Nkarta Inc (NKTX)

[jondoeuk]

AML leukemic stem cells can selectively escape NK cell immune surveillance by suppressing NKG2DL surface expression. This due to enhanced PARP1 expression. Co-treatment with PARP1 inhibitors plus NK cells can inhibit leukemogenesis in vivo https://cancerdiscovery.aacrjournals.org/content/9/9/OF13

[jondoeuk]

SITC titles (presented jointly with CRSP):

A Combined Strategy of CD70 CAR Co-expression with Membrane-bound IL-15 and CISH Knockout Results in Enhanced NK Cytotoxicity and Persistence
Abstract Number and Type:
16439, oral*
Poster Presentation Date and Time:
November 10, 2021, 2:40 p.m. ET

CISH Gene-knockout Anti-CD70-CAR NK Cells Demonstrate Potent Anti-tumor Activity Against Solid Tumor Cell Lines and Provide Partial Resistance to Tumor Microenvironment Inhibition
Abstract Number and Type:
113, poster
Poster Presentation Date and Time:
November 12, 2021, 7:00 am – 8:30 pm ET

NKTX presentations:

Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application
Abstract Number and Type:
151, poster
Poster Presentation Date and Time:
November 12, 2021, 7:00 am – 8:30 pm ET

KIR Haplotype Can Inform Donor Selection in the Production of Allogeneic Memory-Like CAR NK Cells for Clinical Application
Abstract Number and Type:
128, poster
Poster Presentation Date and Time:
November 13, 2021, 7:00 am – 8:30 pm ET

[jondoeuk]

Link to the Cantor Virtual Global Healthcare Conference https://wsw.com/webcast/cantor12/nktx/2120370

[jondoeuk]

NKX019 is now recruiting https://clinicaltrials.gov/ct2/show/NCT05020678

[jondoeuk]

New preclinical data from another group https://jitc.bmj.com/content/9/8/e002866

[jondoeuk]

They have filed for a $500M mixed shelf https://ir.nkartatx.com/node/7466/html

[jondoeuk]

A new patent for anti-BCMA CAR-NK cells, either alone, and/or CAR-T cells that are directed to an additional antigen, and/or an additional epitope of BCMA. Also, in the slide deck, they talk about CISH KO, so I expect that could be used in the anti-CD70 CAR-NK.

[jondoeuk]

The company has signed a lease agreement for a facility to support research and development and future commercial manufacturing of the company's cell therapy pipeline. The 88K square foot facility in South San Francisco will support scaled manufacturing of Nkarta's engineered NK cell therapy candidates. The new facility will also serve as the company's headquarters with office space and research facilities. At full capacity, it is expected to have the flexibility to produce commercial supply of multiple cell therapy products, the company said. The newly leased facility will be built-out as a multi-product facility and is expected to be operational by the end of 2023.

[jondoeuk]

Link to the Raymond James Human Health Innovation Conference webcast https://kvgo.com/rj-health/nkarta-inc-june-2021

[jondoeuk]

Link to the Jefferies conference https://wsw.com/webcast/jeff174/nktx/1884627

[jondoeuk]

Link to the webcast https://www.veracast.com/webcasts/clients/webcasts/218Uf0.cfm

[jondoeuk]

Program three (another CAR-NK) is for CD70+ types. Based on immunohistochemistry, and for hematological malignancies, it is expressed (levels vary) on different non-Hodgkin lymphoma's (including T-cell types), Hodgkin lymphoma's, some leukaemia's and multiple myeloma.

For solid tumours, renal cell carcinoma (mostly clear cell, but also papillary, chromophobe, oncocytomas and sarcomatoid), glioblastoma, astrocytoma, nasopharyngeal (EBV associated), mesothelioma, HCC, esophagus, pancreatic, CRC, breast, ovarian, thyroid, NSCLC (mostly neuro-endocrine, but also adenocarcinoma and squamous), and melanoma.

[jondoeuk]

In April, the FDA approved a protocol amendment to the trial of NKX101. This includes an overall shorter waiting period between enrolment, an additional two-dose regimen to increase patient convenience and to deliver more CAR-NK cells earlier in each cycle, and the earlier introduction of non haplo-related, off-the-shelf NKX101 in the ongoing dose finding cohort. The company aims to present initial data by year end.

[jondoeuk]

Q1 financials. Cash and cash equivalents of $299.7M as of the of March. This should be sufficient to fund its current operating plan into at least the second half of 2023.

[jondoeuk]

Some preclinical data from NKTX last year https://www.nkartatx.com/file.cfm/75/docs/Nkarta_AACR_2020_gene_editing_891_20.pdf https://www.nkartatx.com/file.cfm/75/docs/Nkarta_AACR_2020_NK_plus_T_4235_9.pdf

[jondoeuk]

(OT) FATE has presented preclinical data showing that CD38 knockout improves metabolic fitness, antitumour activity, and overcomes fratricide (self killing). Some addition preclinical data for it and a second target, that I hope this explore explore going forward

https://ashpublications.org/blood/article-abstract/136/21/2416/461232/CD38-deletion-of-human-primary-NK-cells-eliminates https://rupress.org/jem/article/215/9/2379/124250/ARID5B-regulates-metabolic-programming-in-human

[jondoeuk]

In case you weren't aware https://www.globenewswire.com/news-release/2021/05/06/2224961/0/en/CRISPR-Therapeutics-and-Nkarta-Announce-Global-Collaboration-to-Develop-Gene-Edited-Cell-Therapies-for-Cancer.html

[dinogreeves]

This is the next CRSP. Going to triple dollars by early next year. No dilution in sight, the company has over 350 million dollars in the coffers. Awesome news yesterday after hours., anything under 30 dollars is a gift.

[jondoeuk]

In this paper the authors demonstrated that valproic acid, an effective HDACi, was capable of upregulating NKG2DL expression in AML cells, thus enhancing the antitumour efficacy of NKG2D CAR-T cells https://www.frontiersin.org/articles/10.3389/fimmu.2020.580328/full

So a combo trial of that with NKX101 makes sense.

[jondoeuk]

The company has announced that the FDA has cleared an IND application for NKX019. Initiation of a PhI trial of NKX019 in patients with R/R B-cell malignancies, including NHL, CLL and ALL, is planned for the second half of the year (likely Q3).

[jondoeuk]

(OT) Interesting https://cancerimmunolres.aacrjournals.org/content/6/4/458

[jondoeuk]

Some more info https://www.nature.com/articles/d43747-021-00022-0

[jondoeuk]

Preclinical data from another group https://www.frontiersin.org/articles/10.3389/fimmu.2020.586168/full

[jondoeuk]

Going forward, I would like them to insert the CAR into the TRAC locus https://www.nature.com/articles/nature21405

[jondoeuk]

Some interesting info from one of the patents (program four), as it seems both the (CAR) NK cells and (CAR) T-cells will use an OX40 co-stim and mbIL-15 (I don't know about the ex vivo expansion of the T-cells).

Also, the NK cells do not express a detectable level of CIS protein.

The NK cells are further genetically engineered to express a reduced level of a transforming growth factor beta receptor.

The NK cells are further genetically edited to express a reduced level of B2M.

The NK cells are further genetically edited to express a reduced level of CIITA.

The NK cells are further genetically edited to express a reduced level of NKG2A receptor.

The NK cells are further genetically edited to express a reduced level of a Cbl proto-oncogene B protein encoded by a CBLB gene.

The NK cells are further genetically edited to express a reduced level of a tripartite motif-containing protein 29 protein encoded by a TRIM29 gene.

The NK cells are further genetically edited to express a reduced level of a suppressor of cytokine signaling 2 protein encoded by a SOCS2 gene.

The NK cells are further genetically edited to express CD47.

The NK cells are further genetically engineered to express HLA-E.

The NK cells are further genetically edited to disrupt expression of at least one immune checkpoint protein by the NK cells (CTLA4, PD-1, LAG-3, NKG2A receptor, KIR2DL-1, KIR2DL-2, KIR2DL-3, KIR2DS-1 and/or KIR2DA-2, and combinations thereof).

Moving on,

The T-cells comprise at least one genetically edited subunit of a TCR (alpha), or TCR KO, such that they do not exhibit alloreactive effects against cells of a recipient subject.

The T-cells are further genetically edited to reduce expression of one or more of CIS, TGFBR, B2M, and CIITA as compared to non-engineered T cells, or to express CD47 or HLA-E.

The T-cells are further genetically edited to reduce expression of one or more of TRIM29 and SOCS2.

The T-cells are further genetically edited to disrupt expression of at least one immune checkpoint protein, wherein the at least one immune checkpoint protein is selected from CTLA4, PD-1, and LAG-3.

[jondoeuk]

Today, they announced three new exclusive license agreements.

A humanised scFv targeting CLEC12A licensed from Cellerant Therapeutics, creates a fourth preclinical program, ONKT104, for the treatment of acute myeloid leukaemia.

A humanised scFv targeting MUC1 licensed from Glycotope GmbH.

A CCR7 homing receptor licensed from the US NIH, for use in ONKT101, for R/R B-cell malignancies.

[jondoeuk]

ASH slides https://www.nkartatx.com/file.cfm/75/docs/1040_Nkarta_ASH_2020_NKX101_Bachier_TiP.pdf

[jondoeuk]

(OT) Interesting https://www.sciencedirect.com/science/article/abs/pii/S1525001620304809

[jondoeuk]

(OT) Catamaran Bio [1] has raised $42M in a Series A. They are working on CAR-NK cells, allogeneic sources (healthy donors), and uses non-viral methods (which allows for multiplexing) to engineer them further for solid tumours [2,3].

Refs:
1 https://catamaranbio.com
2 https://www.isct-cytotherapy.org/article/S1465-3249(16)30631-4/fulltext
3 https://clincancerres.aacrjournals.org/content/25/14/4400.long

[jondoeuk]

SITC poster https://www.nkartatx.com/file.cfm/75/docs/Nkarta_SITC_2020_NKX019_pre-clinical_poster.pdf

[jondoeuk]

NKX101 trial overview https://ash.confex.com/ash/2020/webprogram/Paper134625.html

[jondoeuk]

Preclinical from FATE (to be presented at ASH) https://ashpublications.org/blood/article/136/Supplement%201/5/470364/Development-of-a-Novel-MICA-B-Specific-CAR-As-a

[jondoeuk]

(OT) Another interesting product https://www.biorxiv.org/content/10.1101/2020.10.07.330043v1.full

[jondoeuk]

(OT) ONK Therapeutics

The company has a three-candidate pipeline led by a dual-targeted NK cell therapy that has a CD19 CAR and membrane-bound TNF-related apoptosis inducing ligand variant. This targets the death receptor 5 pathway [1]. Previously the death receptor 4 pathway, and both were going to be targeted for certain types.

The second candidate is an anti-CD38 CAR and will be given with a systemic anti-IL-6(R) mAb [2].

The third targets MUC-1 and there may be knock-out of genes encoding PD-1 [3], TIGIT [4], CD96 [5] and/or Siglec-7 [6]. Doing the same with a few others, such as CBL-B [7], IL-1R8 [8], and these [9] would help improve efficacy.

All allo (healthy donor) products will use a CD28 co-stim and soluble IL-15 (similar to this [10,11]). Also, they plan to increase trafficking to sites of disease [12-14].

However, cancer cells can develop resistance to the death receptor pathway(s) being targeted [15]. But there could be ways to overcome that [16].

Refs:
1 https://journals.lww.com/immunotherapy-journal/Abstract/2013/06000/Membrane_bound_TRAIL_Supplements_Natural_Killer.4.aspx
2 https://www.frontiersin.org/articles/10.3389/fendo.2018.00788/full
3 https://www.jacionline.org/article/S0091-6749(16)30360-8/fulltext
4 https://www.nature.com/articles/s41590-018-0132-0
5 https://www.nature.com/articles/nri3799
6 https://onlinelibrary.wiley.com/doi/full/10.1111/sji.12455
7 https://www.nature.com/articles/nature12998
8 https://www.nature.com/articles/nature24293
9 https://cancerres.aacrjournals.org/content/80/16_Supplement/891
10 https://www.nature.com/articles/leu2017226
11 https://www.nejm.org/doi/full/10.1056/NEJMoa1910607
12 https://ashpublications.org/blood/article/132/Supplement%201/4547/275557/Providing-a-Homing-Receptor-for-CAR-Engineered-NK
13 https://link.springer.com/article/10.1007%2Fs00262-014-1629-5
14 https://link.springer.com/protocol/10.1007%2F978-1-4939-3684-7_19
15 https://www.nature.com/articles/onc2012164
16 https://ashpublications.org/blood/article/135/9/597/429647/Integrated-drug-profiling-and-CRISPR-screening

[jondoeuk]

Based on papers, such as these [1,2], and IPHA's monalizumab showing activity in humans, the company should move an anti-NKG2A CAR-NK cell product forward in my view [3].

Refs:
1 https://www.cell.com/cell/fulltext/S0092-8674(18)31322-9
2 https://www.cell.com/cell/fulltext/S0092-8674(18)31381-3
3 https://www.jci.org/articles/view/123955

[jondoeuk]

A CAR-NK cell product targeting MICA/B should overcome solid tumor escape from NKG2D-mediated mechanisms of recognition and killing.

A paper demonstrated that antibody targeting of the MICA/B a3 domains specifically prevents shedding and is able to restore NK cell-mediated immunity [1]. Additionally, cancers with B2M and JAK1 inactivating mutations which result in the loss of MHC Class I expression can be effectively targeted with a MICA/B a3 domain-specific antibody to restore NK cell-mediated immunity against solid tumours resistant to cytotoxic T-cells [2].

Refs:
1 https://science.sciencemag.org/content/359/6383/1537.full
2 https://cancerimmunolres.aacrjournals.org/content/8/6/769.long

[jondoeuk]

SITC

Just one entitled: Preclinical evaluation of NKX019, a CD19-targeting CAR NK Cell

[jondoeuk]

Beyond this the product could be further engineered to secrete certain 'payloads,' such as cytokines [1-3] and/or antibodies [4]. Also, in other ways as well (similar) [5,6].

Refs:
1 https://cancerres.aacrjournals.org/content/71/17/5697.long
2 https://www.jci.org/articles/view/58814
3 https://ashpublications.org/blood/article/119/18/4133/30054/Tumor-targeted-T-cells-modified-to-secrete-IL-12
4 https://cancerimmunolres.aacrjournals.org/content/8/4/518
5 https://www.nature.com/articles/nbt.4086
6 https://clincancerres.aacrjournals.org/content/early/2020/09/04/1078-0432.CCR-20-0777

[jondoeuk]

For the allo CAR-T product ('personalised' for certain types) I would like them to insert the CAR(s) into the TRAC locus [1], stop rejection [2], use both CD4/CD8 [3] (of the naive plus (stem) central memory phenotype [4-6]), add a cytokine signal [7], screen donors [8], and make sure the cells are polyfunctional [9] for a start.

In addition, make sure the knockouts are designed to try and overcome the TMEs.

Refs:
1 https://www.nature.com/articles/nature21405
2 https://www.sciencedirect.com/science/article/pii/S0065277615000310
3 https://www.nature.com/articles/leu2015247
4 https://www.nature.com/articles/nm.4241
5 https://www.pnas.org/content/106/41/17469
6 https://www.pnas.org/content/102/27/9571
7 https://www.nature.com/articles/nm.4478
8 https://cancerres.aacrjournals.org/content/80/16_Supplement/879
9 https://ashpublications.org/blood/article/132/8/804/39474/Preinfusion-polyfunctional-anti-CD19-chimeric

[jondoeuk]

I hope for the combo CAR-T plus CAR-NK cell trial, they use an NKG2D CAR (+/- another CAR) NK cell product as these have been observed to shift macrophages towards an M1 phenotype [1], reduce Tregs [2], are antiangiogenic [3], and could induce a host derived CD4+ and CD8+ T-cell response [4].

Refs:
1 https://www.jimmunol.org/content/188/12/6389
2 https://www.jimmunol.org/content/183/11/6939.abstract
3 https://www.jimmunol.org/content/190/5/2455.short
4 https://www.nature.com/articles/gt2010174

[jondoeuk]

Jefferies Cell Therapy Virtual Summit https://wsw.com/webcast/jeff146/nktx/1883310

[jondoeuk]

Here is the link https://www.webcaster4.com/Webcast/Page/2495/37211

[jondoeuk]

At AACR the company showed that an optimised Cas9 gene editing system could successfully disrupt TGFbR2 and CISH. Knockout of the former made CAR-NK cells resistant to TGF-b mediated inhibition of cancer cell killing. For the latter KO CAR-NK cells had improved proliferation, survival, cytokine production and cancer cell killing. The findings showed that gene editing could be combined with CAR engineering to enhance NK cell function and resist the inhibitory tumour microenvironment https://www.nkartatx.com/file.cfm/75/docs/Nkarta_AACR_2020_gene_editing_891_20.pdf

[jondoeuk]

In this paper the authors at MDA demonstrate that IL-15 secreting CAR-NK cells are subject to inhibition by the cytokine induced checkpoint CIS and that CRISPR KO improves the antitumour activity, and the metabolic fitness of the cells https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020007748/463715/Targeting-a-cytokine-checkpoint-enhances-the

[jondoeuk]

Executive management plans to participate in a fireside chat at the Cantor Virtual Healthcare Conference on Tuesday, Sept 15, at 2:00 PM ET. A webcast of the event will be available on the investors section of the website.