TTLC21也開了但和WCLC太近，先不更新了，CAR-TCR 順序比較亂，都是看到哪算哪，有些是個人興趣就展開了一下，有些就是湊個圖
細胞治療未來：實體瘤、多靶向、克服TME、通用型
共刺激結(jié)構(gòu)域
CD28共刺激域使細胞依靠糖酵解，向效應(yīng)T細胞分化，而4-1BB促進線粒體生成，增強呼吸作用和脂肪酸氧化，優(yōu)先分化為中央記憶T細胞，免疫信號上：CD28更快、更強，而4-1BB則相對慢、溫和
TCR-T上表達PD1-4 1BB：胞外PD-1識別腫瘤表面PD-L1，然后胞內(nèi)傳導(dǎo)的是4-1BB共刺激信號
CYAD-101：靶向NKG2D治療MSS CRC的allo CAR-T
引入TIM降低CD3ζ結(jié)合TCR 旨在消除避免GvHD，同時還有選擇性的CD19 marker，這些與CAR一起構(gòu)建編碼，允許通過單次轉(zhuǎn)導(dǎo)就產(chǎn)生同種異體T細胞，便于實際生產(chǎn)，結(jié)果沒有報道DLT和GVHD，也觀察到了初步的療效，半數(shù)以上的患者腫瘤縮小
而后續(xù)產(chǎn)品采取了shRNA敲低CD3ζ
然后是ATARA基于同種異體的EBV-T細胞開發(fā)CAR-T或TCR-T，因為EBV-T特異性識別EBV感染的細胞很少會影響正常細胞，也正是利用這個特點
聯(lián)合治療的策略：增強療效以及在實體瘤中的浸潤
做ARi的怎么選了“”Enhancing Immune Infiltration in the Solid TME“的topic？
Axi-Cel中相關(guān)的毒性及管理
主要是 CRS、 ICANS和 B-cell aplasia及發(fā)生時間、應(yīng)對策略
病毒載體 vs 非病毒載體
Biomarker在CAR-T治療中的應(yīng)用：患者鑒定評估、PK監(jiān)測和PD的論證
德國的Christian Buchholz教授展示了in vivo制備CAR-T，其實他們體內(nèi)制備CAR-T的方法可以追溯到12年在blood上的T-cell receptor gene transfer exclusively to human CD8(+) cells enhances tumor cell killing （DOI: 10.1182/blood-2012-02-412973）：是通過LV（lentiviral vector）顆粒表面展示結(jié)合CD8或CD4的抗體片段特異性結(jié)合CD8+ T或CD4+ T，從而將含特異性CAR基因的慢病毒轉(zhuǎn)入T細胞，實現(xiàn)體內(nèi)制備：
Proposed mechanisms of enhanced tumor cell killing by CD8-LV-transduced t cells. For transduction with a tumor-specific tCr-coding gene, CD8-LV binds to CD8 via CD8-specific OKt8-derived fragments (blue triangle) displayed on the surface of the vector particle. CD8-LV-transduced cells (upper panel) express higher levels of CD8 than cells transduced by the conventional vector VsV-G-LV, which enters cells independently of CD8 (lower panel). the enhanced CD8 level (reflected by the number of CD8 molecules) and activation of t-cell effector functions promoted by the OKt8-derived fragment (depicted with a color change from blue to pink), enhances the sensitivity of the tCr expressed on CD8 + effector cells for peptide MhC (p-MhC) complex recognition and reduces the cell activation threshold. Consequently, upon tumor cell restimulation, CD8-LV-transduced cells become more activated (red color) than VsV-G-LV-transduced cells (orange color), producing higher levels of granzyme B (GrB) and perforin, and hence being more efficient at tumor cell lysis.
CAR-MILs（骨髓浸潤淋巴細胞）
大多數(shù)細胞療法依賴于來自外周的淋巴細胞，但MILs來源于骨髓，骨髓是記憶T細胞的天然儲庫，基于MILs細胞治療產(chǎn)品可能就具有固有的腫瘤特異性、記憶表型造成的最大細胞毒性以及持久性等獨特功能，特別適用于自體細胞治療
https://doi.org/10.1182/blood-2018-99-118580
We have developed a novel platform for ACT called Marrow-infiltrating Lymphocytes (MILs). MILs are a population of polyclonal T cells expanded from the bone marrow (BM) with distinct properties that set them apart from T cells expanded from peripheral blood lymphocytes (PBLs). MILs are enriched with memory T cells and contain tumor antigen-specific T cells that are typically not detected in PBLs. MILs are being developed for several tumor types, including both hematological and solid tumors.
Distinguishing features of MILs compared to PBLs include their memory phenotype, inherent tumor antigen-specificity, and ability to persist long-term. As such, we hypothesized that MILs would provide a robust platform for CAR-T cell therapy with the potential to boost initial response rates and reduce the risk of relapse. Herein, data is presented demonstrating superior anti-tumor activity of CAR-modified MILs (CAR-MILs) compared to CAR-T cells generated from patient-matched PBLs (CAR-PBLs).
Glycostem
NK細胞產(chǎn)品相比于CAR-T的幾點優(yōu)勢：不引起NT、成本低、off-the-shelf制備時間短、可能對實體瘤更有效，首個NK產(chǎn)品oNKord?及后續(xù)的CAR-NK
iNKT
NKT(自然殺傷T)細胞表面既有TCR，又有NK細胞受體，能產(chǎn)生大量的細胞因子；盡管數(shù)量少，但比其他免疫細胞都強大的抗腫瘤功能，另外在安全性和生產(chǎn)上也有優(yōu)勢
CAR-NK+CAR-T combo
增強活性降低CRS
CAR-NK cells show rapid and potent anti-tumor cytotoxic activity even at very low effector-to-target ratios; however, they do not typically expand upon encounter with antigen and lack the long-term persistence commonly associated with autologous CAR-T cells.
Conversely, CAR-T cells generally exhibit persistent killing activity, even though they are activated
more slowly. In addition, the explosive expansion of CAR-T cells is frequently associated with a variety of toxicities (e.g. CRS, CRES, etc.).
To address the potential shortcomings associated with either cell type, we have assessed a novel platform that combines CAR-NK and CAR-T cells as a novel cancer therapeutic.
血液瘤及實體瘤CAR-T的臨床開發(fā)的異同
這個是老朋友了：
引入DAR-T平臺提升親和力和特異性，以及其他：
