jondoeuk
5 months ago
222 Obecabtagene Autoleucel (obe-cel, AUTO1) for Relapsed/Refractory Adult B-cell Acute Lymphoblastic Leukemia (R/R B-ALL): Pooled Analysis of the Ongoing FELIX Phase Ib/II Study https://ash.confex.com/ash/2023/webprogram/Paper179454.html
2114 Long-Term Efficacy and Safety of Obecabtagene Autoleucel (obe-cel) in Adult Patients (pts) with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia ([R/R B-ALL]; Pooled Analysis from ALLCAR19 and FELIX Phase Ib Studies) or Other B-cell Malignancies (ALLCAR19 Extension Study) https://ash.confex.com/ash/2023/webprogram/Paper180666.html
4892 Delivery of Obecabtagene Autoleucel (obe-cel, AUTO1) for the FELIX Pivotal Study Demonstrating Robust Cell Processing, Robust Release Testing, and Reliable Logistics, Together with Readiness for Sustainable Patient (pt) CareClinically Relevant Abstract https://ash.confex.com/ash/2023/webprogram/Paper181574.html
350 Development of a Phase 1 Study Evaluating the Activity of Modular CAR T for Multiple Myeloma (MCARTY) Targeting BCMA and CD19 for Improved Persistence https://ash.confex.com/ash/2023/webprogram/Paper185085.html
jondoeuk
8 months ago
For its next generation T-cell product candidates, the company will incorporate multiple modular enhancements, but as the authors of this point out engineering multiple features into one cell product is limited by the constraints of current viral vectors, which leads to a heterogeneous population of cells.
Using a leucine zipper-based cell sorting enabled a selective single-step purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This facilitated generation of T-cells simultaneously expressing up to four CARs (CD19, CD20, CD79b, and BAFF-R) and co-expressing up to three switch receptors (CD200R-CD27, PD-1-OX40, and Fas-41BB) https://www.biorxiv.org/content/10.1101/2023.09.13.557232v1
jondoeuk
2 years ago
I found this
AUTL presented three posters at ASGCT over the last two days. Most relevant near term to AUTL is the CCR poster, as AUTO6NG (GD2), which is scheduled to enter the clinic this year, contains an IL-7-CCR. The poster noted that gene expression from an IL-7-CCR-GD2CAR-T was largely identical to both an IL-2 and IL-12-CCR-GD2CAR-T. Notably in mice a GM-CSF-CCR-GD2CAR-T produced the greatest CAR-T expansion, persistence and overall survival.
In addition to a lack of cytokine support in the solid tumour microenvironment, FasL expression could trigger killing of activated CAR-T since these cells will express Fas. AUTL described a Fas-CD40 construct that neutralised FasL induced apoptosis while maintaining CAR-T function. Controlled activation of CAR and or cytokine secretion may be advantageous in solid tumours and AUTL describes a two component system based on minocycline. For a CAR, minocycline inactivates the CAR while for IL-12, use of minocycline leads to secretion.
Cytokine support of cell therapy has most often required systemic dosing of cytokines. A chimeric chemokine receptor with constant heavy and light chain domains from an IgG are fused to the transmembrane and intracellular domains of the chosen cytokine receptor. An IL-2 CCR drove significant T-cell expansion in the absence of cytokine starvation CCR control
Of the top fifty genes activated by exogenous IL-2, forty-four were activated by IL-2-CCR. Truncation of the IL2R beta chain resulted in either increased or diminished T cell expansion. Substitution of IL-7 for IL-2, increased T-cell expansion, while IL-18 increased IFNy secretion over IL-2. Substitution of GM-CSF for IL-2 increased myeloid cell expansion.
Eighteen CCR-GD2 CARs were evaluated against a GD2 CAR control and while most preserved CAR-T effector function, the IL-12 and IL-7 CCR's drove greater CAR-T expansion and production of IFNy. Gene expression changes for IL-2-CCR and IL-7-CCR and IL-7-CCR and IL-12-CCR were identical.
In a GD-2 colon cancer model using murinised components, CCR-IL-7 or CCR-GM-CSF GD2 CAR-T, demonstrated improved tumour control compared to GD2 CAR-T; CAR-T expansion was significantly higher for the GM-CSF-CCR and correlated with a pronounced increase in overall survival.
In a metastatic melanoma model similar observations were made and at day fourteen, only GM-CSF-CCR-GD2 CAR-T were detected.
FAS: Fas ligand is expressed by most cancers, regulatory T-cells, endothelial cells, myeloid-derived suppressor cells and cancer-associated fibroblasts. Activated T-cells including CAR-T constitutively express Fas and engagement of FasL leads to CAR-T death via apoptosis. Truncated non signalling Fas rescued T-cells from Fas mediated apoptosis, but significantly diminished CAR-T proliferation and efficacy
Adding the intracellular pro-survival domain of a TNF receptor rescued CAR-T proliferation in the presence of FasL; seventeen different receptors were evaluated including a short of BCMA, 41BB, CD27, CD40 and Fn14.
Against GD2 FasL+ target cells, GD2 CAR-T exhibited a high degree of apoptosis which was reversed in the presence of Fas truncated or Fas-receptors. While all GD2 CAR-T with one of five shortlisted Fas combinations were equipped against GD2+ target cells, with repeat stimulation, Fas-CD40 retained the highest level of activity, correlating with greater retention of a central memory phenotype.
jondoeuk
3 years ago
As of the data cut-off date of May 17, thirteen patients in Cohort D with R/R IBCL had been enrolled in the trial and product was successfully manufactured for twelve patients, with one patientβs cells ongoing in manufacture. As of the data cut-off date, nine had received AUTO1 infusion. Three were pending infusion (including the patient above) and one patient died prior to lymphodepletion due to a Cov infection. Obe-cel was well tolerated and demonstrated a favourable safety profile, despite high disease burden. All treated patients achieved a complete metabolic response and had robust CAR-T engraftment, expansion, and persistence.
Grade 1 CRS was reported in four patients and Grade 2 CRS in one. No immune effector cell-associated neurotoxicity syndrome of any grade was observed. At a median follow-up of six months (range 4.0-8.1), eight of nine patients were disease free, with one relapse at month six, but was rescued with radiotherapy. One died of a Cov infection at month 5.6 whilst in complete metabolic response.
Also, twenty patients in Cohort A with R/R aALL had received obe-cel. The therapy was well tolerated, with no patients experiencing Grade 3 or higher CRS. Three patients, all of whom had high leukaemia burden (over 50% blasts), experienced Grade 3 ICANS that resolved swiftly with steroids.
Of the twenty patients evaluable for efficacy, seventeen achieved minimum residual disease negative complete response at one month. Most notably, the durability of remissions is highly encouraging. Across all treated patients, event free survival at twelve months and twenty-four months is 50.2% with the median not being reached.
The call https://edge.media-server.com/mmc/p/wbmik6fg
Slides https://autolus.gcs-web.com/static-files/b4ca8abe-8b75-4690-a9fd-2680e161f0f5