ROR1 positive

The novel fully human TGFßRIIDN-armored ROR1-CAR-1 T cells are highly potent against ROR1-positive tumors, and withstand the inhibitory effects of TGFß in solid TME. Moreover, TGFβ1 induction represents a novel, CAR-induced checkpoint in the solid TME, which can be circumvented by co-expressing the TGβRIIDN armor on T cells.

The CD5+/CD10- group had a significantly higher proportion of ROR1 positive samples (89.9%) and more brightly expressed ROR1 than the other groups. Our results highlight the importance of evaluating ROR1 expression in the diagnosis of MBLN to contribute to the differential diagnosis, and possibly therapy of mainly CLL, and indicate that this marker could be considered as a useful addition to immunophenotypic panels, particularly for more challenging cases.

Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e. g. , inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers.

Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022)...Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion...The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440

Oncternal’s ONCT-808 autologous CAR T cells are genetically modified via ex vivo transduction with a self-inactivating lentivirus vector to express a ROR1-directed CAR containing single chain variable fragment derived from Oncternal’s clinical stage anti-ROR1 zilovertamab. In cancer therapy efficacy studies using CDX models, treatment with ONCT-808 cells resulted in complete tumor remission in ROR1 Jeko-1 cell-derived CDX mice, and controlled tumor growth in Raji cell-derived CDX mice, reflecting the specificity of the ONCT-808 cells to the ROR1 target. Conclusions ONCT-808 demonstrated high efficacy in inducing ROR1 specific cancer cell death in both in vivo and in vitro studies, suggesting its potential in treating human cancer patients.

P1/2, N=57, Recruiting, Oncternal Therapeutics, Inc | Not yet recruiting --> Recruiting | Initiation date: Feb 2023 --> May 2023

In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients.

This study demonstrates that an anti-ROR1 mAb, Zilovertamab, can eliminate up to 80% of AML LSC insupportive niches. In the future, targeted ROR1 inhibition may represent a vital component of therapeuticstrategies aimed at eradicating therapeutically recalcitrant LSCs in AML and potentially other refractorycancer stem cell-driven malignancies.

In addition, three different ATC cell lines showed overexpression of ROR1, and we could show that pre-treatment with kinase inhibitors like Lenvatinib or Sorafenib does not affect ROR1 surface expression. Animal models are ongoing and will be finalized at presentation. Conclusions In summary our data proof ROR1 as a viable and specific target for several types of thyroid carcinoma which is the basis for the design of a clinical phase I trial using ROR1-CAR T-cells in metastasized ATC and PDTC patients.

Conclusion The zilovertamab-based CAR tested in this study enhances the NK cell response towards ROR1-expressing cancer cells and enables T cells to clear fast-growing cancer cells in an in vivo model. These findings support the development of anti-ROR1 cell therapies for the potential treatment of ROR1-positive hematological malignancies.

HMCLs with high endogenous ROR1 expression were sensitive to in vitro killing by anti-ROR1 CAR T-cell treatment, which employs an scFv generated from the fully humanized ROR1-specific monoclonal antibody cirmtuzumab, at effector:target cell ratios (ET) as low as 0.33:1. Together, these results suggest a central role for Wnt signaling in MM stem cell phenotypes and activation of embryonic transcriptional pathways, while also paving the way towards development of clinical therapies that target a CSC population in MM.

In preclinical studies LYL797 cells reprogrammed with Gen-R and Epi-R led to improved functional activity in the presence of ROR1+ tumor cells compared to conventional ROR1 CAR T cells.Additional studies are underway to determine the mechanisms by which antitumor activity of LYL797 in ROR1-positive solid tumor xenograft models is enhanced. LYL797 is anticipated to enter into Phase 1 clinical trials for TNBC and NSCLC in 2022.

Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton's tyrosine kinase inhibitors...Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax...These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.

In combination with other clinically relevant targeting drugs as venetoclax a synergistic apoptotic effect was seen. Two other small molecules (ARI-1 and strictinin) bound also to ROR1 and inhibited tumor growth. Development of small molecule ROR1 inhibitors is warranted to include this novel therapeutic approach for cancer therapy.

This new DELFIA method can detect cancer-derived ROR1-positive exosomes in the cell supernatant and serum with a wide range and rapidly compared with the conventional Western blot assay. This method may be useful as a companion diagnostics for ROR1-positive cancers.

We conclude that the expression of ROR1, ROR2, and their associated genes correlate with worst prognosis of GC patients, particularly in the intestinal type.

The aim of this study was to investigate any anti-proliferative effect of cirmtuzumab in combination with commonly-used gynaecological cancer therapies (cisplatin, paclitaxel and the PARP inhibitor, olaparib) on high grade serous ovarian cancer (HGSOC) and EC cell lines including models of platinum resistance. Cirmtuzumab alone inhibited proliferation of ovarian cancer and EC cells in vitro, and could enhance the activity of commonly-used chemotherapeutic agents. This study supports the potential of cirmtuzumab or other ROR1 targeting therapies for treating women with HGSOC and EC.