Natural killer (NK) cells are white blood cells that are a part of the body’s defense mechanism. These cells are on the lookout for any kind of disruption in the immune system, and can kill diseased cells like tumor cells.
NK cells are being used in clinical applications to treat a range of diseases. Clinical trials of NK cell infusion have shown promising results, and chimeric antigen receptor (CAR) NK cell therapies have also been making their way to the clinic.
With more and more of these biotechs raising funding to advance their NK cell therapy candidates in the clinic, let us take a look at ten companies in the space to watch out for.
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American company Artiva Biotherapeutics made the headlines last year when its NK cell therapy candidate gained the U.S. Food and Drug Administration (FDA) clearance for Investigational New Drug (IND) for the treatment of lupus nephritis, making it the first of its kind to obtain the approval for an autoimmune disease.
The candidate AlloNK is an allogeneic, non-genetically modified NK cell therapy that is designed to enhance the antibody-dependent cellular cytotoxicity (ADCC) effect of monoclonal antibodies. This way, the drug can kill auto-antibody producing B cells. The candidate is also being evaluated in targeting cancer cells. The company’s oncology pipeline addresses CD30+ lymphomas and B cell malignancies, where the candidate is currently in phase 2 and 1 trials respectively.
According to phase 1 dose-escalation efficacy data that was presented at the 2023 ASCO Annual Meeting, the drug candidate AB-101 which has been developed from Artiva’s AlloNK platform, in combination with the monoclonal antibody rituximab, had a 57.1% Objective Response Rate (ORR) in seven patients.
Last year, the biotech received the Immunology Innovation of the Year award in the 2023 BioTech Breakthrough Awards Program after its launch in 2020.
Focused on bringing its NK cell therapies to the market, American company Dragonfly Therapeutics is developing a number of drug candidates based on its proprietary platform TriNKETs.
TriNKETs engage both the innate and adaptive immune systems by activating NK cells and CD8 T cells, and redirect cytotoxic cells to target cancer cells. The drugs derived from the platform can work in combination with other treatment approaches like chemotherapy and radiation therapy. With the help of its platform, the biotech’s DF1001 is undergoing a phase 1/2 trial for the treatment of solid tumors.
Last year, the company presented results of a phase 1 dose escalation trial of DF1001. The study, which tested the drug candidate on patients with advanced solid tumors who are HER2-positive, found that 67% of patient-paired biopsies showed a pharmacodynamic response, with DF1001 completing its safety evaluation.
The biotech also seems popular among big pharma as it has partnered with AbbVie, Gilead Sciences, Merck, and Bristol Myers Squibb in advancing its other NK cell therapies to the clinic, not only in oncology but also in treating neurological diseases.
Based in the U.S., clinical-stage biotech Fate Therapeutics has four candidates in its pipeline that are designed to target cancer cells. Its candidate FT576 is an off-the-shelf CAR NK immunotherapy that is developed from a clonal master iPSC line.
It targets the B-cell maturation antigen (BCMA) protein with the help of its proprietary CAR, and contains a modified non-cleavable CD16 Fc receptor to improve antibody-dependent cell cytotoxicity, as well as an IL-15 receptor fusion to enhance NK cell activity.
Fate Therapeutics has three more CAR therapy candidates, FT522 for treating relapsed and refractory B-cell lymphoma, FT819 against leukemia, and FT825 targeting HER2-positive solid tumors, which are based on the company’s iPSC platform.
The pluripotent cell platform allows for the iPSC cells to be genetically engineered and expanded in order to create off-the-shelf cell therapy drugs. Its iPSC-based candidate FT825, which is in its preclinical phase, is currently being developed in collaboration with Japanese pharmaceutical Ono Pharmaceutical.
Dutch company Glycostem Therapeutics specializes in natural killer cell therapeutics, and has developed candidates based on two of its platform technologies.
The first, oNKord, aims to treat solid tumors as well as blood cancers like acute myeloid leukemia (AML) and multiple myeloma (MM). The immunotherapy product oNKord, which is composed of unmodified NK cells, is a platform that has been designated the orphan drug status for AML from the European Medicines Agency (EMA) and the FDA. Last year, inaleucel was added to the World Health Organization (WHO) recommended list as the international non-proprietary name (INN) for oNKord. This allows the biotech to use the term ‘inaleucel’ in labeling, drug regulation and in publications.
Its other platform technology viveNK, which is a CAR cell therapy, can boost anti-cancer responses with a minimized risk of developing graft-versus-host disease (GVHD).
Its viveNK candidate, which is currently in preclinical trials, has been developed to address OGD2-positive solid tumors.
CAR NK cell therapy company ImmuneBridge was recently awarded a $12 million seed funding, to advance its immunotherapies for hematologic malignancies and solid tumors. Its proprietary technology uses cord blood-derived immune stem cells that possess the scalability of iPSCs.
The California-based company is developing allogeneic NK cell therapies that are capable of recognizing and attacking tumor cells, and while they are in early stages of development, the company hopes to bring safe and scalable immunotherapy candidates to the clinic.
With the closure of its latest fundraise worth $320 million last week, American company ImmunityBio aims to support its bladder cancer candidate Anktiva in combination with Bacillus Calmette-Guérin (BCG), through clinical trials. Recently, the FDA greenlit its Biologics License Applications (BLA) for the drug combination.
Anktiva is an interleukin-15 superagonist fusion protein designed to boost NK and CD8+ T cells while not simultaneously activating the T regulatory (Treg) cells. With more than 10 ongoing clinical trials in its roster, the company has a few immunotherapy platforms working together to develop its pipeline, among which is ImmunityBio’s CAR NK cell therapy platform, t-haNK.
Based on this CAR-directed platform, the company has created PD-L1 t-haNK, a cryopreserved, bi-specific, cell therapy candidate that targets PD-L1 via a CAR. The candidate contains the receptor CD16 that can bind to an antibody, to enhance its anti-cancer effect. The candidate is to be delivered in combination with a monoclonal antibody and Anktiva. ImmunityBio is also working on M-ceNK, which are memory-like cytokine-enhanced NK cells that are known for their immune-memory, owing to its ability to induce anti-cancer effects for months.
Considered to be among the pioneers of engineering NK cells, Nkarta is a U.S.-based biotech that aims to address the limitations of CAR-T cell therapies that include certain adverse side effects. In an effort to reduce the risk of cytokine storms, which sometimes occurs when the body’s innate immune system turns against itself, NK cell therapies can help mitigate these effects, and on top of that, do not necessarily rely on patient-specific immune cells for its production.
Its four drug candidates are in various stages of development, with NKX101 engineered to target NKG2D ligands – which tends to be overexpressed in cancer cells – in preclinical studies for treating solid tumors and in clinical stages to treat acute myeloid leukemia (AML).
Also in its pipeline is NKX019, which targets the protein CD19, and has entered the clinic to target B cell malignancies and completed preclinical trials in patients with lupus nephritis. For the latter, Nkarta secured the FDA nod for an IND status, and as a result, it had announced back in October, that it would investigate the drug in the clinic soon. The company is also looking to treat other autoimmune diseases as well.
Focused on utilizing the body’s natural killer cells to fight disease, American company NKGen Biotech has developed SuperNK (SNK), an immunotherapy that involves the infusion of an individual’s own activated NK cells into the body to boost immune activity and kill diseased cells.
SNK uses natural killer cells that are obtained from the patient’s blood, which are then activated and sent back into the patient’s body. These autologous cell therapies are said to have a lower chance of side effects when compared to CAR-T treatments.
In its pipeline, the company has a mix of autologous NK, allogeneic NK and CAR NK treatments. Its autologous therapy is in phase 1 studies to treat neurodegenerative conditions, as well as refractory solid tumors, where the latter is being evaluated in combination with avelumab and pembrolizumab. Its CAR NK therapy candidate SNK02, is undergoing preclinical testing to treat HER2-positive solid tumors.
Last month, its autologous NK therapy was cleared by Health Canada to conduct a phase 1/2a clinical trial in people with moderate Alzheimer’s disease.
Leveraging the power of the body’s natural killer cells, ONK Therapeutics is using gene editing and antibody therapeutics to enhance NK cell cytotoxicity within the tumor microenvironment.
The Irish company has a growing portfolio that consists of engineered NK cell therapy candidates that express CAR, among others. Yet to enter the clinic, three of its drug candidates are CAR NK-based that intend to treat AML, multiple myeloma, pancreatic, ovarian, and triple negative breast cancer.
Last year, the biotech was awarded a patent for CISH knockout (KO) in NK cells, which gives the company key IP for CISH KO in NK cells to be used in cancer therapies, from the European Patent Office (EPO). Knockout of the CISH gene is a mechanism used by ONK Therapeutics to optimize NK cell therapies.
More recently, the biotech announced its collaboration with American company NAYA Biosciences to evaluate ONK’s NK cell therapies and the latter’s FLEX-NK bispecific antibodies in combination for treating cancer. This combination therapy is hoped to improve the response rate in patients with hepatocellular carcinoma.
Off-the-shelf CAR-NK company Senti Biosciences, which is situated in San Francisco in the U.S., has a Gene Circuit Technology Platform that looks to program gene therapies with gene circuits.
These gene circuits are made from DNA sequences so as to reprogram cells to compute decisions and respond to their cellular environments. The company aims to target multiple disease pathways with a single drug as well as integrate multiple targets to pick out the diseased cells and spare the healthy ones.
Part of its pipeline is SENTI-202, which is designed to treat AML and myelodysplastic syndrome, among other blood cancers. The candidate is currently being evaluated in the clinic, and data from the ongoing trials are expected to be released this year. Another one of its drug candidates, SENTI-202, was cleared by the FDA to begin phase 1 trials in patients with relapsed or refractory hematologic malignancies like acute myeloid leukemia, last month.
SENTI-202 is an off-the-shelf CAR-NK cell therapy candidate that targets CD33 and FLT3 – proteins which are expressed in blood cancers – and effectively kill leukemic stem cells.
Senti Biosciences has also partnered with other biotechs, namely, Roche subsidiary Spark Therapeutics and Bayer subsidiary Bluerock Therapeutics, for the use of Smart Sensors.
Senti’s Smart Sensor technology helps pick up changing signals from the body as well as identify the location and state of a disease. These sensors can detect different kinds of biomarkers including RNA, DNA and proteins.
NK cell therapy: can it take on CAR T?
While CAR-T therapies are still regarded as a remarkable breakthrough in cancer treatment, CAR NK therapies seem set to take on these immunotherapies. They aim to counter the limitations of CAR-T treatments. For instance, patients who undergo CAR-T therapy sometimes experience side effects like cytokine release syndrome (CRS). This occurs when the immune system goes on overdrive because of the presence of the CAR-T cells. This can trigger a cytokine storm, and result in organ failure and even death, if not treated in time. NK cell therapies including CAR NK, are said to have a lower risk of CRS and neurotoxicity, as well as graft-versus-host disease (GvHD). Moreover, NK cells have been found to be more effective at killing cancer cells, and unlike T cells, target cell death independent of tumor antigen.
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