The data of Nkarta's two CAR-NKs are amazing, and the global market of CAR-NK is continuing to update!

April 27, 2022 / eMedClub News / -- Nkarta Therapeutics recently announced the latest clinical data from independent dose studies of its two CAR-NK cell therapy candidates, NKX101 and NKX019, in different hematological malignancies
.

Notably, both programs are evaluating higher dose regimens of 1.
5 billion x 3 doses of CAR-NK cells
.

NKX101 (targeting NKG2D) NKX101 in the treatment of acute myeloid leukemia (r/r AML) and myelodysplastic syndrome (MDS), 3 out of 5 AML patients in the high-dose group achieved complete remission (60% CR), Two of the CR cases had negative minimal residual disease (MRD)
.

▲ NKX101 clinical activity evaluation (Image source: nkarta official website) NKX019 (targeting CD19) NKX019 achieved partial remission in 6 patients with relapsed/refractory B-cell malignancy (NHL), and 5 out of 6 patients in the high-dose group (83% ORR), of which 3 achieved complete responses (50% CR), and CR cases also included one patient with aggressive diffuse large B-cell lymphoma (DLBCL) and one patient with mantle cell lymphoma (MCL)
.

▲ NKX019 clinical activity evaluation (image source: nkarta official website) In terms of safety, neither project reported dose-limiting toxicity, nor observed cytokine release syndrome (CRS), neurotoxicity or graft resistance at any dose.
Host disease (GvHD)
.

Engineered CAR-NK platform NK cells are the immune system's first line of defense against diseases and pathogens, and are an important part of the innate immune system.
They play a similar role to cytotoxic T cells in the adaptive immune system, but NK cells Because of the non-specific target recognition and killing mechanism of cells, which are different from T cells, scientists attract scientists to follow the engineered CAR-T technology and use it for CAR-NK transformation
.

Both in vitro cell models and mouse animal models, CAR-NK showed good tumor killing effect
.

▲ Image source: The allogeneic strategy on Nkarta's official website maximizes the therapeutic effect of CAR-NK cells, thereby releasing a powerful and lasting anti-cancer immune effect
.

While Nkarta's novel differentiated technology focuses on producing a therapy that overcomes the challenges of naturally occurring immune responses, its advantages include: engineering enhanced NK cells' recognition of their tumor targets; generating large numbers of allogeneic NK cells; enhancing their Persistence of ongoing activity in the body
.

▲ Image source: Nkarta's official website Compared with non-engineered NK cells in preclinical models, NKX101 has a 10-fold increase in NKG2D expression and a 4-fold increase in cytotoxic activity
.

In addition, Nkarta has made peripheral blood NK cells express membrane-bound IL15 (mbIL15) through genetic engineering, which improves the survival, proliferation and killing ability of NK cells
.

According to Nkarta, NKX019 has many advantages compared to CD19-targeting CAR-T cells: in terms of cell transduction efficiency, NKX019 is more effective and faster than CD19 CAR-T cells, and has a cytokine release syndrome (CRS)-related factors were significantly reduced
.

From the indications that Nkarta chooses to treat, NKX101 and NKX019 have respectively selected B cell-related hematological tumors that have achieved remarkable results using CAR-T cell therapy
.

And the journey of CAR-NK Xingchenhai will not stop there
.

Global R&D progress of CAR-NK therapy Currently, there is no CAR-NK cell product on the market.
Compared with CAR-T, the number of R&D pipelines for CAR-NK cells is less
.

Up to now, a total of 19 CAR-NK-related clinical trials are underway, of which 16 are in China
.

▲ Image source: http://clinicaltrials.
gov In addition to Nkarta, domestic and foreign companies deploying CAR-NK tracks include Fate, NantKwest, Celularity, Cytovia, Catamaran, Caribou, Century, Cellectis, Nkarta, ImmunityBio, Xing Yiang, Guojian Chengnuo, Boshengji, Nanjing Legend, Inberry, Hengrun Dasheng, Zhongsheng Suyuan, Jingda Biology, Heluoxintu, Aikai Biology, Xin Chuan Biology, Chongqing Precision Biology, Ascoli , Kelun Botai, Qihan Bio, Saiyuan Bio, Jiakesi, BeiGene, Pumis Bio and Aika Biotechnology,
etc.

(The rankings are in no particular order, if there are any omissions, please add them) NantKwestNantKwest is an immunotherapy company dedicated to the development of NK cell therapy
.

Its main products have three series: haNK cell products with high CD16 receptor expression, taNK cell products with high expression of specific CAR, and t-haNK cell products combining the advantages of both
.

At present, all haNK products have entered the Phase Ib/II clinical trial stage
.

▲ Image source: NantKwestFateFate Therapeutics specializes in engineered NK cells for the treatment of hematological tumors/tumors, and other immune diseases
.

The company's NK cells are derived from iPSC cells generated by the company's patented platform technology, which can be supplied to the majority of patients indiscriminately
.

Based on this platform, Fate has established an extensive off-the-shelf cell therapy product pipeline, which mainly includes iPSC-derived CAR-T, CAR-NK and NK cell therapies, which are being explored in hematological tumors and solid tumors
.

Several iPSC-derived cell therapies are currently in clinical stage
.

▲ iPSC-derived cell therapy and NK cell therapy based on the iPSC platform (Image source: fate) On January 12, 2022, the US Food and Drug Administration (FDA) newly approved Fate's "off-the-shelf", iPSC-derived CAR-NK candidate Investigational New Drug (IND) application for product FT536
.

CatamaranCatamaran is leveraging its TAILWIND platform for engineering, processing and manufacturing NK cells and rapidly advancing its pipeline of allogeneic CAR-NK cell therapy products
.

  ▲ Catamaran's pipeline (Image source: Catamaran's official website) CAT-248 is an allogeneic CD70-targeted CAR-NK cell therapy developed by Catamaran through its TAILWIND™ platform
.

CD70 is expressed in both hematological and solid tumors, but is not naturally expressed in peripheral blood NK cells, but can be up-regulated by activation
.

On December 16, 2021, Catamaran Bio presented the preclinical results of this "off the shelf" CAR-NK cell therapy in poster form at the 63rd Annual American Society of Hematology (ASH)
.

Recommended reading: CAR-NK competes on the same stage, "spot" cell therapy announces preclinical dataYimai Meng broke the news that Senti BioSenti Bio was developed by Timothy K.
Lu, an MIT associate professor of bioengineering and computer science.
) and others founded the cell therapy company to create "smarter" next-generation cell and gene therapies by taking the design of gene circuits in cell therapy
.

▲ Image source: Senti Bio announced the preclinical data of its CAR-NK cell therapy in the treatment of solid tumors at the 2022 American Association for Cancer Research (AACR) annual meeting
.

This data shows that CAR-NK cell therapy engineered using logic gates of gene circuits has the potential to improve the efficacy of allogeneic CAR-NK cells in the treatment of solid tumors
.

And CAR-NK cells equipped with calibrated release of IL-15 (crIL-15) achieved optimal cytokine distribution with excellent lethality and persistence
.

Recommended reading: AACRGuanda Lu's Star Company Announces Preclinical Data on "Smarter" CAR-NK Therapy for Solid Tumors Century On December 16, 2021, Century Therapeutics announced the data presented by its CNTY-101 drug candidate at the ASH2021 Annual Meeting , and update its platform technology and pipeline progress
.

CNTY-101 is Century's main product candidate, a general-purpose CAR-iNK therapy derived from iPSCs, modified to express CD19 CAR, soluble IL-15 and EGFR safety switch, and is also the first cell therapy candidate product with 6 CAR genes
.

The product is indicated for B-cell malignancies
.

Cytovia Cytovia is developing a new therapeutic paradigm that promises to be the first company to use the combination of induced pluripotent stem cell-generated NK cells and multispecific NK cell-engaging antibodies to treat solid tumors
.

▲R&D pipeline (Image source: Cytovia) According to the R&D pipeline disclosed by Cytovia, Cytovia's iPSC CAR-NK cell therapy is in the preclinical stage, and its targets include EGFRvIII/EGFR, GPC3, and CD38
.

Takeda has initiated a pivotal Phase II open-label multicenter clinical study (NCT05020015) on November 22, 2021, according to the U.
S.
ClinicalTrials.
gov database
.

To evaluate the safety and efficacy of its CAR-NK cell therapy TAK-007 in adults with relapsed/refractory B-cell non-Hodgkin lymphoma
.

The trial, which will be conducted globally, is expected to enroll approximately 242 patients and is expected to be completed by October 26, 2029
.

Recommended reading: Takeda's CAR-NK therapy enters key clinical trials! Its Phase II clinical study has been announced to launchYimai Mengxing Star Ionxing Biotech was established in June 2021, focusing on the development and application of iPSC-CAR-NK universal off-the-shelf mass-produced immune cell products, Committed to making 0 to 1 innovation in the field of general-purpose off-the-shelf cell therapy
.

In July 2021, Xingyon, which was just established, announced the completion of an angel round of financing of US$40 million.
The raised funds will be mainly used for the construction of R&D facilities and the early development of general-purpose off-the-shelf immune cell technology platforms and products
.

Guojian Chengnuo On November 11, 2021, the Drug Evaluation Center of the State Drug Administration of China approved the development of Guojian Chengnuo Biotechnology (Beijing) Co.
, Ltd.
for "targeted mesothelial therapy for advanced epithelial ovarian cancer treatment".
Clinical trial application for Mesothelin (MSLN) Chimeric Antigen Receptor NK Cell (CAR-NK) Injection" (abbreviation: CAR-NK Injection)
.

Recommended reading: Guojian Chengnuo obtained the IND approval of the first "off-the-shelf" CAR-NK cell drug in China.
Boshengji Pharmaceuticals Boshengji Pharmaceutical Technology (Suzhou) Co.
, Ltd.
was registered and established in Suzhou Industrial Park on May 31, 2010
.

The company focuses on the development of breakthrough First-in-class and Best-in-class CAR-T cell drugs with international leading level.
Several cell products have entered the POC clinical validation stage, covering most hematological tumors and some solid tumors
.

In 2020, the company completed the development of the iPSC-induced UCAR-NK/T cell preparation platform
.

AIKELLY Yuan/Pumis Bio AIKELLY Yuan focuses on the development of a new generation of generic off-the-shelf cell therapy drugs with iPSCs.
It has formed a profound technical accumulation in iPSC reprogramming, gene editing, stem cell differentiation, etc.
, and has achieved success in the iPSC field.
A series of original breakthrough results
.

In June 2021, Aika Biotech and Primis Biotech reached a global strategic cooperation, which will combine Primis Biotech's CAB structural cell therapy platform with independent intellectual property rights to jointly develop a variety of iPSC-CAB-NK cell therapy products for solid tumors.

.

In October of the same year, the construction of a 2,500-square-meter GMP pilot plant in Suzhou was started, which will be used to accelerate the development and commercialization of product pipelines
.

Based on multi-gene editing platform technology and transplantation immune compatible platform technology, Qihan Biotechnology has developed "Super NK cells" for iPSCs, which has great potential to become the next generation of allogeneic cell therapy products
.

In early April 2022, Qihan Bio announced the preclinical data of the NK cell project at the AACR (American Association for Cancer Research) annual meeting
.

The results showed that the expression of NK cell receptors (such as NKG2D and NCR from engineered hiPSCs) was more than 10-fold higher in "Super NK cells", which were more cytotoxic to solid tumors than non-engineered NK cells.
high
.

Xin Chuan Biology Xin Chuan Biology focuses on the deployment of general-purpose off-the-shelf immune cell therapy to improve the accessibility of cell-based drugs to cure cancer.
Based on its comprehensive and innovative iPSC-CAR-immune cell therapy and organoid high-throughput screening technology, it focuses on lung cancer, For high-incidence cancers such as liver cancer, bowel cancer, and B-lymphoma, Xin Chuan Bio has completed the pipeline layout of a number of iPSC-CAR-NK products
.

Ascoli Ascoli proposed the concept of a broad-spectrum and multifunctional anti-tumor integrated drug (ID), and developed an original ROBO1 CAR-NK immune cell drug that can be industrialized on a large scale, which showed excellent direct and direct clinical performance in the early stage.
The effect of killing + secondary immunity
.

On November 19, 2021, Hangzhou YouKairui Pharmaceutical Technology Co.
, Ltd.
(hereinafter referred to as "YouKairui") announced that the CAR-NK clinical research project carried out in Hebei Yanda Lu Daopei Hospital has made an important breakthrough, and the first case of recurrence Bone marrow morphology reports in patients with refractory acute myeloid leukemia (r/r AML) 30 days after infusion of CAR-NK cells showed complete remission (CR) with 0% residual
.

Hengrun Dasheng was established in July 2015 and is located in Zhangjiang, Shanghai.
It is a bio-tech company based on CAR-T cell tumor immunotherapy.
To support the successful launch of the registration clinical trials of the three CAR-T approvals of Hengrun Dasheng, help the industrialization of domestic self-developed CAR-T products, and new targets for solid tumors CAR-T, TCR-T, CAR-NK Research and development of innovative pipeline products such as oncolytic virus and oncolytic virus
.

CAR-NK cell drugs have not yet been publicly disclosed
.

Legend Bio Legend Bio's official website showcases the company's in-house chimeric antigen receptor (CAR) natural killer (NK) cell therapy platform, including: Legend Bio provides clinical trials of engineered cytokine (LGkine) on the company's in-house CAR-NK cell "armor" Pre-safety and efficacy data
.

Legend Bio has developed a robust NK production process that includes the following features: robust amplification and CAR transduction processes; production of high-purity CAR-NK products with high anti-tumor activity; optimized cryopreservation process to minimize post-thaw viability and loss of functionality
.

BeiGene has invested $45 million in cash, milestone payments and royalties to form an exclusive global strategic partnership with Shoreline Biosciences in the United States, which will leverage BeiGene's preclinical R&D and clinical development capabilities and Shoreline's iPSC NK cell technology, develops and commercializes a portfolio of NK cell therapy based products for the treatment of various malignancies
.

On January 6, 2022, the CAR-NK cell therapy independently developed and produced by Imbrary (Hangzhou) Biopharmaceutical Co.
, Ltd.
(hereinafter referred to as Imbrary) has carried out a treatment for locally advanced or metastatic solid tumors.
The clinical trial was officially launched at Shanghai Tongji University Affiliated Dongfang Hospital and Shanghai Artemont Hospital, and the first subjects were successfully enrolled in the same month
.

Jingda Bio On January 18, 2022, Jingda Biomedical Technology Co.
, Ltd.
and Beijing Wujiahe Gene Technology Co.
, Ltd.
signed a strategic cooperation agreement, announcing in-depth strategic cooperation in the research and development of NK/CAR-NK cell gene drugs
.

Heluo Xintu Heluo Xintu is based on years of innovative cell-directed differentiation technology reserves and the ability to solve core barriers in the iPSC field, and strives to create two innovative platforms, including a universal cell therapy platform: this platform combines iPSC Directed differentiation of NK cells and gene editing to develop iNK cell therapy technology (CAR-iNK), the research and development pipeline will cover blood and lymphatic system tumors, solid tumors and nervous system related diseases
.

Summary With the gradual research and development of CAR-NK cell therapy, some industry insiders believe that in the future, CAR-NK cell therapy may surpass CAR-T cell therapy and better treat hematological tumors and solid tumors
.

In addition, NK cells reduce the risk of allogeneic reactions, and allogeneic CAR-NK therapy could serve as a novel "off-the-shelf" cell therapy
.

We look forward to more CAR-NKs entering the clinic as soon as possible to conquer cancer
.

References: 1.
https://ir.
nkartatx.
com/news-releases/news-release-details/nkarta-announces-positive-preliminary-dose-finding-data-two-lead2.
https://clinicaltrials.
gov /ct2/results?cond=&term=nk&cntry=&state=&city=&dist=——List of recent popular events——▼April 27, Agilent Cell and Gene Therapy Webinar ▼April 28, Focus on mRNA Industrialization: Key Considerations for Raw Materials and Purification Processes