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Preprint WatchStrongOctober 28th, 2026

Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells

Ziccheddu, B.; Savid-Frontera, C.; Saralamma, V. V. G.; Gatenbee, C.; Youssfi, A. A.; Chojnacka, M.; Menges, M.; Cuadrado-Delgado, L.; Durante, M.; Mullinax, J.; Reid, K.; Miranda, J. A.; Corallo, S.; Merritt, E.; Sawyer, W.; Augello, A.; Newsam, A. D.; Chahar, D.; Amador, C.; Spiegel, J. Y.; Davila, M.; Landgren, O.; Alderuccio, J. P.; Robertson-Tessi, M.; Atkins, R.; Usmani, S.; Jain, M. D.; Anderson, A. R. A.; Maura, F.; Schatz, J. H.; Locke, F. L.

Durable CD19 CAR-T efficacy requires cooperation with endogenous tumour-reactive CD8 T cells, and biallelic loss of MHC class I or CD58 confers resistance; CD8 depletion caused universal relapse in mice.

Strong contradiction

5 prior failures

Three or more documented clinical failures match this mechanism, or a Phase 3 efficacy failure is on record.

The preprint reports that durable CD19 CAR-T efficacy in large B-cell lymphoma depends on recruiting endogenous tumour-reactive CD8 T cells rather than on the CAR product alone, that biallelic loss of MHC class I or CD58 confers resistance, and that CD8 depletion produced universal relapse in mice after initial regression. Claidex holds five CD19 failures. Two were efficacy failures of the anti-CD19 antibody LY3541860 in autoimmune disease, ly3541860-cd19-rheumatoid-arthritis-phase2a-efficacy-failure and ly3541860-cd19-relapsing-multiple-sclerosis-phase2a-2b-efficacy-failure. Three were strategic terminations of cell and engager programmes moving between oncology and autoimmunity, kyv-101-cd19-car-t-refractory-lupus-nephritis-kysa-1-strategic-reprioritization, kyv-101-cd19-car-t-diffuse-cutaneous-systemic-sclerosis-kysa-5-strategic-reprioritization and cln-978-cd19-t-cell-engager-b-cell-nhl-phase1-oncology-to-autoimmune-pivot. If CD19-directed benefit depends on an intact endogenous T cell compartment and preserved antigen presentation, then depth of B cell depletion is not a sufficient design endpoint, which bears directly on the two autoimmune efficacy failures. Flagged STRONG.

Abstract excerpt

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy induces durable remissions in a subset of patients with relapsed or refractory large B-cell lymphoma; however, most patients fail to respond or eventually relapse. By integrating whole-genome and transcriptome profiling of 54 patients with functional assays, syngeneic models, and mathematical modeling, we demonstrate that durable CAR-T efficacy requires cooperation between CAR-T cells and endogenous CD8 (eCD8) T cells recruited to join the attack on malignant cells. Tumors with biallelic loss of MHC class I or CD58 exhibited high genomic complexity, increased neoantigen burden, and resistance to CAR-T therapy. MHC-I-deficient lymphomas showed suboptimal response in immunocompetent hosts compared to wild type. Importantly, sustained responses in mice occurred only in the presence of eCD8 cells, whereas all CD8-depleted mice relapsed after initial CAR-T-mediated tumor regression. Patients and murine ELISPOT assays confirmed enhanced endogenous T-cell activation post-CAR-T. These findings reveal that CAR-T therapy functions not only as a cytotoxic modality but also as a catalyst for endogenous anti-tumor immunity.

Matching Claidex post-mortems

5 of 5 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.