CAR-TCR Europe Notes

TTLC21也开了但和WCLC太近，先不更新了，CAR-TCR 顺序比较乱，都是看到哪算哪，有些是个人兴趣就展开了一下，有些就是凑个图

细胞治疗未来：实体瘤、多靶向、克服TME、通用型

共刺激结构域

CD28共刺激域使细胞依靠糖酵解，向效应T细胞分化，而4-1BB促进线粒体生成，增强呼吸作用和脂肪酸氧化，优先分化为中央记忆T细胞，免疫信号上：CD28更快、更强，而4-1BB则相对慢、温和

TCR-T上表达PD1-4 1BB：胞外PD-1识别肿瘤表面PD-L1，然后胞内传导的是4-1BB共刺激信号

CYAD-101：靶向NKG2D治疗MSS CRC的allo CAR-T

引入TIM降低CD3ζ结合TCR 旨在消除避免GvHD，同时还有选择性的CD19 marker，这些与CAR一起构建编码，允许通过单次转导就产生同种异体T细胞，便于实际生产，结果没有报道DLT和GVHD，也观察到了初步的疗效，半数以上的患者肿瘤缩小

而后续产品采取了shRNA敲低CD3ζ

然后是ATARA基于同种异体的EBV-T细胞开发CAR-T或TCR-T，因为EBV-T特异性识别EBV感染的细胞很少会影响正常细胞，也正是利用这个特点

联合治疗的策略：增强疗效以及在实体瘤中的浸润

做ARi的怎么选了“”Enhancing Immune Infiltration in the Solid TME“的topic？

Axi-Cel中相关的毒性及管理

主要是 CRS、 ICANS和 B-cell aplasia及发生时间、应对策略

病毒载体 vs 非病毒载体

Biomarker在CAR-T治疗中的应用：患者鉴定评估、PK监测和PD的论证

德国的Christian Buchholz教授展示了in vivo制备CAR-T，其实他们体内制备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）：是通过LV（lentiviral  vector）颗粒表面展示结合CD8或CD4的抗体片段特异性结合CD8+ T或CD4+ T，从而将含特异性CAR基因的慢病毒转入T细胞，实现体内制备：

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（骨髓浸润淋巴细胞）

大多数细胞疗法依赖于来自外周的淋巴细胞，但MILs来源于骨髓，骨髓是记忆T细胞的天然储库，基于MILs细胞治疗产品可能就具有固有的肿瘤特异性、记忆表型造成的最大细胞毒性以及持久性等独特功能，特别适用于自体细胞治疗

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细胞产品相比于CAR-T的几点优势：不引起NT、成本低、off-the-shelf制备时间短、可能对实体瘤更有效，首个NK产品oNKord®及后续的CAR-NK

iNKT

NKT(自然杀伤T)细胞表面既有TCR，又有NK细胞受体，能产生大量的细胞因子；尽管数量少，但比其他免疫细胞都强大的抗肿瘤功能，另外在安全性和生产上也有优势

CAR-NK+CAR-T combo

增强活性降低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.

血液瘤及实体瘤CAR-T的临床开发的异同

这个是老朋友了：

引入DAR-T平台提升亲和力和特异性，以及其他：