美國FDA目前所通過的兩個CAR-T療法都是透過自體細胞移植的方式進行,自體移植相對安全,但目前在製程仍較繁瑣且製造成本非常高。製程從病人血液中分離出T細胞開始,然後於體外進行細胞擴增及基因編輯,後續的純化、分析及QC檢測也是有相當多的流程要進行,要能順利進行一次製程就成功得到CAR-T細胞其實並是一件容易的事情,而且細胞在體外培養的過程中非常有可能因為一個環節的失誤而死亡。CAR-T是否能有機會變成一種隨手可取得的異體移植(Allogenic)療法呢? 相較於自體移植,異體移植成為的最重要的優勢就是方便且快速,病人不需等待漫長的細胞製程,醫療單位可以隨時取得現成可用的細胞來進行治療。下表為統整出來目前各生技藥廠正在開發的新一代CAR-T療法的計畫,從中可以看到目前僅有一間公司(Cellectis)正在進行異體移植的CAR-T開發計畫,目前已經進入臨床試驗一期,而另一個目前只有進行到臨床前試驗,其他CAR-T的都是以自體移植技術為主。
今年在美國有兩家新成立的公司Allogene Therapeutics及 Celularity分別籌資3億及2.5億美金要進行異體移植的CAR-T細胞治療技術的開發,其中Allogene和Cellectis開發的標的都是UCART19 (CD19-directed CAR-T cell therapy)。若異體移植的CAR-T能開發成功,在未來應該很有機會能夠成為具有商業規模的癌症治療方式。
Developer | Therapy | Description | Target | Indication | Clinical stage |
---|---|---|---|---|---|
Autolus | AUTO2 | Dual-targeting autologous CAR-T cell therapy directed at APRIL, a natural ligand for BCMA and TACI and incorporating the RQR8 suicide switch controlled by Rituxan (rituximab) | BCMA, TACI | Multiple myeloma | Phase 1/2 |
Cellectis, Servier (Suresnes, France) Pfizer | UCART19 | Allogeneic CAR-T cells gene edited with TALENS to disrupt the genes encoding the a-chain of TRAC to reduce risk of graft versus host disease and CD52 to confer Campath resistance | CD19 | Adult relapsed/refractory B-cell acute lymphoblastic leukemia | Phase 1 |
Bellicum Pharmaceuticals (Houston) | BPX-601 | GoCAR-T cell product comprising autologous T-cells containing a MyD88/CD40 activation switch controlled by rimiducid, which amplifies T-cell expansion via toll-like receptor and CD40 signaling | Prostate stem cell antigen | Pancreatic cancer | Phase 1 |
Celyad | Cyad-101 | Autologous T cells engineered to express NKG2D receptor that binds stress ligands | Allows targeting of multiple tumor types | Seven refractory solid and hematological cancers | Phase 1 |
Celularity, Sorrento Therapeutics (San Diego) | CD38 CAR-T | Autologous CAR-T cell therapy based on adult T cells to be followed by allogeneic CAR-T cell therapies based on placental T cells and placental natural killer cells modified to express a CD38- directed CAR, with disruptions in the TCR and b2 microglobulin loci | CD38 | Multiple myeloma | Phase 1 |
CRISPR Therapeutics (Zug, Switzerland) | CTX101 | CD19-directed allogeneic CAR-T cell therapy with CRISPR–Cas9-mediated disruption of the TRAC and b2 microglobulin loci | CD19 | B-cell malignancies | Preclinical |
Poseida Therapeutics (San Diego) | P-BCMA-Allo1 | Allogeneic CAR-T cells genetically modified with the nonviral piggyBac DNA transposition system and further modified with CRISPR-engineered deletions of the TCR and b2 microglobulin genes | B-cell maturation antigen (BCMA) | Multiple myeloma | Preclinical |
Ziopharm Oncology, University of Texas MD Anderson Cancer Center (Houston) | CD19 third generation CAR with mbIL15 (P-O-C) | Autologous CAR-T cells genetically modified with the Sleeping Beauty transposon system to express CD19 and membrane-bound interleukin 15 (mbIL15) | CD19 | Leukemia, lymphoma | Preclinical |
參考資料: NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 5 MAY 2018
今年在美國有兩家新成立的公司Allogene Therapeutics及 Celularity分別籌資3億及2.5億美金要進行異體移植的CAR-T細胞治療技術的開發,其中Allogene和Cellectis開發的標的都是UCART19 (CD19-directed CAR-T cell therapy)。若異體移植的CAR-T能開發成功,在未來應該很有機會能夠成為具有商業規模的癌症治療方式。
Allogene Therapeutics Pipeline
Celularity Pipeline
參考資料: NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 5 MAY 2018