ASH abstracts
1) Targeting of tumor antigen CD38 and stress antigens MICA/B by CAR T cells provides a unique approach for the comprehensive treatment of multiple myeloma
Introduction: Recently approved autologous chimeric antigen receptor (CAR) T-cell therapies (Abecma® and Carvykti®) have demonstrated clear clinical benefit for patients with relapsed/refractory multiple myeloma (MM) with initial response rates ranging between 73-98%. Unfortunately, many of these patients ultimately relapse, often as the result of antigen shedding and tumor heterogeneity, tumor microenvironment suppression, and poor CAR T-cell functional persistence, highlighting the need for alternative therapies that can simultaneously mitigate and overcome these tumor-intrinsic and -extrinsic challenges. Furthermore, broad patient access of patient- and donor-derived CAR T cells are limited by manufacturing challenges and the use of conditioning chemotherapy.
Methods: FT836 is an iPSC-derived CAR T cell that uniquely targets the conserved a3 domain of the inducible stress ligands MICA/B, enabling broad recognition of both hematologic and solid tumors. The unique engineered elements of FT836 further enable (i) multi-antigen targeting by antibody-dependent cellular cytotoxicity (ADCC) in combination with the high-affinity non-cleavable CD16a Fc receptor (hnCD16) and therapeutic monoclonal antibodies (e.g. sarclisa and daratumumab), (ii) functional persistence in an allogeneic setting without the reliance on conditioning chemotherapy using dual Sword and ShieldTM engineering, incorporating a synthetic alloimmune defense receptor (ADR) that selectively eliminates 41BB+ alloreactive immune cells and genetic deletion of CD58 to avoid recognition by host immune cells, and (iii) improved tumor homing and resistance to immunosuppression via expression of the chemokine receptor CXCR2 and the TGFß signal redirection receptor, respectively.
Results: Analysis of MM at both the mRNA and protein level revealed MICA/B and CD38 to be highly enriched with comprehensive disease coverage, as demonstrated by i) the Cancer Cell Line Encyclopedia (median Log2(TPM+1) MICA/B: 4.39 and CD38:5.022), ii) primary multiple myeloma patient samples (MMRFCoMMpass, Skerget et al. 2024; median Log2(TPM+1) MICA/B: 4.23 and CD38: 7.64), and iii) surface expression analysis of a panel of multiple myeloma cancer cell lines, including RPMI-8226, NCI-H929, OPM2, and MM.1s. In vitro cytotoxicity assays exhibited dose-dependent killing in combination with CD38 antibodies (daratumumab and sarclisa), uniquely enabling multi-antigen targeting through both innate and adaptive immunity (CAR+ADCC). Importantly, unlike NKG2D-mediated cytotoxicity, the presence of soluble MICA/B did not impact the anti-tumor efficacy of FT836. In a xenograft model of solid tumor using RPMI-8226, the tumor burden was effectively controlled by FT836 and the depth of response was extended when combined with daratumumab, underscoring the potential for potent and effective control of MM using FT836 by simultaneously targeting MICA/B and CD38 antigens. In a two-way MLR assay against a panel of HLA-mismatched PBMC donors, FT836 limited the generation of alloreactive immune cells (4x, p<0.0005) and demonstrated significantly enhanced functional persistence (21x, p<0001), displaying the utility of Sword and ShieldTM engineering compared to control. Similarly, in the presence of HLA-mismatched PBMCs previously primed to react to product material to represent a supraphysiological allogeneic environment, FT836 demonstrated improved functional persistence (3x, p<0.01), eliminated reactive allogeneic cells (3x, p<0.05), and maintained potent anti MICA/B CAR-mediated anti-tumor activity compared to control.
Conclusion: The data demonstrates that FT836 mediates potent and comprehensive control of MM without the need for intense conditioning chemotherapy, and that its depth of coverage can be uniquely enhanced in combination with therapeutics antibodies. As an off-the-shelf CAR T-cell therapy derived from a multiplex-engineered iPSC master cell bank, FT836 is scalable and cost-effective, with the potential to broadly and effectively treat patients with MM.
2) Development of next generation multi-antigen targeting off-the-shelf CAR T cells for conditioning-free treatment of B-cell lymphoma
Autologous chimeric antigen receptor (CAR) T-cell therapy has had tremendous success in the treatment of hematological malignancies, yet its clinical application remains hindered by several significant limitations. Major challenges include the high cost, complex manufacturing process, the requirement for intense lymphodepleting chemotherapy prior to infusion, and the limited accessibility and scalability of the therapy. FT839 is an induced pluripotent stem cell (iPSC) derived CAR T cell designed to overcome these limitations and provide potent and versatile therapy against lymphocytic cancers. FT839 is a multiplex-engineered CAR T cell equipped with anti-CD19 and anti-CD38 dual-CAR system to target lineage specific or activated pathological cell subsets, including cells of hematologic malignancies. FT839 also incorporates Sword and ShieldTM technology, the synergistic action of a novel Alloimmune Defense Receptor (ADR), which eliminates 4-1BB+ alloreactive immune cells, and the genetic ablation of CD58 (CD58KO), which limits synapse formation with alloreactive cells to promote functional persistence and evade host alloreactive immune responses, designed to eliminate the need for intensive conditioning chemotherapy.
Co-targeting of CD19 and CD38 on B cell acute lymphoblastic leukemia cell line NALM6, both in combination or individually through engineered isogenic lines (CD19+CD38+, CD19-CD38+ and CD19+CD38-) to represent cancer heterogeneity, showed enhanced and durable efficacy (91.6%, 92.8%, & 82.6% vs 52.8%, 0%, & 50%) respectively, when comparing FT839 and CD19 primary CAR T cells at low effector: target ratio. FT839 CAR T cells are also uniquely engineered to express a novel CD3-chimeric fusion receptor (CD3CFR) and a high-affinity, non-cleavable CD16 (hnCD16). These engineered attributes allow for flexible multi-antigen targeting in combination with clinically approved T cell engagers (TCEs) or monoclonal antibodies (mAbs). Indeed, in combination with the CD20-specific mAb rituximab or the CD38-specific mAb daratumumb, FT839 potently eliminated the mantle cell lymphoma cell line Jeko-1 (97.8% CD20+, 54,888 rMFI) and Burkitt’s lymphoma cell line RAJI (91.6% CD38+, 101,129 rMFI), respectively, highlighting the flexible and broad multi-antigen targeting of FT839 via CAR and hnCD16 activation. FT839 also demonstrated potent control of NALM-6 xenografts in vivo, as a monotherapy, and with further deepening response in combination with mAb, compared to control.
With Sword and ShieldTM engineering (ADR & CD58 KO), FT839 demonstrated resistance to potent pre existing as well as de-novo generated host vs graft allogeneic immune responses, maintaining functional anti-tumor activity. In a 2-way MLR with HLA-mismatched donor peripheral blood mononuclear cells (PBMCs), FT839 demonstrated enhanced persistence (21x, p<0001) and reduced alloreactive expansion (4x, p<0.0005), compared to control CAR-T cells. FT839 also showed higher resistance (113% of base wells) to pre-existing allogeneic responses (primed allogeneic T cells), as compared to CD58-sufficient, ADR negative CAR-T cells (2.4% of base wells). Finally, FT839 maintained durable anti-tumor activity against repeat challenges with NALM6 tumor cells 1.17x p=ns) even in the presence of primed allogeneic PBMCs that elicit potent reaction against mismatched cells.
Compared to traditional CAR T-cells, FT839 demonstrates versatility in targeting cancer cells via multiple antigen-receptor activation pathways, enabling potent and flexible multi-antigen targeting for the successful treatment of relapsed/refractory B cell lymphomas that is otherwise challenging to treat because of its heterogenous cellular composition. Furthermore, unlike autologous and allogeneic CAR T cells, expression of ADR and deletion of CD58 ensures the functional persistence of FT839, potentially eliminating the need for intense conditioning chemotherapy regimen and ensuring broad and on demand access for patients with relapsed/refractory B-cell leukemia/lymphoma.
3) The development of an off-the-shelf CAR T-cell therapy co-targeting CD19 and CD38 for broad application in autoimmune disease
CD19-targeting chimeric antigen receptor (CAR) T-cell therapies have demonstrated profound clinical efficacy in the treatment of a growing list of autoimmune diseases through their ability to target and reset pathogenic B cell immune compartments. The extension of CAR T-cell therapy to additional autoimmune indications offers substantial therapeutic potential, especially for patients with refractory disease and limited treatment options.
Currently approved autologous CAR T-cell therapies face several important limitations including their
narrow, single antigen targeting (e.g., CD19) mechanism of action that is unlikely to eliminate all disease causing immune cell types in complex autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Moreover, broad patient access to these therapies is limited due to inconsistencies associated with the manufacturing of heterogeneously edited cells, production costs, the inability to be available on-demand, and the need for intense conditioning chemotherapy which requires hospitalization and treatment at specialized centers to monitor adverse events, including the risk of severe infection.
FT839, a next generation off-the-shelf CAR T-cell therapy, is designed to overcome these limitations by expanding CAR T-cell therapy access to a broader pool of autoimmune disease patients. Derived from a clonal, multiplex precision-engineered induced pluripotent stem cell that allows for routine and scaled manufacture, FT839 incorporates novel synthetic functional elements that enable multi-antigen targeting to effectively eliminate a range of pathogenic immune cell types while simultaneously resisting immune rejection in allogeneic patient settings.
FT839 co-expresses two distinct CARs: the first targets the B-cell lineage marker CD19, and the second targets the immune activation marker CD38. Combined with genomic deletion of CD38 to avoid fratricide and T-cell receptor to eliminate the risk of graft-versus-host disease, this multi-antigen targeting approach enables selective elimination across a comprehensive range of disease-causing immune cell subsets. FT839 also expresses a high-affinity, non-cleavable CD16 receptor and a chimeric CD3-fusion receptor, enabling synergistic combinations with standard-of-care monoclonal antibodies and clinically approved T-cell engagers to achieve potentially enhanced therapeutic activity and functional versatility through engagement of one or more activating receptors on separate lineage markers.
In vitro cytotoxicity assays exhibited CAR-mediated targeting of CD19 and/or CD38, resulting in potent
elimination of antigen-expressing target cells, including CD19+ B cells, CD38+ plasma cells, and CD38+ alloreactive immune cells. In vivo, FT839 demonstrated potent and specific elimination of xenografts consisting of CD19+ and CD38+ target cells. Notably, FT839 simultaneously eliminated autoimmune disease driving cell types in vitro, such as B cells, plasma cells, activated Th1 and Th17 CD4+ T cells, activated CD8+ T cells, and inflammatory macrophages (>90% depletion of all CD19+ and CD38+ targets), underscoring the broad suitability of FT839 for the control of autoreactive immune subsets.
To eliminate the current requirement to administer conditioning chemotherapy alongside CAR T-cell
therapy, FT839 incorporates Sword and Shield™ technology engineering with a novel allo-immune
defense receptor (ADR), designed to eliminate 4-1BB+ alloreactive immune cells, and genetic disruption of the immune synapse adhesion ligand CD58 (CD58KO) to enable passive evasion from host allogeneic immune cells. In the presence of alloreactive peripheral blood mononuclear cells, FT839 demonstrated sustained cytotoxicity upon serial rechallenge in vitro and maintained tumor growth inhibition and functional persistence in vivo, consistently displaying superior durability and potency compared to controls that lack Sword and Shield™ (p<0.001). These results demonstrate the unique ability of FT839 to functionally persist in an allogeneic and mismatched setting without the need for intensive conditioning chemotherapy.
In summary, FT839 enables the simultaneous and selective elimination of multiple disease-driving
immune cells without the need for supportive conditioning chemotherapy. Its scalable, cost-effective
manufacturing and off-the-shelf delivery supports broad clinical accessibility across a range of
autoimmune disease settings.
Market Data 
Markets 
AI
