Prospective Causal Forecast and Resistance-Attribution Framework for Neogene-Specific TCR-T Therapy in Ewing Sarcoma
Year: 2026
Type: report
Abstract: Prospective Causal Forecast and Resistance-Attribution Frameworkfor Neogene-Specific TCR-T Therapy in Ewing Sarcoma A pre-specified HISTAMOS analysis before THEODORA clinical readout HISTAMOS Prospective Adjudication P1 (R0) Document type: Prospective analysis / preregistered forecast | Evidence cutoff: 30 August 2026 Institutional author HISTAMOS Independent Research Correspondence [email protected] – www.histamos.com Version R0 — prospective freeze candidate for public deposition Clinical authority None. No THEODORA clinical outcome data are used or claimed. INDEPENDENT PROVENANCE AND RELATIONSHIP STATEMENT This analysis was conducted independently by HISTAMOS using only information available in the public domain before the evidence cutoff. Before this R0 freeze, HISTAMOS had no scientific discussion, consultation, feedback, protocol review, or other substantive communication with THEODORA investigators or participating institutions concerning this analysis; had no access to unpublished results, non-public protocols, internal biomarker or monitoring plans, confidential correspondence, or patient-level data; and had no contractual, advisory, employment, collaborative, financial, licensing, or other relationship with THEODORA or its participating institutions relevant to this work. No conflict of interest relevant to this analysis is declared at the time of this release. Any contact or relationship established after R0 does not alter the provenance of this frozen record. Abstract Background: Public preclinical evidence supports a mechanistic chain from EWSR1::FLI1-driven neogene expression to HLA-I presentation and neogene-specific TCR-T recognition and killing in Ewing sarcoma. THEODORA is a European program scheduled to begin on 1 September 2026, with a first-in-child neogene-targeted TCR-T substudy planned within its master-protocol framework. The unresolved question is not whether the target concept is biologically plausible, but whether clinical resistance, if it occurs, can be localized to antigen source, cognate peptide–MHC presentation, tumor state, or downstream immune execution. Methods: We prospectively specify five competing causal models, a qualitative and probabilistic forecast, decisive measurements, and explicit future scoring rules. The analysis is based on public evidence only. A previously completed internal synthetic design-qualification exercise is used solely to assess whether the proposed measurement architecture can distinguish the prespecified causal worlds under simulated conditions; it is not treated as biological or clinical evidence. Prospective forecast: We assign higher prior probability to demonstrable biological activity in at least a subset of appropriately treated patients than to complete target-concept failure. We expect clinical activity, if present, to be heterogeneous in depth and durability. Baseline HLA match plus neogene presence is not expected to be a sufficient selector of durable response. Conditional on resistance, source/presentation/visibility failure and downstream immune execution are prioritized over complete invalidity of the neogene concept, while durable TCR-selected coupled state escape remains a higher-evidence claim that requires direct demonstration. If exact cognate pMHC is not measured directly or with a sufficiently proximal validated surrogate, some resistance states may remain attributionally unresolved. Conclusion: This document is a falsifiable prospective record, not a prediction of broad clinical success and not a critique of unpublished THEODORA design. Its purpose is to pre-specify what HISTAMOS expects, what would count as a miss, and what measurements would be required to interpret a future negative or heterogeneous clinical result without conflating program failure with target failure. Keywords: Ewing sarcoma; EWSR1::FLI1; neogene; TCR-T; peptide–MHC; antigen presentation; tumor plasticity; resistance attribution; prospective forecast; THEODORA. 1. Rationale and public evidence boundary Ewing sarcoma is driven in most cases by an EWSR1::ETS fusion, most commonly EWSR1::FLI1. Recent work has identified EWSR1::FLI1-induced neogenes generated through neomorphic transcriptional activity at GGAA microsatellites. A 2026 preprint reported that peptides encoded by these neogenes are presented on HLA-I complexes on Ewing sarcoma cells and can be recognized by neogene-specific CD8 T cells and engineered TCR-T cells. Killing was HLA-I restricted and dependent on EWSR1::FLI1 and the corresponding neogene, with in vivo activity reported in preclinical models [1]. This establishes a credible biological chain but does not establish durable clinical control. EWSR1::FLI1 activity is heterogeneous and dynamic; graded or transient reductions can produce distinct phenotypic states and persistent transcriptional consequences [2,3]. EWS-FLI1-low cells have also been reported to show reduced susceptibility to T-cell-mediated apoptosis and increased PD-L1/PD-L2 expression [4]. In parallel, HLA-I expression is frequently reduced in Ewing sarcoma, especially in advanced disease [5], and paired human tumor analyses have implicated low HLA-I together with altered IFN and TGF-beta signaling in an immunologically resistant state [6]. Single-cell studies further support a functionally impaired immune microenvironment [7]. THEODORA (Horizon Europe Grant Agreement 101288100) is coordinated by Institut Curie, has an official project start date of 1 September 2026, and publicly describes a first-in-child neogene-targeted TCR-T substudy within a European master-protocol framework. Public descriptions state that liquid biopsy, AI-enhanced imaging, immune profiling, TCR-T monitoring, circulating tumor DNA analysis, and statistical modelling will be used to track response and resistance [8,9]. These public descriptions do not establish whether exact cognate pMHC will be measured directly; therefore this paper does not claim that THEODORA lacks such a measurement. It identifies the consequence if that layer is absent or insufficiently resolved. ANTIGEN SOURCE ≠ EXACT COGNATE pMHC ≠ PRODUCTIVE TCR VISIBILITY INITIAL TREATMENT FAILURE ≠ DURABLE TUMOR-INTRINSIC RESISTANCE 2. Scope, authority, and question under adjudication The object of this preregistration is not to predict an overall response rate or to judge a protocol that is not publicly available in full. The object is narrower: to specify in advance which causal structures HISTAMOS considers most plausible, which observations would support or refute them, and which future data may remain non-identifying. The primary adjudication question is: if neogene-specific TCR-T treatment produces heterogeneous response or progression in Ewing sarcoma, can the available evidence distinguish loss of antigen source from loss of cognate pMHC presentation, coupled state/visibility escape, or downstream effector failure? Authority boundary: all predictions below are HYPOTHESIS / PROSPECTIVE FORECAST. The synthetic stress test described later has DESIGN-IDENTIFIABILITY authority only and zero biological or clinical authority. No patient-level treatment recommendation is made. 3. Prespecified competing causal models M0 — No durable tumor-intrinsic escape: Initial non-response or progression is dominated by transient exposure, trafficking, effector fitness, microenvironmental suppression, or other non-persistent factors; recovered tumor remains susceptible to a fresh qualified TCR-T challenge. M1 — Presentation-dominant escape: Neogene source is substantially preserved, but cognate pMHC falls below productive TCR visibility because of HLA/antigen-processing or presentation-level failure. M2 — Source-loss-dominant escape: EWSR1::FLI1/neogene source falls sufficiently to reduce cognate pMHC and TCR recognition; source restoration should recover pMHC and function if downstream presentation remains competent. M3 — TCR-selected coupled visibility escape: Repeated TCR pressure selects or stabilizes a durable tumor state with coupled source/pMHC loss and resistance that persists after washout and survives fresh independently qualified TCR-T rechallenge. This model requires the strongest evidence. M4 — Effector/TME-dominant failure: Source and cognate pMHC are sufficiently preserved, but TCR-T trafficking, persistence, activation, cytotoxic execution, or the tumor microenvironment prevents durable killing. 4. Frozen prospective forecasts The following claims are frozen as the primary prospective record. Probability bands are subjective HISTAMOS priors derived from causal synthesis of the cited public evidence; they are not estimated from THEODORA data, are not population parameters, and are secondary to the categorical scoring contract in Section 5. Frozen claim Prospective statement Prior / interpretation P1 — Biological proof-of-mechanism Neogene-specific TCR-T is more likely to show interpretable biological antitumor activity in at least a subset than to show complete target-concept non-functionality, assuming adequate manufacturing, delivery, and T-cell exposure. 70–85% prior probability for some mechanistically interpretable biological activity. P2 — Response heterogeneity Biological and clinical activity, if observed, will be heterogeneous across eligible patients; a consistently high, deep, durable response across most eligible patients is less likely. 45–65% prior for objective tumor responses in at least some patients; 15–30% prior for broad, deep, durable control across most evaluable patients. P3 — Baseline eligibility is not a sufficient durable-response selector HLA match plus neogene presence alone will not fully determine productive TCR visibility or durable response. Downstream presentation and execution state will contain additional decision-relevant information. Qualitat
Author: Bouchelit, Mohammed El Amin
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204784801