P1, N=22, Completed, Barbara Parker, MD | Active, not recruiting --> Completed | Phase classification: P1b --> P1

P1, N=58, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=180, Recruiting, Numab Therapeutics AG

The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.

P1, N=15, Not yet recruiting, Pure Biologics S.A.

P1, N=29, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Nov 2023 --> Jun 2024 | Trial primary completion date: Nov 2023 --> Jun 2024

Strictinin was further identified as synergistic with docetaxel [combination index (CI) = 0.311] and the combination therapy was found to reduce the IC of strictinin to 38.71 µmol/L in PC3 cells. ROR1 is an emerging molecular target that can be utilized for treating prostate cancer. The data from this study establishes strictinin as a potential therapeutic agent that targets AR-AI prostate cancer with elevated ROR1 expression to reduce the migration, invasion, cell cycle progression, and survival of prostate cancer.

P1, N=32, Recruiting, University of California, San Diego

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P1/2, N=102, Active, not recruiting, Oncternal Therapeutics, Inc | Phase classification: P1b/2 --> P1/2

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.

P2, N=5, Active, not recruiting, University of California, San Diego | Recruiting --> Active, not recruiting | N=16 --> 5

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=32, Recruiting, University of California, San Diego | Phase classification: P1b --> P1

Zilo + Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. For pts with CLL, Zilo + Ibr is very active and results in durable remissions. The PFS and OS for the subgroup with TP53 mut/del(17p) are particularly encouraging in reference to other trials of BTK inhibitors, maintaining 100% PFS and OS at ∼42 mos.

We utilized the humanized scFv binding domain of zilovertamab (formerly UC-961 and then cirmtuzumab), which showed high affinity and specificity for human ROR1 and a highly favorable safety profile in Phase-1 clinical evaluation [1]...We conclude that lentivirus encoding this anti-ROR1 CAR construct can generate anti-ROR1 CAR T cells using T cells of healthy donors or patients with CLL that are highly effective in killing ROR1-expressing leukemia cells in vitro or in vivo. Moreover, the anti-ROR1 CAR T cells generated using this construct may provide for selective killing of CLL cells without affecting normal CD19/CD20-expressing B cells of patients with CLL, thereby mitigating the risk for further enhancing immune deficiency, such as observed in patients treated with anti-CD19 CAR T cell therapy.

P1, N=58, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

P1/2, N=40, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P1, N=90, Recruiting, NovalGen Ltd. | Phase classification: P1/2 --> P1

Overall, our results highlight that incorporation of a functional αCD38-CAR construct into a suitable NK-cell expansion and activation protocol results in a potent and feasible immunotherapeutic strategy for the treatment of patients with MM.

Collectively, our study indicated that dexamethasone up-regulated ROR1 levels on gastric cancer cells. ROR1 participated in and mediated the role of dexamethasone in promoting gastric tumor growth, and blocking ROR1 can prevent the tumor growth.

P1b, N=22, Active, not recruiting, Barbara Parker, MD | Trial completion date: Jan 2023 --> Jan 2024

P1b/2, N=102, Active, not recruiting, Oncternal Therapeutics, Inc | Recruiting --> Active, not recruiting | Trial completion date: Apr 2027 --> Aug 2024 | Trial primary completion date: Mar 2025 --> Aug 2024

P3, N=365, Ongoing, Oncternal Therapeutics, Inc

P1, N=0, Withdrawn, Sichuan Baili Pharmaceutical Co., Ltd. | N=29 --> 0 | Recruiting --> Withdrawn

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.

Clinical studies using ROR1 targeting antibodies (Zilovertamab) to treat hematologic malignancies did not reveal relevant clinical toxicity, encouraging the initiation of clinical trials to assess the safety and efficacy of ROR1-CAR-T therapy... With this novel protocol, we aim to obtain the first manufacturing license for CAR-T in Europe that integrates our optimized approach with SB100X mRNA and MC for CAR gene-transfer on the MaxCyte transfection platform. The quality of the drug product supports the developement of a clinical trial with ROR1-CAR-T, and will serve as a blueprint for other CAR-T products.

Finally, results of tumor challenge in immunized mice showed that immunization with TT-mROR1-Fc fusion proteins completely inhibited ROR1+ tumor cells growth in two different syngeneic tumor models until day 120 post tumor challenge. Our preclinical findings, for the first time, showed that our fusion proteins could be considered as a potential candidate vaccine for active immunotherapy of ROR1-expressing malignancies.

We have generated a first in class ROR1 targeting half-life extended TCE that maintains the functional and biophysical properties of the clinically promising NVG-111. Our systematic evaluation suggests that careful selection of HLE format is critical for the development of a molecule with good yield, biophysical characteristics and potency. The selected ROR1 HLE-TCE supports weekly administration whilst maintaining potency at sub-nanomolar concentrations, properties which differentiate it from other TCEs in development.

Early data shows that NVG-111 is generally well tolerated with a predictable and manageable safety profile. Promising evidence of efficacy was observed which appears to be durable in two subjects with MRD4 negative CR. Dose escalation is ongoing in combination or as monotherapy to determine the MTD/RP2D.

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 this study, Zilo+Ibr is well-tolerated with a safety profile that is very similar compared with Ibr alone. With respect to grade ≥3 neutropenia in RR MCL, the rate observed with Zilo+Ibr was 9.1%, which is lower than the 29% reported for Ibr alone in its Phase 3 study. The combination is very promising in pts with RR MCL (ORR 85.2%, CR 40.7%, mPFS 35.9 mos), compared with historical results for Ibr alone (ORR 66%, CR 20%, mPFS 12.8 mos; Rule 2017).

The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.

These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.

The subsequent key areas hold promise: Alternative Inhibitors of BTK Here, non-covalent BTK inhibitors, such as pirtobrutinib (LOXO- 305) and nemtabrutinib (ARQ-531), have shown effi cacy in CLL resistant to covalent BTK inhibitors...AZD5991 is a highly selective BH3-mimetic that demonstrates high potency in MCL1-dependent cell lines.9 Our group has shown that selective targeting Mcl-1 induced metabolic dysfunction and abrogated survival of lymphoid cells in vitro and in vivo.10 Other BH3- mimetics targeting Mcl-1 include AMG-176 and S63845.11,12 However, Mcl-1 targeting agents may be associated with toxicities, including against the hematopoietic stem and progenitor cells, potentially leading to cytopenias in the clinic.13 The therapeutic window for these agents needs to be defi ned. BH3-mimetics which target Bcl-xL, such as navitoclax, are not being developed in CLL due to concerns of thrombocytopenia.14 However, AZD4320, an alternative Bcl-2/xL inhibitor, is being studied in lymphoid malignancies as an intravenous formulation, with hope to mitigate its effect on platelets.15 Therapeutic Antibodies Targeting surface receptors and inducing both direct and immunemediated apoptosis has been a success story in CLL with use of anti-CD20 agents...Lanalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells.16 In a phase 1 study in combination with ibrutinib in 32 patients with CLL, CR was achieved in 38% of patients, and 42% demonstrated undetectable minimal residual disease (uMRD) in the blood/bone marrow, a promising result not expected with ibrutinib alone.17 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab) and CD19 (tafasitamab)...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confi rmed effi cacy in patients with relapsed/refractory CLL.18 In this study, patients had a median of 4 prior therapies, including ibrutinib and venetoclax...In a Phase 1/2 trial, HLA-mismatched CD19-targeting CAR NK cells induced CRs in patients with CLL after a single infusion and without CRS or neurotoxicity attributable to the cellular product.19 Finally, bi-specifi c antibodies have demonstrated impressive effi cacy in non-Hodgkin lymphoma and are also an off-the-shelf product which boasts high tolerability. Development of bi-specifi c antibodies in CLL is still in early stages, however epcoritamab (a subcutaneously administered CD3xCD20 Duobody) demonstrated responses in an ongoing Phase 1 study.20 In sum, targeted therapy replaced chemo-immunotherapy in treatment of CLL, and emerging small molecule and cell therapy approaches auger an expansion of the therapeutic armamentarium for CLL in the next decade.

Porcupine inhibitors, β-catenin protein-protein interaction inhibitors, β-catenin proteolysis targeting chimeras, ROR1 inhibitors and ROR1-targeted biologics are investigational drugs targeting WNT signaling cascades. Mechanisms of cancer plasticity regulated by the WNT signaling network are promising targets for therapeutic intervention; however, further understanding of context-dependent reprogramming trajectories might be necessary to optimize the clinical benefits of WNT-targeted monotherapy and applied combination therapy for patients with cancer.