Session Information
Date: Monday, November 18, 2024
Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster
Session Type: Poster Session C
Session Time: 10:30AM-12:30PM
Background/Purpose: Developed initially as a novel strategy to treat B cell malignancies, chimeric antigen receptor (CAR) T cells have now been used to treat multiple autoimmune diseases (AIDs), where rapid and deep depletion of pathogenic B cells is a key driver of therapeutic benefit. Similar to oncology, patients treated with autologous anti-CD19 CAR T cells achieved disease remission, including in refractory systemic lupus erythematosus. However, widespread application of CAR T cell therapy across AIDs faces many challenges including the requisite patient administration of intense conditioning chemotherapy (CCT), which induces cytopenia, increases susceptibility of severe infection and secondary malignancies, risks hospitalization, and limits patient access and reach.
Methods: To enable broad outpatient utilization, reduce toxicities for the treatment of AIDs and promote durable elimination of AID pathology, we have developed a multiplexed-engineered, next-generation (NG) CAR T-cell product candidate derived from a clonal induced pluripotent stem cell line (CAR iT cell), which incorporates a collection of novel synthetic edits designed to enable targeting and potent killing of multiple subsets of aberrant immune cells, to enhance bio-distribution to secondary and tertiary tissues where residual disease resides, and to avoid the need for administration of intense CCT to patients.
Results: Anti-CD19 NG CAR iT cells exhibit a desired CD8αβ+ phenotype that is consistent with a potent T-cell state poised for activation, without expression of exhaustion markers, and demonstrate robust and specific elimination of CD19+ B cells in multiple in vitro cytotoxicity assays, including those containing peripheral blood mononuclear cells (PBMCs) sourced from various AID patients. In xenograft models of AID, where disseminated disease resides in secondary and tertiary tissues, anti-CD19 NG CAR iT cells display tissue-wide functional persistence, including durable elimination of CD19+ B cells in the bone marrow. Furthermore, the co-expression of a second CAR targeting BCMA or CD38 showed a unique ability to enhance engagement and elimination of aberrant plasma cells and activated T cells. To overcome the need for administration of intense CCT, NG CAR iT cells also contain a novel allo-immune defense receptor (ADR), which has been shown to promote CAR T-cell expansion, function, and persistence in an allogeneic setting. For example, ADR-armed NG CAR iT cells display enhanced persistence and cytotoxicity in an in vitro allogeneic re-stimulation assay, relative to control T cells, eliminating target cells through multiple rounds of re-challenge in the presence of alloreactive PBMCs, and maintain tumor growth inhibition and persistence in vivo in the presence of unmatched T cells. Importantly, NG CAR iT cells can be manufactured at scale to support off-the-shelf availability and cost-effective utilization.
Conclusion: Collectively, NG CAR iT cells represent a promising off-the-shelf approach to cell therapy for the treatment of AIDs, with the unique potential to elicit durable elimination of an array of aberrant immune cells, to avoid toxicities associated with intense CCT, and to maximize patient access and reach.
To cite this abstract in AMA style:
Goulding J, Reiser J, O'Connor A, Hancock B, Tuncel J, Groff B, Mbofung R, Morales-Mantilla D, Williams A, Lu D, Yang B, Peralta E, Gutierrez A, Meza M, Rezner B, Sims A, Witty A, Pan Y, Jelcic M, Sikaroodi S, Denholtz M, Lee T, Bagri A, Wong L, Goodridge J, Valamehr B. Development of Next Generation CAR T Cell Therapy for the Off-the-shelf Treatment of Autoimmune Diseases Without Conditioning Chemotherapy [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/development-of-next-generation-car-t-cell-therapy-for-the-off-the-shelf-treatment-of-autoimmune-diseases-without-conditioning-chemotherapy/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-next-generation-car-t-cell-therapy-for-the-off-the-shelf-treatment-of-autoimmune-diseases-without-conditioning-chemotherapy/