{"title":"用α-gal微囊免疫疗法将实体瘤中的自身肿瘤抗原转化为疫苗","authors":"Uri Galili","doi":"10.3390/pharmaceutics16101263","DOIUrl":null,"url":null,"abstract":"<p><p>A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen \"α-gal epitope\" (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called \"anti-Gal\" (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510312/pdf/","citationCount":"0","resultStr":"{\"title\":\"Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy.\",\"authors\":\"Uri Galili\",\"doi\":\"10.3390/pharmaceutics16101263\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen \\\"α-gal epitope\\\" (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called \\\"anti-Gal\\\" (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. 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引用次数: 0
摘要
免疫系统无法检测到肿瘤抗原(TAs)的一个主要原因是抗原呈递细胞(APCs)对TAs的摄取、处理和呈递不足。通过原位靶向肿瘤细胞,让抗原呈递细胞(APC)摄取肿瘤抗原,可以显著提高患者体内肿瘤抗原的免疫原性,而无需识别和描述肿瘤抗原。瘤内注射α-gal胶束是可行的,这种胶束由呈现碳水化合物抗原 "α-gal表位"(Galα1-3Galβ1-4GlcNAc-R)的糖脂组成。人类会产生一种名为 "抗gal "的天然抗体(约占免疫球蛋白的 1%),这种抗体会与α-gal 表位结合。注入肿瘤的α-gal胶束会自发地插入肿瘤细胞膜,因此肿瘤细胞上会出现多个α-gal表位。与这些表位结合的抗-Gal 会激活补体系统,从而杀死肿瘤细胞,并通过趋化补体裂解肽 C5a 和 C3a 将多种 APC(树突状细胞和巨噬细胞)招募到处理过的肿瘤中。在将处理过的肿瘤转化为个性化 TA 疫苗的过程中,被招募的 APC 吞噬抗 Gal 蛋白化的肿瘤细胞和细胞膜,处理内化的 TA 并将其运送到区域淋巴结。APC上呈现的TA肽可激活TA特异性T细胞,使其增殖并摧毁呈现TA的转移性肿瘤细胞。对抗α-gal小鼠的研究表明,向原发性肿瘤注射天然和合成的α-gal胶束后,可有效防止高度致瘤的B16黑色素瘤的远处转移。研究还发现,这种疗法与抗 PD1 抗体的检查点抑制剂疗法具有协同作用。1 期临床试验表明,α-gal 胶束免疫疗法是安全的,而且能诱导 CD4+ 和 CD8+ T 细胞浸润未经治疗的远处转移灶。有专家建议,除了将治疗过的转移瘤转化为自体TA疫苗外,还应该考虑将这种疗法作为一种新辅助疗法,在发现原发性肿瘤后立即将α-gal胶束注射到肿瘤中。这种免疫疗法将在肿瘤切除前将肿瘤转化为个性化的抗 TA 疫苗。
Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy.
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen "α-gal epitope" (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called "anti-Gal" (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection.
PharmaceuticsPharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍:
Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications, and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.