Synthekine Cleared to Tackle Lupus With CAR-T and IL-2 Combination Therapy in US Clinical Trial

Naiyer Rizvi, MD

(Credit: Synthekine)

Synthekine’s SYNCAR-001 + STK-009, a combination therapy consisting of an autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) product that expresses an engineered IL-2 receptor (SYNCAR-001) and an engineered pegylated IL-2 cytokine (STK-009), has received clearance of an investigational new drug application from the FDA for clinical evaluation in patients with nonrenal systemic lupus erythematosus (SLE) and lupus nephritis (LN).¹

Notably, the combination therapy, which is based on the company’s proprietary orthoIL-2 technology, will be administered without the use of lymphodepletion. In the planned multicenter, dose-escalation study, SYNCAR-001 will be administered as a one-time, fixed dose. On the other hand, patients will receive a limited course of STK-009 administered by subcutaneous injection each week. Synthekine anticipates enrollment of the first patient in the trial to take place in the second half of this year.

“Recent studies have shown that CD19-targeted cell therapies can make a meaningful impact on nonrenal SLE, LN, and other autoimmune conditions,” Naiyer Rizvi, MD, the chief medical officer of Synthekine, said in a statement.¹ “However, successful treatment with CD19 CAR-Ts requires patients to be lymphodepleted, a significant burden on the patient, physician, and healthcare system. By leveraging Synthekine’s orthoIL-2 technology, STK-009 has the potential to drive SYNCAR-001 cell engraftment and controlled cell expansion without lymphodepletion. We look forward to bringing our highly differentiated treatment option to patients.”

SYNCAR-001 + STK-009 is currently being evaluated for the treatment of CD19-positive hematologic malignancies in a separate phase 1 clinical trial (NCT05665062) that was launched in June 2022. As of March 2024, that trial, which is the first-in-human study for SYNCAR-001 + STK-009, is actively recruiting patients. Synthekine announced the dosing of the first patient in July 2023.² Notably the hematologic malignancies trial includes 1 cohort that treats patients with SYNCAR-001 + STK-009 with lymphodepletion and another cohort that treats patients with SYNCAR-001 + STK-009 without lymphodepletion.

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“Lymphodepleting chemotherapy may increase the risk to patients with SLE who already have significant comorbidities,” Amit Saxena, MD, an associate professor of medicine at NYU Grossman School of Medicine, added to the statement.¹ “This requirement also limits access to many patients who have marrow and organ dysfunction related to their underlying SLE. Synthekine’s cytokine-inducible CD19 CAR-T cell therapy has the potential to address critical segments of the patient population who face these barriers and offer them the remarkable potential benefit of this breakthrough approach to treating a devastating disease.”

STK-009 is intended allow for control of the activation and expansion of SYNCAR-001.³ Preclinical results related to the program that were originally reported in Science Translational Medicine were summarized by the company in December 2021. These results indicated that STK-009 allowed for control of cell expansion and activation of SYNCAR-001 in models of human lymphoma. Furthermore, in the preclinical studies it was observed that systemic and intratumoral expansion and activation of SYNCAR-001 was effected by the administration of STK-009, leading to complete responses in large lymphoma lesions.

“CAR-T cell therapies are an important emerging modality in the treatment of cancer,” Martin Oft, MD, the chief development officer at Synthekine, said in a December 2021 statement.³ “However, the limitations of these therapies must be addressed to expand their utility. The data described in this paper demonstrates the potential of STK-009 + SYNCAR-001 to address key limitations of current CD19 CAR-T cell therapies by increasing the expansion, activity, and persistence of CAR-T cells in vivo to improve the depth and durability of responses.”

REFERENCES
1. Synthekine announces U.S. FDA clearance of IND application for CD19 CAR-T and orthogonal IL-2 combination therapy, SYNCAR-001 + STK-009, for treatment of lupus without lymphodepletion.Synthekine Inc. News release. March 26, 2024. Accessed March 26, 2024. https://www.synthekine.com/news/synthekine-announces-u-s-fda-clearance-of-ind-application-for-cd19-car-t-and-orthogonal-il-2-combination-therapy-syncar-001-stk-009-for-treatment-of-lupus-without-lymphodepletion/
2. Synthekine doses first patient in phase 1 clinical trial of orthogonal IL-2 and CD19 CAR-T combination therapy, STK-009 + SYNCAR-001, for treatment of CD19+ hematologic malignancies. Synthekine Inc. News release. July 27, 2023. Accessed March 26, 2024. https://www.synthekine.com/news/synthekine-doses-first-patient-in-phase-1-clinical-trial-of-orthogonal-il-2-and-cd19-car-t-combination-therapy-stk-009-syncar-001-for-treatment-of-cd19-hematologic-malignancies/
3. Synthekine announces publication of preclinical data demonstrating in vivo control of CD19 CAR-T cells with its orthogonal IL-2 system. Synthekine Inc. News release. December 23, 2021. Accessed March 26, 2024. https://www.synthekine.com/news/2021/synthekine-announces-publication-of-preclinical-data-demonstrating-in-vivo-control-of-cd19-car-t-cells-with-its-orthogonal-il-2-system/