Overview of ROR1-Targeted CAR Cell Therapies

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Background of ROR1

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a surface antigen that belongs to the orphan receptor tyrosine kinase-like family. It consists of three main sections: an extracellular domain, a transmembrane segment, and a cytoplasmic region. The extracellular section contains an immunoglobulin-like domain (IG), a cysteine-rich domain (CRD), and a Kringle domain (KD). On the other hand, ROR1's intracellular side has two serine/threonine-rich domains (Ser/Thr), a proline-rich domain (PRD), and a tyrosine kinase domain (TKD).

Fig.1 Structure of ROR1

ROR1 is expressed in undifferentiated embryonic stem (ES) cells, but its expression decreases upon differentiation in conditioned medium. ROR1-positive B cell non-Hodgkin's lymphomas (B-NHL), including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma, are identified. Despite previous findings, ROR1 is also expressed on several normal tissues such as parathyroid, pancreatic islets, and regions of the esophagus, stomach, and duodenum. The Human Protein Atlas project confirms that ROR1 is expressed in various tissues like bone marrow, lymphoid tissues, and testis.

The biological function of ROR1 is not fully understood, but it may play a role in embryonic development and the regulation of cell migration and survival. As a result, ROR1 has been identified as a potential therapeutic target for cancer treatment.

ROR1 Signaling Pathways

Studies have shown that ROR1 activates cell survival signaling events, particularly the non-canonical WNT pathway, which is important in oncogenesis. Specifically, ROR1 binds to Wnt5a to activate this pathway, which has been linked to cancer progression. However, further research is needed to fully comprehend the role of ROR1 in the Wnt pathway and develop effective treatments targeting it.

Clinical Status of ROR1-Targeted CAR Cell Therapies

RORs are highly expressed in tumor cells but not in normal tissues, making them ideal targets for treating minimal residual disease, the final obstacle to curing many cancers, including solid tumors like neuroblastoma.

ROR1 is a surface receptor that can be targeted by monoclonal antibodies and T-cells modified to express a chimeric antigen receptor (CAR) specific for ROR1. This approach overcomes the low receptor density of ROR1 and retargets T-cell-mediated cytotoxicity against tumor cells.

Currently, there are two ongoing CAR cell therapies targeting ROR1 mainly for hematologic malignancies (see Table 1). Preclinical studies have shown promising results in using ROR1-targeted CAR cells to treat B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

Table 1. Ongoing ROR1-Targeted CAR Cell Therapy Clinical Trials

NCT Number	Title	Status	Conditions	Phases	Sponsor/Collaborators
NCT02706392	Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies	Terminated	Hematopoietic and Lymphoid Cell Neoplasm\|Malignant Solid Neoplasm\|Metastatic Lung Non-Small Cell Carcinoma\|Metastatic Triple-Negative Breast Carcinoma\|Recurrent Acute Lymphoblastic Leukemia\|Recurrent Mantle Cell Lymphoma\|Refractory Chronic Lymphocytic Leukemia\|Stage III Lung Non-Small Cell Cancer AJCC v7\|Stage IIIA Lung Non-Small Cell Cancer AJCC v7\|Stage IIIB Lung Non-Small Cell Cancer AJCC v7\|Stage IV Breast Cancer AJCC v6 and v7\|Stage IV Lung Non-Small Cell Cancer AJCC v7\|Unresectable Lung Non-Small Cell Carcinoma	Phase 1	Fred Hutchinson Cancer Center\|National Cancer Institute (NCI)
NCT02194374	Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL)	Withdrawn	Leukemia	Phase 1	M.D. Anderson Cancer Center\|CLL Global Research Foundation Alliance

References

Rebagay, Guilly, et al. "ROR1 and ROR2 in human malignancies: potentials for targeted therapy." Frontiers in oncology 2 (2012): 34.
Menck, Kerstin, et al. "The WNT/ROR pathway in cancer: from signaling to therapeutic intervention." Cells 10.1 (2021): 142.
Mikels, Amanda, Yasuhiro Minami, and Roel Nusse. "Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling." Journal of Biological Chemistry 284.44 (2009): 30167-30176.
McDonald, S. L., and A. Silver. "The opposing roles of Wnt-5a in cancer." British journal of cancer 101.2 (2009): 209-214.
Barna, Gábor, et al. "ROR1 expression is not a unique marker of CLL." Hematological oncology 29.1 (2011): 17-21.
Baskar, Sivasubramanian, et al. "Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia." Clinical Cancer Research 14.2 (2008): 396-404.
Blanc, Etienne, et al. "Low expression of Wnt-5a gene is associated with high-risk neuroblastoma." Oncogene 24.7 (2005): 1277-1283.
Choudhury, Aniruddha, et al. "Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells." British journal of haematology 151.4 (2010): 327-335.