0087: SYNCAR: An Engineered IL-2/IL-2R-system That Selectively Enhances CD19 CAR T Cells to Deplete B Cells and Provide Therapeutic Benefit in SLE and RA Mouse Models Without Lymphodepletion
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Ethan Jung1, Marie semana1, Ivan Cheng1, Helena Silva1, Sandro Vivona1, Somya Singh1, Michele Bauer1, Mohammed Ali1, Henry Rosas1, Woei Chang1, Deepti Rokkam1, Patrick Lupardus1, Martin Oft1 and Paul-Joseph Aspuria2, 1Synthekine, Menlo Park, 2Sythekine, Menlo Park, CA Background/Purpose: CD19 CAR-T therapy has demonstrated efficacy in autoimmune (AI) diseases like systemic lupus erythematosus (SLE) and lupus nephritis (LN), showing its potential beyond oncology. Its application in other B cell-related AI conditions, such as rheumatoid arthritis (RA), could expand its therapeutic impact. Lymphodepleting (LD) chemotherapy, essential for T cell engraftment and efficacy, also carries risks like cytokine release syndrome, cytopenia, infections, genotoxic risk, and secondary malignancies. To fully utilize CD19 CAR-T therapy, strategies to reduce LD while maintaining efficacy are needed. IL-2 can stimulate T cell proliferation but causes systemic toxicities due to widespread immune activation. An orthogonal oIL-2/oIL-2R system was developed, consisting of a pegylated IL-2 mutein (STK-009) that doesn't significantly activate the wild-type (WT) receptor and a mutated IL-2 Receptor Beta (oRβ) that doesn't respond to WT IL-2. This system provides a "private IL-2 signal" to engineered oRβ-expressing cells, reducing toxicities. STK-009 selectively expands oRβ-expressing CD19 CAR T cells (SYNCAR-001), enhancing anti-tumor control and durable responses in lymphoma models. Methods: To explore the orthogonal IL-2/IL-2R system's potential, CD19 CAR T cells were used in autoimmune mouse models without LD whereby murine T cells co-expressing mCD19 CAR and moRβ (mSYNCAR-001) were administered alone or with mSTK-009, the murine surrogate of STK-009. Two AI mouse models, SLE and RA, were employed. In the SLE model, aged NZB/NZWF1 mice with elevated anti-dsDNA/nuclear antibodies and kidney dysfunction were used. For RA, a non-lymphodepleted collagen-induced arthritis model was utilized. The impact on CD19+ B cell depletion, autoantibody production, kidney function, and arthritis symptoms were assessed in the relevant model. Rituximab mouse surrogate (anti-CD20 mAb) was also administered for comparison.
Results: Co-administration of mSTK-009 and mSYNCAR-001 effectively depleted CD19+ B cells in both SLE and RA models. mSTK-009 was essential for significant expansion of mSYNCAR-001 and subsequent CD19+ B cell depletion. In non-lymphodepleted NZB/NZWF1 mice, mSTK-009 enabled mSYNCAR-001 to significantly reduce autoantibody production, improving kidney function. In the RA model, mSTK-009 promoted mSYNCAR-001 to reverse arthritis, evidenced by the normalization of swollen paws and toes. The combination of mSTK-009 and mSYNCAR-001 showed superior efficacy compared to the rituximab surrogate, which achieved incomplete B cell depletion and minimal therapeutic benefit, highlighting the enhanced potential of the orthogonal IL-2/IL-2R system in AI models. Conclusion: These findings support clinical exploration of SYNCAR-001 + STK-009 in AI diseases like SLE and RA to achieve CD19 CAR T expansion and significant B cell aplasia without genotoxic, lymphodepleting agents. SYNCAR-001 + STK-009 is in Phase I trials for heme malignancies (NCT05665062), with LN and SLE patient enrollment expected later this year.
E. Jung: Synthekine, 3; M. semana: Synthekine, 3; I. Cheng: Synthekine, 3; H. Silva: Synthekine, 3; S. Vivona: Synthekine, 3; S. Singh: Synthekine, 3; M. Bauer: Synthekine, 3; M. Ali: Synthekine, 3; H. Rosas: Synthekine, 3; W. Chang: Synthekine, 3; D. Rokkam: Synthekine, 3; P. Lupardus: Synthekine, 3; M. Oft: Synthekine, 3, 4; P. Aspuria: Synthekine, 3.