前驅細胞移植，與適當的預備療法(Preparative regimen)一同進行，針對患有影響造血系統的遺傳性、後天性或骨髓盡除 (myeloablative)治療引起之疾病的患者可進行造血和免疫重建^10-17。而OMISIRGE(omidubicel-onlv)則是源自臍帶血經菸鹼醯胺改造的異體造血前驅細胞治療，適用於計劃在骨髓盡除式前置化療後接受臍帶血移植且12歲以上的成人和小兒血液惡性腫瘤患者，以縮短中性球的恢復時間和感染發生率¹⁸。

針對造血疾病共有5種治療，主要應用於鐮刀型貧血(sickle cell disease, SCD)、血友病、和β型地中海貧血(β thalassemia)的患者。應用於SCD患者的兩項治療分別為CASGEVY exagamglogene Autotemcel (exa-cel)]和LYFGENIA[lovotibeglogene autotemcel (lovo-cel) ]，兩者均為自體造血幹細胞基因療法，可治療12歲以上患有復發性血管閉塞性危機(Vaso occlusive crises, VOC)的SCD患者^19,20。血友病患者亦有兩項治療HEMGENIX(etranacogene dezaparvovec-drlb)和ROCTAVIAN(valoctocogene roxaparvovec-rvox)，均為以腺相關病毒(Adeno-Associated Virus, AAV)載體為基礎的基因治療。HEMGENIX用於治療患有曾發生危及生命的出血或反覆嚴重自發性出血的B型血友病成人患者，ROCTAVIAN則用於無既有抗AAV第5血清型的嚴重A型血友病成人患者^21,22。最後，ZYNTEGLO(betibeglogene autotemcel)則為自體造血幹細胞為基礎的基因療法，適用於需要定期輸血的成人和小兒β型地中海貧血患者²³。

針對不同的罕見疾病共有6項治療被核可。ELEVIDYS (delandistrogene moxeparvovec-rokl)、LUXTURNA (voretigene neparvovec-rzyl)和ZOLGENSMA (onasemnogene abeparvovec-xioi)均為以AAV載體為基礎的基因治療。ELEVIDYS適用於4至5歲患有裘馨氏肌肉失養症（Duchenne muscular dystrophy, DMD）且不需臥床的兒童。LUXTURNA適用於確認患有雙等位RPE65突變相關視網膜失養症(biallelic RPE65 mutation-associated retinal dystrophy)的患者。ZOLGENSMA則適用於2歲以下患有脊髓性肌肉萎縮症(spinal muscular atrophy, SMA)且運動神經元存活基因1 (survival motor neuron gene, SMN1)中具有雙等位突變的患者^24-26。 RETHYMIC為經處理的異體胸腺組織(allogeneic processed thymus tissue–agdc)使用於先天性無胸腺症(congenital athymia)小兒患者的免疫重建²⁷。SKYSONA(elivaldogene autotemcel)以慢病毒載體(lentiviral vector, LVV)為基礎，能減緩4至17歲早期且處於活躍期的腦腎上腺腦白失養症(cerebral adrenoleukodystrophy, CALD)患者之神經功能障礙惡化²⁸。VYJUVEK (beremagene geperpavec)以第一型單純皰疹病毒( herpes simplex virus type1, HSV-1 )為基礎，適用於6個月以上患有失養型表皮溶解水泡症( dystrophic epidermolysis bullosa)且膠原蛋白第VII型α1鏈(COL7A1)基因突變的患者治療其傷口²⁹。

FDA亦核可4種不同用途的細胞支架(allogeneic cellularized scaffold)。GINTUIT為牛膠原蛋白異體培養之角質細胞和纖維母細胞(Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen)可局部塗抹於手術創建的血管性傷口床，以治療成人的黏膜牙齦問題³⁰。 LAVIV(Azficel-T)應用於改善中重度法令紋(nasolabial folds)之外觀³¹。 MACI為豬膠原蛋白膜上自體培養的軟骨細胞 (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane)，可修復有症狀的單一或多重的全層軟骨缺損³²。 STRATAGRAFT為小鼠膠原蛋白中異體培養的角質細胞和真皮纖維母細胞，包含完整的真皮元素可用於臨床上需手術的深層部分皮層(deep partial-thickness)燒燙傷³³。

最後，一項基因治療核可用於糖尿病患者，即異體胰島細胞LANTIDRA(donislecel-jujn)，適用於已接受密集糖尿病處置和教育後仍反覆發生嚴重低血糖，無法達到HbA1c目標的第一型糖尿病成人患者³⁴。

References

BREYANZI (lisocabtagene maraleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel.
YESCARTA (axicabtagene ciloleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta.
KYMRIAH (tisagenlecleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah.
TECARTUS (brexucabtagene autoleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus.
ABECMA (idecabtagene vicleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel.
CARVYKTI (ciltacabtagene autoleucel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/carvykti.
ADSTILADRIN (nadofaragene firadenovec-vncg). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin.
IMLYGIC (talimogene laherparepvec). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/imlygic.
PROVENGE (sipuleucel-T). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/provenge-sipuleucel-t.
ALLOCORD (HPC Cord Blood). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/allocord-hpc-cord-blood.
CLEVECORD (HPC Cord Blood). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/clevecord-hpc-cord-blood.
DUCORD (HPC Cord Blood). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/ducord-hpc-cord-blood.
HEMACORD (HPC, Cord Blood). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/hemacord-hpc-cord-blood.
HPC (Cord Blood). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/hpc-cord-blood.
HPC, Cord Blood - MD Anderson Cord Blood Bank. U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/hpc-cord-blood-md-anderson-cord-blood-bank.
HPC, Cord Blood – LifeSouth. U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/hpc-cord-blood-lifesouth.
HPC, Cord Blood – Bloodworks. U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/hpc-cord-blood-bloodworks.
OMISIRGE (omidubicel-onlv). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/omisirge.
CASGEVY (exagamglogene autotemcel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/casgevy.
LYFGENIA (lovotibeglogene autotemcel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/lyfgenia.
HEMGENIX (etranacogene dezaparvovec-drlb). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix.
ROCTAVIAN (valoctocogene roxaparvovec-rvox). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/roctavian.
ZYNTEGLO (betibeglogene autotemcel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/zynteglo.
ELEVIDYS (delandistrogene moxeparvovec-rokl). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys.
LUXTURNA (voretigene neparvovec-rzyl). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna.
ZOLGENSMA (onasemnogene abeparvovec-xioi). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/zolgensma.
RETHYMIC (allogeneic processed thymus tissue–agdc). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/rethymic.
SKYSONA (elivaldogene autotemcel). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/skysona.
VYJUVEK (beremagene geperpavec-svdt). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/vyjuvek.
GINTUIT (allogeneic cultured keratinocytes and fibroblasts in bovine collagen). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/gintuit-allogeneic-cultured-keratinocytes-and-fibroblasts-bovine-collagen.
LAVIV (azficel-T). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/laviv.
MACI (autologous cultured chondrocytes on porcine collagen membrane). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/maci-autologous-cultured-chondrocytes-porcine-collagen-membrane.
STRATAGRAFT (allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen-dsat). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/stratagraft.
LANTIDRA (donislecel-jujn). U.S. Food and Drug Administration. Accessed on 13 May 2025 at: https://www.fda.gov/vaccines-blood-biologics/lantidra.