Command Palette

Search for a command to run...

Preprint WatchModerateOctober 29th, 2026

Spatially enforced engagement of PD-1⁺ T cells with AXL⁺ cells reprograms the tumor microenvironment and overcomes anti-PD-1 resistance

Yegodayev, K. M.; Perelman, G.; Shami, T.; Kaufman, B.; Raviv, D.; Marripati, D.; Khateeb, A.; Ben-uri, R.; Levi Galibov, O.; Milo, I.; Raizman, A.; Veinblat, A.; Nissani, A.; Zuri, N.; Babu Manikandan, D.; Rudnitsky, E.; Novoplansky, O.; Zorea, J.; Eisdorfer, S. A.; Jagadeeshan, S.; Ezri, G.; Waidha, K.; Abu Shareb, R.; Wainer, M.; Hadad, U.; Itzhaki, O.; Shapira-Frommer, R.; Wolf, Y.; Cohen, M.; Kong, D.; Wang, H.; Porgador, A.; Keren, L.; Aharoni, A.; Carmi, Y.; Cohen, O.; Elkabets, M.

A tetravalent non-tandem IgG bispecific that physically tethers PD-1 positive T cells to AXL positive tumour cells reprograms the tumour microenvironment and overcomes anti-PD-1 resistance, which conventional anti-AXL plus anti-PD-1 combinations do not achieve because they act independently.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The Claidex graph holds two AXL failures. Sitravatinib in post-checkpoint non-small cell lung cancer was recorded as a translational mismatch at Phase 3 (sitravatinib-axl-tam-post-checkpoint-nsclc-sapphire-phase3-translational-mismatch), and bemcentinib in lung adenocarcinoma ended on strategic grounds at Phase 1b/2 (bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination). This preprint offers a mechanistic account of why the first of those may have failed, arguing that simple co-administration of an AXL inhibitor with checkpoint blockade never enforces the spatial proximity the biology requires. That is a testable alternative to the conclusion that AXL is the wrong target in checkpoint-resistant disease, and it predicts that AXL-directed agents will keep reading out as inactive in this setting unless the delivery format changes. Programs still pursuing AXL after checkpoint failure should treat engagement geometry, not AXL inhibition per se, as the variable under test.

Abstract excerpt

Background: AXL overexpression promotes tumor-cell plasticity, local immune suppression, and resistance to PD-1 blockade. Conventional anti-AXL and anti-PD-1 antibodies combinations act independently and do not ensure physical proximity between PD-1+ T cells and AXL+ cells within the immunosuppressive tumor microenvironment. Methods: To address this limitation, we developed a non-tandem, tetravalent IgG bispecific antibody designed to simultaneously engage PD-1 and AXL (BiTE-AXL/PD-1). Its antitumor activity was evaluated using in vitro functional assays and humanized and immunocompetent head and neck squamous cell carcinoma (HNSCC) models and compared with the combination of monospecific anti-AXL and anti-PD-1 antibodies. Spatial multiplex imaging was used to characterize treatment-associated changes in the tumor microenvironment of an anti-PD-1-resistant murine model. Results: BiTE-AXL/PD-1 enhanced T-cell activation, promoted AXL-dependent tumor-T-cell conjugation, and increased tumor-cell killing in vitro, outperforming the combination of the two monospecific antibodies. In humanized and immunocompetent HNSCC models, BiTE treatment significantly delayed tumor growth compared with the antibody combination and was well tolerated, with no overt toxicity. Spatial multiplex imaging revealed a shift from a fibroblast-dominated microenvironment characterized by exhausted CD8+ T cells toward dendritic-cell- and CD8+ T-cell-enriched niches associated with antitumor immune activity. Conclusion: BiTE-AXL/PD-1 promotes physical proximity between PD-1+ T cells and AXL+ cells, enhances antitumor immune responses, and remodels the immunosuppressive tumor microenvironment. These findings support PD-1/AXL bispecific targeting as a promising therapeutic strategy to overcome resistance to PD-1 blockade in HNSCC.

Matching Claidex post-mortems

2 of 2 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.