{"id":642,"date":"2026-08-23T15:57:36","date_gmt":"2026-08-23T15:57:36","guid":{"rendered":"https:\/\/syrian-biomedica.com\/?page_id=642"},"modified":"2026-08-23T15:57:36","modified_gmt":"2026-08-23T15:57:36","slug":"mohammad-toutanjy-abstract","status":"publish","type":"page","link":"https:\/\/syrian-biomedica.com\/ar\/mohammad-toutanjy-abstract\/","title":{"rendered":"Mohammad Toutanjy Abstract"},"content":{"rendered":"

Mohammad Toutanjy<\/strong><\/h1>\n
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Beyond Mutation Count: Neoantigen Quality, Clonality and Presentation Competence as Determinants of Response to Personalized Cancer Immunotherapy<\/strong><\/p>\n<\/div>\n

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Background<\/u>:<\/strong><\/p>\n

Individualized neoantigen therapies have moved from proof of concept to randomized evidence. In resected high-risk melanoma, mRNA-4157\/V940 combined with pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561; 18-month RFS 79% vs 62%), and in resected pancreatic ductal adenocarcinoma, autogene cevumeran induced de novo neoantigen-specific T cells in 8 of 16 patients, with responders showing markedly longer recurrence-free survival than non-responders (median not reached vs 13.4 months; P = 0.003). The unresolved problem is not whether these vaccines can work, but why they work in some patients and not others. Tumour mutational burden (TMB), the biomarker most widely used to select candidates for immunogenic therapy, quantifies mutation number but is blind to whether the resulting epitopes are immunogenic, whether they are present in every tumour cell, and whether the host can present them at all.<\/p>\n<\/p>\n

Objective<\/u>:<\/strong><\/p>\n

This talk synthesizes published patient-level and cohort-level evidence to argue that neoantigen quality, clonality, and antigen presentation competence (not mutation count) are the operative determinants of response, and that each is measurable with existing sequencing workflows.<\/p>\n<\/p>\n

Evidence Reviewed<\/u>:<\/strong><\/p>\n

Four independent lines of published data are examined. First, the limits of TMB: across 37 studies and more than 15 tumour types, high TMB predicted checkpoint-inhibitor response only in cancers where neoantigen load correlated with CD8 T-cell infiltration (ORR 39.8%), and failed where it did not (ORR 15.3%). Second, quality over quantity: a neoantigen fitness model based on differential MHC presentation and homology to known pathogen epitopes identified long-term pancreatic cancer survivors in two independent datasets, whereas a neoantigen-quantity model did not; longitudinal analysis of 70 pancreatic cancers over a decade further showed that the immune system preferentially edits high-quality neoantigens, indicating that quality is under active selection in human tumours. Third, clonality: high clonal neoantigen burden was associated with improved survival, greater T-cell infiltration and durable checkpoint-blockade benefit, whereas chemotherapy-induced subclonal neoantigens increased total mutational load yet were enriched among poor responders, a direct demonstration that rising TMB can accompany worsening immune control. Fourth, host presentation competence: HLA class I evolutionary divergence has been reported to predict immunotherapy benefit independently of TMB, and allele-specific HLA loss of heterozygosity (detectable in approximately 40% of non-small-cell lung cancers) removes the capacity to present otherwise high-quality epitopes. Counter-evidence is presented alongside: germline HLA divergence did not predict pembrolizumab efficacy in a large pan-tumour analysis, and the host-genetic contribution remains contested.<\/p>\n<\/p>\n

Synthesis and Implications<\/u>:<\/strong><\/p>\n

Critically, differential vaccine response does not appear to reflect global immune fitness: in the pancreatic cohort, responders and non-responders mounted equivalent immunity to a concurrent, unrelated SARS-CoV-2 mRNA vaccine. The relevant variation therefore lies in the antigens and their presentation, not in the patient’s general capacity to respond. Quality-weighted neoantigen burden, clonal neoantigen fraction, expressed-neoantigen count, HLA-I divergence and HLA LOH status are all derivable from paired tumour\u2013normal whole-exome and RNA sequencing using published, open tools, and can be assembled into an interpretable, multi-axis selection framework.<\/p>\n<\/p>\n

Conclusion<\/u>:<\/strong><\/p>\n

The evidence supports replacing mutation counting with a structured assessment of neoantigen quality, clonality and presentation competence for selecting patients for individualized neoantigen vaccination and for prioritizing epitopes during vaccine design. A concrete framework and the prospective validation required to test it are proposed.<\/p>\n<\/div>\n


\n<\/p>\n","protected":false},"excerpt":{"rendered":"

Mohammad Toutanjy Beyond Mutation Count: Neoantigen Quality, Clonality and Presentation Competence as Determinants of Response to Personalized Cancer Immunotherapy Background: Individualized neoantigen therapies have moved from proof of concept to randomized evidence. In resected high-risk melanoma, mRNA-4157\/V940 combined with pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561; 18-month RFS 79% vs 62%), and in […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":"","_et_pb_custom_css":""},"class_list":["post-642","page","type-page","status-publish","hentry"],"_et_pb_custom_css":"","_links":{"self":[{"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/pages\/642","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/comments?post=642"}],"version-history":[{"count":0,"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/pages\/642\/revisions"}],"wp:attachment":[{"href":"https:\/\/syrian-biomedica.com\/ar\/wp-json\/wp\/v2\/media?parent=642"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}