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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/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/