They don't give any IL-2.

Still the only company I'm aware of that is able to induce such a rapid, robust and consistent large number of CD8+ T-cells.



But having a strong CD8+ T-cell response is useless without the right selection https://www.science.org/doi/10.1126/scitranslmed.aax7918

EDGE does not specifically model immunogenicity but performs reasonably well at predicting immunogenic peptides (immunogenicity is >50% of mutations per patient generate a detectable CD8+ T-cell response).

CD4+ T-cell responses are important as well (but prediction is a lot harder) https://www.nature.com/articles/s41586-019-1671-8

Also, what setting it is given is equally important. They (vaccines in general) likely offer a greater benefit to the patient if administered in earlier clinical settings, such as the adjuvant setting, for a number of reasons.

The IPO was way too early, and one of the few pillars of its business plan was the partnership. The fact that Moderna walked away means that has collapsed. In the future, IP could be another issue.

(OT) From Modulus Therapeutics (before DNA had acquired its cell therapy platform assets). The OX40 co-stim domain is used by Nkarta.

Try not to end up being a bag holder for VC's shifting overvalued ''dream companies.''

MRNA walks away from the deal that could have generated up to $3B, handing back full global rights and related technologies.

Upcoming at ASCO https://finance.yahoo.com/news/tscan-therapeutics-announces-upcoming-presentations-200500617.html

Initial data from a phase 1, first-in-human clinical trial for T-Plex, a multiplexed, enhanced T cell receptor-engineered T cell therapy (TCR-T) for solid tumors https://meetings.asco.org/abstracts-presentations/233898

A phase 1 trial of TSC-100 and TSC-101, engineered T cell therapies that target minor histocompatibility antigens to eliminate residual disease after hematopoietic cell transplantation https://meetings.asco.org/abstracts-presentations/238322

The majority of abstracts will be released on the 23rd, at 5:00 PM (ET).

No, these will be preclinical. I know they will also give an oral presentation (at ASGCT) as well. From memory, around a quarter are selected for this.

(OT) A post on LinkedIn by Max Qian (CEO and Co-Founder at Rui Therapeutics):

''I am so pleased today to share an exciting clinical development with our CAR-NK therapeutic platform on Autoimmune disease space. Attached six slides describe our ongoing FIH clinical trial of KN5501 (CD19 CAR-NK) that is used to treat three severe SLE (systemic lupus erythematosus) patients. We innovatively designed this dose-escalation clinical trial with 1+2+3=6 patients to complete low, medium and high dose.
SLEDAI 2K score (SLE disease activity index 2000), the most commonly used system that evaluates the severity of SLE, is used to determines changes in the disease activity of patients diagnosed with SLE: 1) mild activity (SLEDAI-2K = 6); 2) moderate activity (SLEDAI-2K 7 to 12); 3) severe activity (SLEDAI-2K>12).
· The higher the score, the more significant is the degree of disease activity.
· Scores of 6 and above are considered to be consistent with active disease requiring therapy. However, scores greater than 20 are very rare.
· Modifications of score of 6 (improvement) and of 8 (worsening) are considered clinically relevant.

Consistently, as we observed in r/rDLBCL trials, CAR-NK demonstrated a supper safety profile, i.e., no CRS nor ICANS. Very most exciting is that we observed the efficacy from the 1st three patients on low and medium dose (we even have not completed three doses with medium dose patients yet!). This might be the very 1st FIH data available globally to support CAR-NK therapy in SLE.

In earlier this year, we may hear CAR-T on SLE, but latest FDA announcement may give us (patients, hospital and manufacturers) a 2nd thought of the CAR-T approach in autoimmune disease spaces; don’t mention its other safety and economic concerns. Welcome discussions!''

Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00473-X

Discovery of Novel CARs for Solid Tumors Using Senti REVEAL™, a Massively Parallel Technology Platform Comprising Pooled Screening, Machine Learning, and Lab Automation

Introduction. CAR-T and CAR-NK therapies have limited efficacy in solid tumors due to multiple factors including the immunosuppressive tumor microenvironment and the limited potency of the signaling domains of current approved CAR therapies. More potent CAR signaling domains may address this limitation by activating different pathways (or combinations) that increase robustness to the immunosuppressive tumor microenvironment. FDA-approved CAR therapies for liquid tumors tend to use a limited set of intracellular domains, highlighting a need for new signaling domains for solid tumors. Conventional approaches of screening and optimizing CAR designs are manual labor intensive, low throughput, and can suffer from operator and batch error.

Methods. We developed a massively parallel technology platform, REVEAL™ (Research Engine for Validation of Engineered Asset Libraries), comprising (1) pooled screens of CAR libraries of 10,000s to 100,000s of signaling domains, (2) machine learning models to predict performance, and (3) parallel clonal validation of 100s to 1,000s of candidates using a purpose-built automated liquid handler. Here we used CAR-NK cells, but we anticipate that this framework can be used for other types of effector cells such as CAR-T. We designed libraries of CARs with a fixed extracellular domain targeting CEA, an antigen expressed on a range of solid tumors including colorectal cancer, and over 50,000 combinatorial signaling domains consisting of arrays of subdomains derived from native receptors. High-performing CARs in the libraries were discovered using a sort-seq approach: cells expressing CARs driving robust degranulation (CD107a+) were sorted, and CARs enriched in these cells were identified via NGS. We used these data to train machine learning models mapping CAR structure (i.e., the position and identity of constituent subdomains) to performance. In addition to reproducing experimental CAR performance, these models were used to predict CAR structures not present in the dataset due to cloning or coverage constraints. The highest performing library CARs and model-predicted CARs were then clonally validated in parallel using a liquid handler-based workflow that automated viral production, NK transduction, co-culture assay setup, and imaging-based readout of target killing.

Results. Our library screens and modeling indicate, and our clonal validations confirm, that signaling domains enriched for TRAF-binding motifs have high performance in the context of anti-CEA CAR-NK cells. Among highest performing CARs, however, TRAF domains are typically accompanied by other functional motifs, constituting a more diverse signaling array than would be found in a single native immune receptor. Successful CARs often comprised multiple canonical immune signaling types, i.e., signal 1 (CD3z), signal 2 (one or more costimulatory motifs) and signal 3 (cytokine signaling), demonstrating that a variety of signaling features can be successfully packaged into a single compact CAR. Additionally, these CARs contained sequences from a wide variety of sources outside of canonical CAR domains such as CD3z, CD28, 4-1BB, indicating the untapped potential for designing new CARs for solid tumors.

Conclusion. The REVEAL™ framework described here is capable of extensive optimization of CAR structures, and could potentially be applied to development of potent CAR cell therapies targeting solid tumors and hematologic malignancies beyond B cell cancers.

https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=60213

The management has been substandard for many years https://www.fiercebiotech.com/biotech/gilead-gives-49b-antibody-solid-tumor-plan-unravels and https://www.fiercepharma.com/pharma/gilead-writes-24b-trodelvy-ceo-underscores-time-focused-execution

From Jan 19, 2023: ''ImmunityBio also announced that it held two productive Type B meetings with the FDA in December. The first was to present the recent data and obtain guidance toward a registration pathway in metastatic pancreatic cancer.'' https://www.businesswire.com/news/home/20230119005337/en/ImmunityBio-Announces-Presentation-at-ASCO-GI-2023-of-Fully-Enrolled-Trial-in-Third-Line-and-Greater-Pancreatic-Cancer-and-Update-on-FDA-Type-B-Meetings-Regarding-Paths-to-Registration

What happened?

Nothing listed in the pipeline.

A case report https://www.ejcancer.com/article/S0959-8049(24)00727-5/fulltext

Found this https://www.nature.com/articles/s41591-024-02964-1

They used two cycles of low-dose blinatumomab in refractory rheumatoid arthritis (N=6). There was robust B-cell depletion with a 50% reduction in relevant auto-antibodies. Some minor fevers. However, most patients were then put on maintenance abatacept, so little insight into durability.

Found it

https://www.globenewswire.com/news-release/2024/04/22/2867236/0/en/CRISPR-Therapeutics-to-Present-Oral-Presentation-at-the-American-Society-of-Gene-Cell-Therapy-ASGCT-2024-Annual-Meeting.html

EDIT is also pursuing myocilin-related glaucoma https://www.globenewswire.com/news-release/2024/04/22/2867244/0/en/Editas-Medicine-to-Present-Pre-clinical-Data-Demonstrating-Progression-of-in-vivo-Medicines-Pipeline-at-the-American-Society-of-Gene-and-Cell-Therapy-Annual-Meeting.html

I'm sure in the (near) future they will (functionally) cure (rare) diseases, but not before they dilute a whole bunch more.

Management can try and spin this as much as they want, but this is a failure https://www.businesswire.com/news/home/20240416117356/en/Precision-BioSciences-Announces-Return-of-Programs-and-Conclusion-of-Collaboration-with-Prevail-Therapeutics

Tunable Universal OR-gated CAR T cells for AML https://www.biorxiv.org/content/10.1101/2024.04.13.589307v1

A SUPRA CAR system (usually) consists of a zipCAR and a zipFv. A zipFv has a scFv linked to a leucine zipper (AZip). A zipCAR has a cognate leucine zipper (BZip) that can bind to the AZip. Through the binding between A- and B-leucine zippers, any extracellular signal linked to the AZip can activate the T (or NK) cells. Therefore, the SUPRA CAR remains constant and can serve as a universal CAR. The affinity between the A- and B- leucine zippers can be adjusted so that the signalling strength and activity can be dialled up or down as desired. When AZip isn't linked to an antigen, the signalling is quenched, and T (or NK) cells become inactive.

Last year Clade Therapeutics announced the acquisition of Gadeta B.V. https://www.globenewswire.com/news-release/2023/10/02/2752753/0/en/Clade-Therapeutics-Announces-the-Acquisition-of-Gadeta-B-V.html

Gadeta was developing cell therapies expressing defined gamma-delta T-cell receptors that specifically recognise cancer cells. In order to harness the unique targeting properties of gamma-delta TCRs, Gadeta developed the TEG platform, which equips alpha-beta T-cells (used in the production of CAR and TCR therapies) with a defined gamma-delta TCR https://www.sciencedirect.com/science/article/pii/S0006497120448153

Gadeta also developed a novel proprietary gamma-delta TCR discovery engine based on a 'TCR centric' selection approach that sourced patient material (for a broad range of naturally selected gamma-delta TCRs from different tissues), screened (to identify tumour reactive gamma-delta TCRs from co-cultures of patient material) and selected gamma-delta TCRs optimal properties. Some preclinical data https://aacrjournals.org/cancerres/article/82/12_Supplement/2818/701504/Abstract-2818-Targeting-solid-tumors-with-GDT002-a

So they have chosen to not communicate with their customers as to the issue(s) and timing of a return? If they are closing down the website, then should have the courtesy of letting the paying customers know.

The question remains, was it due to a refocused R&D strategy or data driven.

Upcoming (Fri, May 10) https://annualmeeting.asgct.org/program/agenda-speaker-details?agendaId=37279



As for the antibody degrader, I don't see them being able to combine the cells with therapeutic antibodies. But they might not need to add it.

Upcoming Investor Day (Apr 18, 8:00 am EDT) https://adaptimmune.zoom.us/webinar/register/WN_SAFMQyw3QbiyM9wSLIaTqw#/registration

The multi-year strategic collaboration they struck with RHHBY's Genentech has been terminated. The agreement, established initially for eight years, aimed at launching cell therapies for various cancer indications using ADAP's iPSC platform. Per the terms, ADAP received $150M upfront and was expected to receive $150M in additional payments over five years. ADAP was also eligible to receive development and other milestone-based payments totalling as much as $3B.

https://finance.yahoo.com/news/strategic-collaboration-between-adaptimmune-genentech-120000529.html

Is NTLA-3001 over before it even starts? https://crisprmedicinenews.com/news/genome-editing-with-cas9-and-aav-generates-frequent-insertion-of-viral-vectors-that-are-difficult-to/

I expect more dilution is on the way after the R/S. Unless they sell non-strategic assets, which is hardly a sustainable business practice.

What?

Acquisition of Clade Therapeutics https://www.globenewswire.com/news-release/2024/04/11/2861378/0/en/Century-Therapeutics-Strengthens-Position-in-Autoimmune-Disease-with-Strategic-Pipeline-Expansion-Supported-by-60-Million-Private-Placement-and-Acquisition-of-Clade-Therapeutics.html

Some slides

(OT) Shinobi announced their $51M Series A funding https://www.prnewswire.com/news-releases/shinobi-therapeutics-launches-with-completion-of-51m-series-a-to-advance-hypoimmune-ips-t-cell-therapy-platform-302012188.html

Targeting tech https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(23)00148-1

Immune evasion tech https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00365-X

If there was any good data for the three ongoing CAR-T programs, we would have heard about it.

They have cash until the end of Q3, but if additional funding isn't in place by then (at the latest) it's lights out. Shareholders should consider voting "against" a number of corporate incentives on the table. Officers should not be receiving bonuses this time around.

If one of the companies that are developing off-the-shelf succeed, I don't see why any insurer will pay the price tag of an autologous therapy (assuming similar data/success). On paper, it should be easier than oncology.

Companies usually raise cash after positive (trial) results. This secondary was on the promise in autoimmune https://www.globenewswire.com/news-release/2024/03/25/2851470/0/en/Nkarta-Announces-Pricing-of-240-Million-Underwritten-Offering.html

There is going to be clinical data from LYEL, CRSP and Arsenal Bio* over the next few years that could show if T-cell ''exhaustion'' can be overcome.

* The synthetic pathway activators that Arsenal Bio have created help with maintenance of T-cell stem-like phenotypes, and restrict accessibility of various exhaustion marker genes

It could,* but as I said still think the product doses, cell phenotype(s) and neoantigen-reactivity will play a role as well. There is data from different groups to support that.

As for the innate arm, it would be interesting to test single and dual CARs against PD-L1 and HLA-G in a select patient population https://aacrjournals.org/cancerres/article/83/7_Supplement/5965/724047/Abstract-5965-B2M-loss-of-heterozygosity-in https://elifesciences.org/articles/54854

* Back in the 2000s, Dr Rosenberg's group the US NCI tested three consecutive protocols (in patients with metastatic melanoma) to increase the levels of lymphodepletion. In the first protocol, 43 patients were treated with TIL following the administration of a non-myeloablative chemo regimen consisting of cy/flu. A second trial was then conducted in 25 patients in which the same chemo was given followed by 200cGy whole body irradiation the day before TIL administration. In a third trial in 25 patients, the total body irradiation was intensified for a total of 1200cGy. In the latter two trials, circulating CD34+ haematopoietic stem cells were administered. In all protocols high-dose IL-2 was given as well. The ORR in the three sequential protocols were 49%, 52% and 72%, respectively.

Now they dangle yet another carrot (enhanced host conditioning). I still think the product doses, cell phenotype(s) and neoantigen-reactivity will play a role as well.

https://www.globenewswire.com/news-release/2024/04/04/2857599/0/en/Achilles-Therapeutics-Provides-Interim-Phase-I-IIa-Update-on-Clonal-Neoantigen-Reactive-T-Cells-in-Advanced-NSCLC-and-Melanoma-Including-First-Patients-Dosed-with-Enhanced-Host-Con.html

Slides https://ir.achillestx.com/static-files/d1f75ff0-b8d4-4b0c-8827-0931e5b91e70

From last year https://finance.yahoo.com/news/cellorigin-announced-treatment-first-patient-170000142.html