免疫療法利用個體自身免疫系統的成分來識別和攻擊癌細胞。免疫療法的一種形式是過繼性細胞轉移（ACT），其中收集患者的免疫細胞，進行遺傳修飾並重新輸注。
CAR-T免疫療法是一種ACT，對血癌和實體瘤都有很好的前景。CAR-T細胞是表達稱為嵌合抗原受體（CAR）的特化工程受體的T細胞，其通過改善對腫瘤細胞的識別特異性和消除對MHC共刺激的需要來抵抗腫瘤逃避。
Locked on Target:
T-Cell ReceptorMediated Cancer
Cell Killing
mmunotherapy enlists and empowers components of an individual’s own immune system to attack cancer cells, in contrast to traditional cancer treatment plans that involve
surgery, drugs, and radiation. Among several types of adoptive cell transfers (ACTs) where the patient’s immune cells are collected,genetically modified, and re-infused to attack and eliminate cancer cells, CAR-T immunotherapy shows exceptional promise
against both blood cancers and solid tumors.1 In a clinical trial using CD19-targeted CAR T-cells,2 durable remission was achieved in 27 of 30 patients with acute myelocytic leukemia.
However, the dynamic heterogeneity of cancer cells and their complex icroenvironment pose hurdles in the success of CAR-T immunotherapy.
Role Of T Cells In Mounting An Immune Response
Against Cancer
T lymphocytes, a type of multifunctional white blood cell, play an essential role in mounting adaptive immune responses. T lymphocytes can gauge the state of a cell’s interior by scanning for antigens on its surface. Cytotoxic lymphocytes (CTLs) or killer T
cells, hunt down and eliminate compromised cells (e.g., infected, cancerous, etc.) while helper T cells regulate other T- and B-lymphocyte subsets.
CTLs, a subset of the αβT lymphocytes expressing CD8 cellsurface co-receptors, harbor on their surface copies of a multisubunit receptor molecule, the T-cell receptor (TCR). TCRs, when triggered by Major Histocompatibility Complex 1 (MHC1), activate T ymphocytes. This, in turn, activates signaling cascades leading to cell proliferation, differentiation, cytokine production,and ultimately, the death of cancerous cells. Cancer cells must present processed antigens bound to MHC1 on their surface, together with co-stimulatory molecules (CD8 and CD28), to activate CTLs.
Upon CTL activation, the microtubule organizing center (MTOC) polarizes secretory granular traffic so that these granules fuse with the plasma membrane and release degrading enzymes like granzymes and perforins that effectively digest and eliminate
cancer cells. FasL and TRAIL expressed on reactivated CTLs are also able to kill susceptible cancer cells through interaction with death receptors or by inducing apoptotic pathways.
TCR: Components, Structure, Co-Receptors,
Signaling
The TCR heterodimer is composed of six peptide chains that detect the antigen presented on cells by MHC molecules. The alpha and beta chains have amino-terminal variable and constant regions and are linked by disufide bonds. Each TCR provides
a single antigen-binding site. Since the cytoplasmic domains of TCR are relatively short, the intracellular signaling steps that follow TCR binding to the antigen are primarily carried out by CD3. CD3 molecules assemble together with the TCR and include immunoreceptor tyrosine-based activation motifs (ITAMs).
Tumor Immune Evasion
Cancer cells are recognized by TCRs through the expression of neo-antigens. In order to grow, cancer cells use multiple strategies to neutralize and evade the host’s immune response.3 Cancer cells escape immune recognition by generating neo-antigens with weak immunogenicity, downregulating and modulating the expression of neo-antigens on cancer cells, and synthesizing immune suppressants that inhibit effector cell function and generate a milieu of tumor tolerance.
The immunosuppressive microenvironment limits and impairs therapeutic CAR-T cells
as well. Studies show tumor-mediated blocking of indoleamine 2,3-dioxygenase (IDO), an enzyme that converts tryptophan into metabolites, can impair CAR T-cell function.4 Therefore, one of the primary considerations in designing CAR-T cells is to find
means to overcome the various ploys tumor cells use to avoid detection and thrive.
下載原始電子書 以了解更多信息：
T細胞受體介導的癌細胞殺傷
構建CAR-T細胞
生產CAR-T細胞
為醫院製造CAR-T細胞
此免費的電子書是由北美的PHC公司提供。
下載方法：
第一步：長按以下本公眾號二維碼，關注本公眾號
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第三步：發送PDF文件《AN INTRODUCTION TO CAR T-CELL PRODUCTION
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