P1, N=54, Recruiting, Lyell Immunopharma, Inc.

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

After successful LYL797 manufacturing, pts receive fludarabine and cyclophosphamide followed by a single infusion of LYL797 at the protocol-assigned dose level. Study objectives include assessment of safety and tolerability (primary), as well as anti-tumor activity and pharmacokinetics (secondary) of LYL797. Additional exploratory objectives include evaluation of the effects of Lyell’s genetic and epigenetic reprogramming technologies on T-cell phenotype and activity, as well as evaluation of the relationship between ROR1 expression and LYL797 activity.

1x106 CAR T cells (figure 2). Conclusions These data suggest that LYL119, which combines c-Jun overexpression, NR4A3 KO, Epi-R protocol, and Stim-R technology, can limit exhaustion, maintain stem-like features, and has potential to provide effective and durable CAR T-cell antitumor activity in patients with ROR1+ solid tumors.

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, N=5, Terminated, Bristol-Myers Squibb | N=65 --> 5 | Trial completion date: Mar 2025 --> May 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2025 --> May 2023; Business objectives have changed.

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

To fill the void in CRC treatment with ROR1 as a target of CAR-T immunotherapy, we designed and prepared antiROR1-CART. This third-generation CAR-T cell can effectively inhibit the growth of colorectal cancer in vitro and in vivo.

P1, N=65, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting | Trial completion date: Jan 2029 --> Mar 2025 | Trial primary completion date: Jan 2029 --> Mar 2025

Finally, we incorporated NR4A3 KO + c-Jun and Stim-R into the Epi-R protocol and showed that combining our four reprogramming technologies in ROR1 CAR T cells showed additive benefits to prolong in vitro cytotoxicity using A549 tumor cells compared to controls (Figure 1B). Together these data suggest that stacking these four technologies can limit exhaustion and has the potential to provide effective and durable ROR1 CAR T-cell functional activity in patients with ROR1+ solid tumor malignancies.

P1/2, N=12, Recruiting, 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China

P1, N=24, Not yet recruiting, Shen Lin

Study subjects undergo leukapheresis followed by lymphodepletion with either fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days (Arm 1) or 60 mg/kg cyclophosphamide for 2 days (Arm 2). All subjects will be followed for adverse events, CAR-T-related toxicities, disease response and PRGN-3007 cell expansion and persistence. In addition, the mechanisms of safety and effectiveness of PRGN-3007 cells will be evaluated with correlative assays of specific immune response pathways.

After leukapheresis and manufacturing, pts receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by LYL797 infusion at the protocol-assigned dose level. Primary objectives include LYL797 RP2D determination and safety and tolerability; secondary objectives include anti-tumor activity and PK. The trial began screening in March 2022.

These studies collectively demonstrate that Gen-R and Epi-R technologies can give rise to enhanced and prolonged anti-tumor functional capacity of CAR T-cell therapy in solid tumors. Based on these promising preclinical data, LYL797 is being studied in a phase I clinical trial to assess the safety, pharmacokinetics, immunogenicity, efficacy, and duration of effect for patients with ROR1+ TNBC and NSCLC.

P1, N=54, Recruiting, Lyell Immunopharma, Inc. | Not yet recruiting --> Recruiting

P1, N=21, Terminated, Fred Hutchinson Cancer Research Center | N=60 --> 21 | Trial completion date: Dec 2023 --> Sep 2021 | Recruiting --> Terminated | Trial primary completion date: Dec 2022 --> May 2021; Terminated due to slow accruals.

P1, N=54, Not yet recruiting, Lyell Immunopharma, Inc.

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.

Data shown is from 8 mice/group at the start of the study. * p<0.05, ***p<0.001; log rank test.

P1, N=60, Recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Dec 2037 --> Dec 2023

P1, N=60, Recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Dec 2036 --> Dec 2037 | Trial primary completion date: Dec 2021 --> Dec 2022

In a B cell tumor xenograft model, targeted Neo-2/15 effectively increased CAR-T cell expansion and prolonged survival compared to treatment with CAR-T cells and non-targeted Neo-2/15. Together, these results show that engineered versions of Neo-2/15 induce robust expansion of CAR-T cells and can enhance their antitumor activity.

P1, N=60, Suspended, Fred Hutchinson Cancer Research Center | Recruiting --> Suspended

The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.

The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.

Celularity has developed a GMP process for generating off-the-shelf and allogeneic human Placental Hematopoietic Stem Cell derived Natural Killer (PNK-007) cells... The novel PNK-CAR38 demonstrated enhanced in vitro cytotoxic potential against lymphoma and MM lines and showed no on-target off-tumor cytotoxicity against healthy donor-derived cells in vitro. In vivo anti-tumor activity of PNK-CAR38 was shown in a lymphoma disseminated NSG model. Further development of PNK-CAR38 for hematological malignancies is warranted.