CAR-NK: Can natural killer cell therapy pick up from where CAR-T left off?

Photo/Elena Resko
CAR NK therapy

Riding on the success of CAR-T cell therapy, a breakthrough in the treatment of blood cancers, CAR-NK therapies are an emerging field in therapeutic research that aim to boost an even stronger immune response against cancer.

What is CAR-NK cell therapy?

Natural killer (NK) cells, like T cells, are white blood cells that are a part of the body’s defense mechanism. These NK cells are on the lookout for any kind of disruption in the immune system. As cancer cells downregulate major histocompatibility complex (MHC) expression to avoid being killed by T cells, this response is flagged by NK cells, which then locates the cancer cells, and, as its name suggests, kills them.

CAR-NK therapy more effective than CAR-T?

While chimeric antigen receptor (CAR)-T cells have been hailed as a step forward in cancer research, it comes with a set of drawbacks. Firstly, a major side effect that patients have experienced with CAR-T therapy is cytokine release syndrome (CRS). This occurs when the immune system goes on overdrive because of the presence of the CAR-T cells. This triggers a storm of cytokines which are released, causing a toxic immune environment. This can result in organ failure and even death, if not tackled in time. In addition to that, as CAR-T cells are derived from the patient’s cells instead of a donor’s cells – as a measure to prevent graft-versus-host disease (GvHD) – this can limit the scalability of autologous CAR-T therapy. 

The mechanism behind CAR-NK therapy aims to counter these limitations. So far, according to clinical data, CAR-NK therapy does not result in CRS and neurotoxicity, nor in GvHD. Moreover, with companies like multinational pharmaceutical Thermo Fisher designing high-throughput NK-therapy specific instruments and cell media, scalability is not an issue, making it potentially more affordable.

Besides this, NK cells are more effective in attacking cancer cells. They have spontaneous cytotoxic activity and can target cell death independent of tumor antigen, unlike T cells, which can only destroy their targets by a CAR-specific mechanism.

But sometimes, cancer cells can modify themselves so as to not be detected by the body’s immune system. And, that’s where genetically modifying the NK cells come into play. Patients’ NK cells are engineered to express CARs, to have a much better chance at targeting antigens. For the past few years, researchers at the MD Anderson Cancer Center in Texas in the U.S. have been on a mission to treat cancer through CAR-NK treatment. Upon collecting NK cells from umbilical cord blood that has been donated after a baby’s birth, the CAR molecule is attached to the NK cell. 

Prior to administering CAR-NK, patients receive chemotherapy to prepare the body for CAR-NK treatment. While side effects like lower blood counts and weaker immune system have been associated with administering chemotherapy, Katy Rezvani, from the Department of Stem Cell Transplantation and Cellular Therapy at the institute, said that “these are very easily manageable,” in an explainer video. While CAR-NK can treat blood cancers, researchers at the cancer center are developing ways to leverage the technology to treat breast cancer and glioblastoma (brain tumor).

A recent study conducted at MD Anderson found that the loss of metabolic fitness in CAR-NK is a mechanism of resistance, eventually resulting in tumor relapse. This led to the discovery that CAR-NK cells that express the gene interleukin-15 (IL-15) can provide a prolonged anti-tumor response. 

“Our data suggest that successful treatment using CAR-NK cells may require multiple infusions in order to achieve a robust NK cell population capable of mounting a strong anti-tumor response, especially for difficult to treat and highly metabolically active tumors,” Rezvani said in a press release.

Biopharmas race to bring CAR-NK therapy to the bedside

There are also a number of pharmaceutical companies that are engaged in CAR-NK research. San Diego-based Artiva Biotherapeutics is one of them. The company’s cell therapy manufacturing platform, like at the MD Anderson Cancer Center, uses cells from the umbilical cord of a healthy donor. Cord blood is increasingly used in blood cancers as it contains hematopoietic stem cells. And in the case of CAR-NK therapy, despite a lot of naive NK cells circulating in the umbilical cord blood, most of the NK cells that are collected are adequate to differentiate into mature and active effector cells, according to a research paper published in Biomarker Research.

At Artiva, these NK cells are then cultured in a bioreactor and cryopreserved. Its pipeline consists of NK-based therapies for the treatment of blood cancers like CD30-Positive lymphomas and non-Hodgkin lymphoma, as well as autoimmune conditions like lupus nephritis.

Last year, the company announced that it had received the U.S. Food and Drug Administration (FDA) nod for investigational new drug (IND) status for its drug candidate AB-201, a CAR-NK therapy for the treatment of solid tumors. AB-201 became the first CAR-NK therapy candidate to tend to HER2-positive cancer indications, like breast and gastric carcinomas, according to Fred Aslan, chief executive officer (CEO) at Artiva. 

Currently in phase 1 studies, AB-201 uses a HER2-directed antibody that is converted to Artiva’s CAR structure. The engineered cell maintains a high expression of CD16, as well as other activating innate cell tumor engaging receptors. 

Meanwhile, Fate Therapeutics, also located in San Diego in the U.S., is trying to bring CAR-NK immunotherapy to the market as well. Its investigational, off-the-shelf treatment FT576, for multiple myeloma targeting the B-cell maturation antigen (BCMA), is being clinically studied. The therapy is derived from a clonal master induced pluripotent stem cell (iPSC line), just like the company’s other CAR-NK candidate FT522, which is being tested for the treatment of B cell lymphoma, genetically engineered to target the antigens CD19 and 41BB. At present, FT576 is in phase 1 trials, where patients are being enrolled in two, three-dose treatment cohorts at 1 billion cells per dose. The candidate is being reviewed as a monotherapy as well as in combination with CD38-targeted monoclonal antibody (mAb) to examine the therapeutic potential of dual-antigen targeting of myeloma cells.

Challenges and hopes: what lies ahead?

However, CAR-NK cell therapy is not without its shortcomings. NK cells tend to have a short lifespan in the absence of cytokine support, limiting its efficacy, according to a report published in Targeted Oncology. Another roadblock is that because NK cells are relatively low in number – as they account for five percent to 20% of lymphocytes in the body – they often need ex vivo expansion and activation. Moreover, they can be susceptible to the immunosuppressive tumor microenvironment, challenging its efficacy, yet again.

Nevertheless, biotechs are looking to get past these hurdles, as they move into the clinic. With companies like Senti Bio narrowing down its pipeline to focus on its CAR-NK therapy – which is on track for its IND later this year –  among others, the field is fast-growing. American biotech Nkarta’s robust NK-based pipeline also has two candidates in clinical stages, with one of them (NKX101) recently showing encouraging results in patients with acute myeloid leukemia. Three years ago, pharma giant Sanofi also entered the space with a $358 million takeover of Dutch biotech Kiadis, which solely specialized in its NK platform.

As research in the field progresses, and as we wait to hear from ongoing clinical trials – hopefully having found ways to overcome the obstacles that come with developing a cancer immunotherapy treatment like this –  it’s fair to say that if successful, this off-the-shelf therapy could be transformative in cancer research.

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