First Patient Dosed in Phase 1/1b Dose Escalation/Expansion Study of PRGN-3007 in Advanced ROR1+

ROR1
Receptor Tyrosine Kinase-like Orphan Receptor 1 or ROR1 is a type I orphan-receptor that is expressed during embryogenesis and by certain hematological and solid tumors but is undetectable on normal adult tissues. [2][3][4] ROR1 plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. [5] Aberrant expression of ROR1 is detected in multiple hematological malignancies including CLL, [6] MCL [7], ALL [8], and DLBCL.[9] Elevated ROR1 expression is detected in various solid tumors, including breast adenocarcinoma encompassing TNBC, pancreatic cancer, ovarian cancer, Ewing’s sarcoma and lung adenocarcinoma.[10][11][12][13][14][15] Many human breast adenocarcinomas express high levels of ROR1, which is not expressed by normal breast tissue. [16]

Study target
The target patient population for the study includes chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and diffuse large B-cell lymphoma (DLBCL) and solid tumors, including breast adenocarcinomas encompassing triple-negative breast cancer (TNBC).

There are estimated to be more than 100,000 patients diagnosed in both the hematological and TNBC target populations in the United States, European Union and Japan in 2023.^a

UltraCAR-T – a Novel approach
PRGN-3007 is engineered using a single multicistronic transposon plasmid to simultaneously express a chimeric antigen receptor (CAR) targeting ROR1, membrane-bound interleukin–15 (mbIL15), a kill switch, and a novel mechanism for the intrinsic blockade of PD-1 gene expression.

The innovative design of PRGN-3007, where the blockade of PD-1 expression is intrinsic and localized to UltraCAR-T cells, is aimed at avoiding systemic toxicity and the high cost of checkpoint inhibitors by eliminating the need for combination treatment.

PRGN-3007 UltraCAR-T is a first-in-class investigational multigenic, autologous CAR-T cell therapy based on Precigen’s clinically validated delivery system.

This process uses the company’s proprietary UltraPorator® electroporation system at a treatment center and is administered to patients only one day following gene transfer.

The UltraPorator system is an exclusive device and proprietary software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies and potentially represents a major advancement over current electroporation devices by significantly reducing the processing time and contamination risk. The device is a high-throughput, semi-closed electroporation system for modifying T-cells. UltraPorator is being utilized for clinical manufacturing of Precigen’s investigational UltraCAR-T therapies in compliance with current good manufacturing practices.

The overnight UltraCAR-T manufacturing process does not use viral vectors and does not require ex vivo activation and expansion of T-cells, potentially addressing major limitations of current T-cell therapies.

The company has further advanced the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsic checkpoint blockade without the need for complex and costly gene editing techniques.

Study design
The Phase 1/1b clinical trial is an open-label study designed to evaluate the safety and efficacy of PRGN-3007 in patients with advanced ROR1⁺hematological (Arm 1) and solid (Arm 2) tumors.

The study is enrolling in two parts: an initial 3+3 dose escalation in each arm followed by a dose expansion at the maximum tolerated dose (MTD). Arm 1 and Arm 2 are enrolling in parallel. The investigator-initiated study is being conducted in collaboration with the H. Lee Moffitt Cancer Center & Research Institute (Moffitt).

“We are excited to work with Precigen and announce that the first patient, a CLL patient, has been dosed in the first-in-human study of PRGN-3007 UltraCAR-T,” said Javier Pinilla-Ibarz, MD, PhD, Senior Member, Lymphoma Section Head and Director of Immunotherapy, Malignant Hematology Department, Moffitt, and Principal Investigator for the PRGN-3007 clinical study.

“ROR1 is a promising target for addressing a wide variety of tumors and we are hopeful that the PRGN-3007 study will further the development of this novel CAR-T treatment, which combines intrinsic PD-1 inhibition and ease of administration from the validated overnight manufacturing of UltraCAR-T performed at our medical center bringing therapy to patients within one day.”

“Dosing the first patient with PRGN-3007, the next generation of UltraCAR-T incorporating PD-1 inhibition, is a significant milestone for the UltraCAR-T platform,” said Helen Sabzevari, PhD, President and CEO of Precigen. “The PRGN-3007 study targets a broad range of hematological and solid tumor indications and this milestone helps us move closer to our vision for UltraCAR-T, which aims to deliver a library of personalized autologous UltraCAR-T therapies using overnight manufacturing at the patient’s medical center.”

Clinical trials
Dose Escalation/Dose Expansion Study of PRGN-3007 UltraCAR-T Cells in Patients With Advanced Hematologic and Solid Tumor Malignancies – NCT05694364

References
[1] GlobalData Epidemiology Market Size Research.
[2] Balakrishnan, A., et al., Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res, 2017. 23(12): p. 3061-3071.
[3] Green, J.L., et al., ROR receptor tyrosine kinases: orphans no more. Trends in Cell Biology, 2008. 18(11): p. 536-544.
[4] Rebagay, G., et al., ROR1 and ROR2 in Human Malignancies: Potentials for Targeted Therapy. Front Oncol, 2012. 2(34).
[5] Zhao Y, et al., Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies. Front. Oncol, 2021.
[6] Baskar, S., et al., Unique Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Human B-Cell Chronic Lymphocytic Leukemia. Clin Cancer Res,2008. 14(2): p. 396-404.
[7] Hudecek, M., et al., The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood, 2010. 116(22): p. 4532-4541.
[8] Enayati H, et al., Expression of ROR1 Gene in Patients with Acute Lymphoblastic Leukemia. IJBC 2019; 11(2): 57-62.
[9] Ghaderi, A., et al., ROR1 Is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells. Biomedicines, 2020. 8(6).
[10] Zhang, S., et al., The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am J Pathol, 2012. 181(6): p. 1903-10.
[11] Zhang, S., et al., ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One, 2012.7(3): p. e31127.
[12] Potratz, J., et al., Receptor tyrosine kinase gene expression profiles of Ewing sarcomas reveal ROR1 as a potential therapeutic target in metastatic disease. Mol Oncol, 2016. 10(5): p. 677-92.
[13] Zheng, Y.Z., et al., ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma. Sci Rep, 2016. 6: p. 36447.
[14] Choi, M.Y., et al., Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1. Clin Lymphoma Myeloma Leuk, 2015. 15 Suppl: p. S167-9.
[15] Balakrishnan, A., et al., Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res, 2017. 23(12): p. 3061-3071.
[16] Zhang S. et al., ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One, 2012, 7:e31127.