𝗔n𝘁𝗶𝗴𝗲𝗻 𝗘𝘀𝗰𝗮𝗽𝗲: 𝗠𝗲𝗰𝗵𝗮𝗻𝗶𝘀𝘁𝗶𝗰 𝗢𝘃𝗲𝗿𝘃𝗶𝗲𝘄 
Antigen escape occurs when tumor cells los𝘦, down𝘳𝘦g𝘶𝘭a𝘵e,  or 𝘮𝘰𝘥𝘪fied t𝘩𝘦  t𝘢𝘳𝘨𝘦𝘵 𝘢𝘯𝘵i𝘨𝘦n 𝘰f 𝘢 t𝘩𝘦𝘳𝘢𝘱𝘺. Selective pressure from treatments such as CD19-directed CAR-Ts can lead to outgrowth of antigen-negative clones. Mechanisms: 
• genetic mutations creating alternative splice variants (e.g. CD19) [1] 
• epigenetic silencing 
• lineage switching (e.g. B-ALL to myeloid phenotypes) 
• trogocytosis, reducing antigen density on tumour cells [2] 
 
Tumor 𝗛𝗲𝘁erogeneity
Tumors are composed of 𝘥𝘪𝘷𝘦𝘳𝘴𝘦 𝘴𝘶𝘣𝘤𝘭𝘰𝘯𝘢𝘭 𝘱𝘰𝘱𝘶𝘭𝘢𝘵𝘪𝘰𝘯s with distinct genotypes, phenotypes, and antigen profiles (between patients, tumor sites, and even within a single lesion). 
In solid tumours, the microenvironment also varies. A tumor cell outside this context is often not ´tumorigenic´, the niche defines its behavior. 
 
𝗖𝗔𝗥-𝗧 Example: Yescarta (Axi-Cel) 
Yescarta targets CD19 and is effective in DLBCL, where malignant cells circulate systemically and share this antigen. 30–60% of patients relapse due to CD19 modulation or loss [3], and healthy B cells are also depleted due to on-target/off-tumor effects. 
 
𝗨𝗻𝗶𝗖𝗔𝗥 and 𝗔𝗠𝗟 Diversity
AML illustrates extreme heterogeneity, with multiple molecular subtypes (e.g. FLT3-ITD, MLL-rearranged). Modular platforms such as UniCAR aim to address this with switchable targeting, yet no antigen is uniformly expressed across AML populations [4]. 
 
Bias in Clinical Trials
Demographic underrepresentation: 
• Women, pregnant/lactating individuals 
• paediatric patients 
are frequently excluded. 
• Most genomic datasets overrepresent individuals of European ancestry. 
These gaps limit our understanding of antigen distribution and treatment response. 
 
𝗟𝗮𝗯𝗼𝗿𝗮𝘁𝗼𝗿𝘆 𝗔𝗽𝗽𝗿𝗼𝗮𝗰𝗵𝗲𝘀 𝘁𝗼 𝗦𝘁𝘂𝗱𝘆 𝗛𝗲𝘁𝗲𝗿𝗼𝗴𝗲𝗻𝗲𝗶𝘁𝘆 𝗮𝗻𝗱 𝗘𝘀𝗰𝗮𝗽𝗲 
Tools: 
• scRNA seq 
• CyTOF and high-dimensional flow cytometry 
• spatial transcriptomics 
• tumor organoids 
• longitudinal liquid biopsies 
These methods inform next-generation immunotherapies targeting multiple antigens. 
 
𝗤𝘂𝗲𝘀𝘁𝗶𝗼𝗻 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗔𝘂𝗱𝗶𝗲𝗻𝗰𝗲 
Should future immunotherapies focus on multi-antigen targeting, or is TME reprogramming the more promising strategy? 
 
Stay tuned for 𝗗𝗮𝘆 𝟲𝟲: 𝗖𝗼𝗺𝗯𝗶𝗻𝗮𝘁𝗶𝗼𝗻 𝗥𝗲𝗴𝗶𝗺𝗲𝗻𝘀 𝗶𝗻 𝗖𝗮𝗻𝗰𝗲𝗿 𝗜𝗺𝗺𝘂𝗻𝗼𝘁𝗵𝗲𝗿𝗮𝗽𝘆 
 
𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲𝘀 
1. DOI: 10.1158/2159-8290.CD -15-1020 
2. DOI: 10.1126/scitranslmed.aau5907 
3. DOI: 10.1056/NEJMoa1707447 
4. DOI: 10.1182/blood.2020009759 
 
hashtag#Immunology hashtag#CancerBiology hashtag#AntigenEscape hashtag#TumorHeterogeneity hashtag#CAR hashtag#UniCAR hashtag#ImmunoOncology hashtag#Hematology hashtag#SolidTumors hashtag#TME hashtag#AML hashtag#PrecisionMedicine hashtag#100DaysofImmunology