Autolus Therapeutics PLC (AUTL)

AUTL............................https://stockcharts.com/sc3/ui/?s=AUTL&p=w&b=5&g=0&id=p86431144783

AUTL.........................................https://stockcharts.com/sc3/ui/?s=AUTL&p=W&b=5&g=0&id=p86431144783

AUTL..............................................P/M

AUTL...........................................https://stockcharts.com/h-sc/ui?s=AUTL&p=W&b=5&g=0&id=p86431144783

AUTL, under $2

AUTL under $3

Why the free fall monk?

AUTL under $5

AUTL under $4

AUTL under $5

AUTL under $5

AUTL under $5

AUTL BOTTOM PLAY TO 5.23

AUTL under $5

WOOOOOOOOW 32000 SHARE BUY $7 OVER $210000 BUY $$$$$$$$$$$$$$$$$$

WOOOOOOOOOW 25000 SHARE BUY OVER $150000 BUY $$$$$$$$ MONSTER NEW PRODUCTS GETTING APPROVED SOON

AUTL new 52 week high

Filed with the FDA https://uk.finance.yahoo.com/news/autolus-therapeutics-submits-biologics-license-120000708.html

AUTL new 52 week high

AUTL new 52 week high

Upcoming https://uk.finance.yahoo.com/news/autolus-therapeutics-host-analyst-investor-120000268.html

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

Very nice paper on the use of circular RNA for large scale manufacturing of base edited CAR-T cells https://t.co/QVq2Okc9NF— Alex Rampotas (@ARampotas) October 9, 2023

New #JITC article: AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival https://t.co/TYkm4ivSl4 @drclaireroddie pic.twitter.com/J9hTCgHYBe— Journal for ImmunoTherapy of Cancer (@jitcancer) September 14, 2023

New data https://www.globenewswire.com/news-release/2023/09/05/2737154/0/en/Autolus-Therapeutics-announces-data-from-AUTO1-22-trial-in-pediatric-Acute-Lymphoblastic-Leukemia-published-in-the-journal-Blood.html

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

Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukaemia https://www.nature.com/articles/s41591-023-02415-3

Our paper is out!
Phase 1 trial of APRIL CAR-T cells for myeloma.
It wasn’t straightforward but some fantastic translational work by Lydia Lee and Martin Pule’s team explain why….👇#mmsm @uclcancer https://t.co/r1laVLgHir— Rakesh Popat (@DrRakeshPopat) July 3, 2023

(OT) Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies https://jitc.bmj.com/content/11/6/e006287

Dr. Pule is one of the authors.

AUTO4 has a unique targeting mechanism. Mature T-cells express either T-cell receptor B-chain constant domains 1 or 2 (TRBC1 or TRBC2). T-cell lymphomas are clonal and either express TRBC1 or TRBC2. So a targeting strategy based on mutually exclusive expression of TRBC domains can spare a proportion of the normal T-cell compartment.

CART is like a big bomb while carpet bombing with bomblets is needed to rid cancer everywhere in the body.

Rare and aggressive group of NHLs without the benefit of B-cell targeted treatments. Few options after CHOP like regimens A privilege to be involved in this first in human #CAR-T trial in R/R #PTCL - an area of unmet need.
Promising Ph I safety data- no ICANS, only 1/13 Gr3 CRS
& encouraging efficacy at highest dose: CMR in 2/4 patients w/ highest dose at 12 & 15 months#17ICML @gloria_iacoboni https://t.co/edUCXhI1tx— Kate Cwynarski (@CwynKate) June 15, 2023

AUTL the bio beast is unstoppable!

Monster bio beast

AUTL the monster is angry and wants to run through the streets

Another oral presentation is planned for a different (peer-reviewed) medical/scientific even, with long-term follow-up planned for ASH. The company is targeting the BLA submission for the program towards the end of this year, MAA filing towards the end of the first quarter of 2024, and the UK filing in the second quarter of next year.

ASCO

Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study https://meetings.asco.org/abstracts-presentations/219864

Another paper https://www.biorxiv.org/content/10.1101/2023.04.26.538403v1

New preclinical data https://www.biorxiv.org/content/10.1101/2023.04.24.538039v1

Preclinical data https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(23)00141-7.pdf

A PhI trial (CARPALL) is ongoing.

New preclinical data https://www.biorxiv.org/content/10.1101/2023.02.22.529492v1.full

ASH abstracts

3318 Safety, Efficiency and Long-Term Follow-up of AUTO1, a Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies https://ash.confex.com/ash/2022/webprogram/Paper167053.html

4650 Dual Antigen Targeting with Co-Transduced CD19/22 CAR T Cells May Prevent Antigen-Negative Relapse after CAR T Cell Therapy for Relapsed/Refractory ALL https://ash.confex.com/ash/2022/webprogram/Paper164879.html

4634 First in Human Study of AUTO4, a TRBC1-Targeting CAR T-Cell Therapy in Relapsed/Refractory TRBC1-Positive Peripheral T-Cell Lymphoma https://ash.confex.com/ash/2022/webprogram/Paper165971.html

258 A Novel Protein-Based Approach to Generate Allogeneic CAR-T Cells with Simultaneous TCR and MHC Class 1 Downregulation https://ash.confex.com/ash/2022/webprogram/Paper167980.html

Some slides https://clin.larvol.com/trial-detail/NCT04384393

I found out that a Chinese group [1] is doing a similar allo approach to the company's [2], with some promising clinical data. So far, no GvHD and a high response rate.

Refs:
1 https://library.ehaweb.org/eha/2022/eha2022-congress/357128/lei.xue.preliminary.analyses.of.a.non-gene-editing.allogentic.car-t.in.cd192B.html
2 https://ashpublications.org/blood/article/132/Supplement%201/700/266123/A-Protein-Based-Method-to-Develop-Allogeneic

PR https://www.globenewswire.com/news-release/2022/06/10/2460244/0/en/Autolus-Therapeutics-Presents-Clinical-Data-Updates-at-the-European-Hematology-Association-Congress.html

Slides https://autolus.gcs-web.com/static-files/4b067a97-f89e-4287-a195-0660f35dceac

Webcast https://edge.media-server.com/mmc/p/9hqfvps4

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.

EHA PR https://www.globenewswire.com/news-release/2022/05/12/2442194/0/en/Autolus-Therapeutics-to-Present-Four-Clinical-Data-Updates-at-the-European-Hematology-Association-Congress.html

1105: CAR-T Cells Engineered to Express a FAS-CD40 Chimera Display Superior Persistence and Tumour Cytotoxicity https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=2004

1096: Enhancing CAR T Cell Therapy Using Fab Based Constitutively Heterodimeric Cytokine Receptors https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1996

311: Development of a Minocycline Mediated Protein-Protein Displacement Platform Using an Anti-Minocycline Single Domain Antibody and a Dedicated Displaceable Peptide https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1267

ASGCT titles:

CAR-T Cells Engineered to Express a FAS-CD40 Chimera Display Superior Persistence and Tumour Cytotoxicity.

Enhancing CAR T Cell Therapy Using Fab Based Constitutively Heterodimeric Cytokine Receptors.

Development of a Minocycline Mediated Protein-Protein Displacement Platform Using an Anti-Minocycline Single Domain Antibody and a Dedicated Displaceable Peptide.