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Preclinical data (Stim-R tech) https://www.nature.com/articles/s41598-024-72392-1
From this: “Without a doubt there's big biological risk here,” says Carisma CSO Michael Klichinsky. Researchers have yet to prove either the efficacy or the approvability of CAR macrophages. But solid tumours account for 90% of the cancer burden, making the possibility of activity in these settings with an in vivo reprogramming agent all the more appealing. “We’re going after a real unmet need,” he adds. https://www.nature.com/articles/d41573-024-00150-z
While ICEs could help reduce antigen escape, TGFb signaling limits tumour immunosurveillance by converting NKs into (intermediate) type 1 innate lymphoid cells https://www.nature.com/articles/ni.3800
Engineering the NKs with a dnTGFb receptor not only protects the cells from TGFb induced dysfunction, but also locally reduces TGFb signaling to other cells within the tumour microenvironment. This could elicit more durable responses.
I would be surprised if there were no responses to SENTI-202, but complete remission has long been the critical therapeutic response, ideally MRD-negative. Toxicity is another, as cytarabine (used for lymphodepletion with fludarabine) has potent immunosuppressive effects so that could lead to (additional) myelosuppression and infections. A third will be how well the logic-gated gene circuit (for the CARs) protects healthy hematopoietic stem cells.
As for SENTI-301A, I don't think there will be (RECIST) responses. For solid tumours, more will need to be done, such as additional engineering https://www.drugtargetreview.com/news/151575/treating-hcc-with-genetically-modified-nk-cell-therapy/
Finally, funding is a concern.
iPSC-derived NK cells expressing high-affinity IgG Fc receptor fusion CD64/16A to mediate flexible, multi-tumor antigen targeting for lymphoma https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1407567/full
Based on this and other (preclinical) data, I don't think it's unreasonable to assume that the next-gen iNKs FATE is working on will have this receptor. One question is are they able to further optimise the function of it with different transmembrane regions and signaling/co-signaling domain(s).
A thread
Happy to share the final work from my post-doc with @MalmbergLab published in @CellStemCell today https://t.co/ZcC8Q32kts
— Quirin Hammer (@QuirinHammer) July 8, 2024
extensive 15-post-🧵 below pic.twitter.com/jlTbeASoVJ
I assume (rightly or wrongly) it is down as they were supposed to have shared data on ~20-30 patients. There was also no conference call and they cut two indications (I agree with melanoma). Data shows promise, but you have to show the market more than that.
https://finance.yahoo.com/news/turnstone-biologics-corp-reports-positive-200100662.html
Earlier this year development of the lead CAR-NK programme, CB-020, was stopped, and now they are out of CAR-NK altogether. They disclosed it in an SEC filing and outlined a 12% workforce reduction https://www.sec.gov/Archives/edgar/data/1619856/000161985624000054/crbu-20240716.htm
This should extend their cash runway by at least six months, into the second half of 2026.
The study showed that blocking TGF-B signalling is necessary for the effective treatment of hepatocellular carcinoma (and likely other solid tumours that have high TGF-B levels) with iPSC-derived NK cells https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00217-0
https://www.oncologypipeline.com/apexonco/ideaya-socks-it-gsk
I look forward to data from the PRMT5 combo trial (AMGN's AMG-193 had single-agent activity and cleaner toxicity than first-gen versions) https://aacrjournals.org/cancerres/article/83/7_Supplement/1644/722821/Abstract-1644-Dual-inhibition-of-MAT2A-and-PRMT5
Depending on the toxicity (and activity), triplets could be tested. PRMT5 inhibition could disable mechanisms protecting cancer cells from DNA damage caused by chemotherapy, radiotherapy or PARP inhibitors http://www.cell-stress.com/researcharticles/2020a-kim-cell-stress/
Something else Gadeta had been working on https://aacrjournals.org/cancerres/article/84/6_Supplement/3611/737213/Abstract-3611-A-patient-derived-organoid-platform
They will use the standard flu/cy as part of the conditioning regime, but also either cyclophosphamide or bendamustine. They have been testing the integration of the ADR tech in next-gen iPSC-derived CD8+ CAR T-cells, which could allow conditioning-free therapy. Adding additional edits could prevent rejection as well https://www.biorxiv.org/content/10.1101/2023.10.09.557143v1.full
FDA places partial hold on ADC trial after multiple deaths https://www.biospace.com/article/fda-slaps-biontech-medilink-adc-with-partial-clinical-hold-due-to-significant-risk-of-illness-/
In the second half, they expect to read-out initial PhI data for the first 3-5 patients treated with FT819 for moderate to severe SLE. They seek to administer FT819 without fludarabine and instead with commonly used treatment regimens for autoimmune diseases. They seek to demonstrate the potential of the proprietary ADR tech. Specifically, they expect to read-out 3-5 patients treated with FT522 in the PhI for B-cell lymphoma. They seek to broadly investigate FT522 without conditioning chemo for treatment of various B-cell autoimmune diseases. They seek to establish an initial clinical proof-of-concept with the first 3-5 patients treated with FT825 in the PhI for advanced solid tumours. Also, plan to disclose new target(s) and product configurations for at least two next-gen product candidates.
Looking at HbF levels, EDIT-301 appears to achieve slightly higher levels than Casgevy. For total Hb levels, EDIT-301 seems to outperform Casgevy https://finance.yahoo.com/news/editas-medicine-announces-safety-efficacy-070000921.html
However, the ongoing trials and launch are going to be costly, and they aren't working on busulfan free conditioning.
(OT) Dr Restifo is Co-founder and Chief Scientist at Marble Therapeutics. From this: ''At Marble Therapeutics, he is working to figure out how to rewind the epigenetic clock on these cells, using any means possible. The company started out with a focus on skin rejuvenation, adds CEO Denitsa Milanova, but expanded to also work on adoptive cell therapy to prove their platform works.'' https://web.archive.org/web/20231218233715/https://www.nature.com/articles/d41573-023-00206-6
They have a license for TIL plus a neoantigen vaccine https://www.federalregister.gov/documents/2024/02/07/2024-02491/prospective-grant-of-an-exclusive-patent-license-vaccine-augmented-adoptive-cell-therapy-for-the
Preclinical data on the vaccine https://jitc.bmj.com/content/11/Suppl_1/A418
I think they did, but there are still a lot of vampires sucking away at the (limited) revenue.
(OT) BlueSphere Bio, a T-cell receptor (TCR) T-cell therapy company utilizing a powerful TCR discovery platform to identify novel therapeutic candidates for patients with hematologic malignancies and solid tumors, today announced a strategic collaboration with the National Cancer Institute (NCI), part of the National Institutes of Health. The collaboration will seek to advance a novel TCR T-cell therapy targeting recurrent respiratory papillomatosis (RRP), a rare orphan disease.
Under the terms of a Cooperative Research and Development Agreement (CRADA), BlueSphere will collaborate with the Center for Cancer Research (CCR) at the NCI. The clinical studies contemplated under the CRADA will be conducted under the leadership of Clint Allen, M.D. and Scott Norberg, D.O. at the CCR, NCI. An earlier Material Transfer Agreement had granted BlueSphere access to HPV+ tumor samples collected by the NCI, with which BlueSphere leveraged its proprietary high-throughput TCR discovery platform, TCXpress™, to identify multiple TCRs with a high affinity for human papilloma virus (HPV) 6 and 11, strains of the virus intricately linked to RRP.'' https://finance.yahoo.com/news/bluesphere-bio-establishes-strategic-collaboration-140000958.html
Among patients with four or more matching HLA alleles, mPFS was 14.4 months, versus 2.8 months in patients with three or fewer matches. But this is based on a retrospective analysis, so they will need to prove the theory prospectively. It was better in LBCL, with mPFS not reached, versus 2.8 months. Also, some improvement in the now-selected dose, 80 million CAR-T cells.
The BCMA-targeted space is already crowded enough and off-target toxicities, including agranulocytosis* could be a problem for its anti-CLL-1 CAR.
* CLL-1 is also highly expressed on almost all granulocytes and monocytes and on parts of myeloid progenitors in the normal bone marrow and peripheral blood.
The single doses were nothing to write home about, and only one patient enrolled so far for the multiple doses https://www.globenewswire.com/news-release/2024/06/03/2892097/0/en/Century-Therapeutics-Presents-Interim-Results-from-Phase-1-ELiPSE-1-Study-at-ASCO-2024-Annual-Meeting.html
Poster https://www.centurytx.com/wp-content/uploads/20240517_Century_ASCO_FINAL.pdf
The CEO should follow (or be kicked) given his poor communication and disastrous performance https://ir.fatetherapeutics.com/node/13526/html
It gets worse. The updated (CB-010) data shows that the ORR (including CR rate) has fallen, so has the mDOR, the six-month PFS is poor and the pivotal trial has been delayed until H2 2025 following a new HLA partial matching strategy. The latter completely alters (in a bad way) the commercial strategy for an allo CAR-T product. They now need thirteen different off-the-shelf batches to be able to cater to ~90% of patients based on an ideal HLA match.
There is barely any move on this news. Seems the market had already written it off. O'Day needs to go, they need to rebuild in areas they have expertise in and refocus in oncology.
They guided that a third of revenues will be from oncology by 2030...! https://www.businesswire.com/news/home/20240530516266/en/Gilead-Provides-Update-on-Phase-3-TROPiCS-04-Study
Shinobi Therapeutics and Anocca will co-develop allogeneic T-cell receptor engineered induced pluripotent stem cells (TCR-iPs-Ts) for solid tumors https://www.bioprocessintl.com/deal-making/shinobi-and-anocca-to-advance-cancer-killing-ips-t-cell-therapies
''Using independent datasets, we validate that CD8-fit T cells (1) are present premanufacture and are associated with clinical responses in individuals treated with axicabtagene ciloleucel, (2) longitudinally persist in individuals after treatment with CAR T cells and (3) are tumor migrating cytolytic cells capable of intratumoral expansion in solid tumors.'' https://www.nature.com/articles/s43018-024-00768-3
https://medicalxpress.com/news/2024-05-cancer-optimal-cells.html
The oNKo-Innate team, along with scientists at Kite, have just published a research article https://onlinelibrary.wiley.com/doi/10.1002/cti2.1507
Optimised manufacturing dramatically improves lentiviral transduction efficiency of primary human NK cells. The field has progressed greatly with CAR transduction rates in human NK cells (it was ~5% just a few years ago). The oNKo-Innate R&D team were able to raise CAR transduction efficiency to ~80%. After testing various NK cell sources, they conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make PB-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.
''No doubt CAR-NK cells have faced several challenges in oncology settings, and we hope our new findings assist researchers in addressing some of these challenges while also improving the potential for CAR-NK cell therapies in treating autoimmune disease such as lupus'' said Nicholas Huntington, PhD, oNKo-innate's CSO.
The CMO (in an email interview to FB) suggested that an ORR readout from TILVANCE-301 could be used to support an accelerated approval in the front-line setting and to covert Amtagvi monotherapy's post anti-PD-1 into a full approval. The PhIII will then continue to potentially seek a full approval for the combo based on PFS.
Medigene & BioNTech Extend T Cell Receptor Immunotherapy Collaboration https://www.contractpharma.com/contents/view_breaking-news/2024-05-21/medigene-biontech-extend-t-cell-receptor-immunotherapy-collaboration/
MRNA wins patent dispute over PFE and BNTX https://www.fiercepharma.com/pharma/eu-patent-office-backing-key-patent-moderna-wins-one-battle-covid-patent-war-against-pfizer