{"id":1970,"date":"2023-07-07T18:22:48","date_gmt":"2023-07-07T18:22:48","guid":{"rendered":"https:\/\/www.thermofisher.com\/blog\/life-in-the-lab\/?p=1970"},"modified":"2025-08-18T14:29:23","modified_gmt":"2025-08-18T14:29:23","slug":"what-is-car-nk-therapy-and-is-it-the-off-the-shelf-solution-the-cancer-research-field-needs","status":"publish","type":"post","link":"https:\/\/www.thermofisher.com\/blog\/life-in-the-lab\/what-is-car-nk-therapy-and-is-it-the-off-the-shelf-solution-the-cancer-research-field-needs\/","title":{"rendered":"What is CAR-NK therapy & how is it changing cancer research?"},"content":{"rendered":"

\"Digital<\/p>\n

In just a few decades, chimeric antigen receptor T-cell therapy (CAR-T cell therapy) has undergone a meteoric rise into the spotlight as the pharmaceutical darling of 21st<\/sup> century oncology. It is the foundation of a rapidly expanding biotech field that has already supplied personalized cell therapy treatments to at least 1,000 patients in the US.<\/p>\n

When cell therapy works, it really <\/em>works. It\u2019s common to hear stories of stunning cures<\/a> in gravely ill patients with leukemia and other blood cancers who hadn\u2019t experienced relief with any other treatment.<\/p>\n

Still, among all the successes there are clear gaps. In building a new therapeutic industry from scratch, researchers and their manufacturing partners have learned a lot about what doesn\u2019t<\/em> yet work with CAR-T therapy.<\/p>\n

A new class of therapy focused on CAR-engineered natural killer (NK) cells is now emerging in early trials to help fill these gaps \u2013 comparable enough to CAR-T to build off existing manufacturing approaches, but distinct in ways that really matter for wider access and better safety. And crucially, CAR-NK promises the same potential for significant therapeutic benefit, perhaps even beyond blood cancers and into the realm of solid tumors.<\/p>\n

Could these natural killers<\/em> be the key to safe, \u201coff-the-shelf\u201d allogeneic therapies that would crack open a major bottleneck for patient access to cell therapy?<\/p>\n

We spoke with thought leaders from the product engineering side of cell therapy on the state of the field, what\u2019s coming next, and why now is the right time to be excited about CAR-NK therapy.<\/p>\n

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What is CAR-NK therapy and how does it work?<\/strong><\/h2>\n

Like T cells, NK cells are lymphocytes that originate in the bone marrow \u2013 NK accounts for 5-20% of these effector cells. But unlike T cells, which must first be primed to respond, NK cells are part of the innate immune system responsible for the body\u2019s first line of defense.<\/p>\n

As their namesake suggests, natural killer cells have an intrinsic cytotoxic capacity aimed squarely at the \u201cnon-self.\u201d It\u2019s a philosophical question for a single cell to grapple with but in the body\u2019s language, the \u201cself\u201d boils down to a net activating signal mediated by MHC class I molecules acting as cell-surface ligands for NK receptors.<\/p>\n

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\"Natural

Natural killer (NK) activation mechanism. NK cells recognize target cells as healthy \u201cself\u201d through a net inhibitory signal mediated by MHC Class I molecules at the target surface. In cancer or infected cells that have lost inhibitory MHC Class I ligand signaling pathtways, NK signal balance shifts further towards activation via activating receptor induction. The activated NK cell releases cytotoxic granules to trigger target cell lysis. Like T-cells, NK cells can be enhanced with chimeric antigen receptor (CAR) expression for more targeted cell therapy applications. <\/em><\/p><\/div>\n

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\u201cWe\u2019re talking about a balance of activation and inhibitory molecules at the surface. What\u2019s different between NK cells and T cells is how they respond to MHC. Whereas MHC acts as an activation ligand for T cells to kill, it\u2019s an inhibitory receptor for NK cells. With cancer or viral infection, the balance changes \u2013 the cancer cell is trying to avoid being killed by T cells, so it downregulates MHC expression. What the NK cell can then do is come along and say, \u2018Wait a minute, every cell in the human body is supposed to express MHC. Something must be wrong.\u2019 And it can kill the cell,\u201d said Erica Heipertz, a cell biologist at Thermo Fisher Scientific who specializes in NK cell research.<\/p>\n

\u201cNK is like the sensor going around making sure everything is in balance. Once you get that out-of-balance surface molecule expression, NK will recognize it independent of antigen. It\u2019s the check-and-balance system of the immune system,\u201d said Heipertz.<\/p>\n

You might close your eyes for a moment and think of this whole, complex dance unfolding at the molecular scale as not unlike your average office parking lot. Hired tow trucks scan the lot looking to remove any cars without an employee permit tag on the rearview \u2013 and so it is with NK cells patrolling to rid the body of cells lacking the proper MHC I credentials. T cells can also oust offenders, but someone would need to call ahead with the specifics \u2013 the license plate, make and model to look for (the antigen).<\/p>\n

One big benefit of a natural killer<\/em>, our in-house tow truck happy to intervene without instruction?<\/p>\n

\u201cThey\u2019re already killer cells \u2013 they\u2019re already really functional. But if you can make them even more functional and targeted to a specific cancer, the therapy may not require as many doses or as many cells,\u201d said Heipertz.<\/p>\n

Another major upside to CAR-NK therapy lies in the fact that it has not triggered any severe side effects even when derived from donor cells, a key divergence from CAR-T therapy.1, 2<\/sup><\/p>\n

\u201cWhat\u2019s really cool about NK cell therapy is that so far, we haven\u2019t seen severe side effects. In fact, many of the clinical trials for NK cells, from what I\u2019ve heard, are being done as outpatient procedures,\u201d said Heipertz.<\/p>\n

Allogeneic therapy \u2013 or therapy produced from a donor cells rather than the patient\u2019s own \u2013 \u00a0has long been a challenge with CAR-T since it\u2019s likely to trigger deadly graft-versus-host disease (GVHD) where native immune cells react against transplanted ones. Even autologous CAR-T therapy, the preferred method, can unleash fierce cytokine storms (clinically known as cytokine release syndrome) and serious neurologic side effects in a notable percentage of patients.<\/p>\n

\"Live-cell

Live-cell imaging<\/a> of an NK cell stained with Invitrogen CellLight Actin-RFP and GFP-centrin interacting with a target K562 cell stained with Invitrogen CellLight Actin-GFP.<\/em><\/p><\/div>\n

NK therapy does not appear to carry the same side effects or risk of GVHD even in allogeneic form, and it requires none of the immune HLA mapping and matching that can take precious time and make it difficult to source a donor. Heipertz pointed out that preliminary evidence suggests that there may even be a therapeutic benefit to not <\/em>matching donor and recipient HLA profiles.3,4<\/sup><\/p>\n

All of this adds up to another exciting option for treating blood cancers, and perhaps even solid tumors. There\u2019s early hope that NK cells may migrate more easily than T cells to the tumor microenvironment.<\/p>\n

\u201cWe collaborated with a group from the University of Maryland who had a mouse model with a skin tumor,\u201d said Heipertz. \u201cWe infused NK cells into the blood, and the cells made it to the tumor site and controlled growth. It wasn\u2019t completely gone, but NK cells did make it to the site. So I think there is some early indication that they could be effective for solid tumors.\u201d5<\/sup><\/p>\n

 <\/p>\n

Why CAR-NK over CAR-T genetic engineering?\u00a0<\/strong><\/h2>\n

The next question is, why now? We\u2019ve known about NK cells\u2019 role in preventing cancer since their discovery in the 1970s<\/a>.<\/p>\n

It was a dead end, perhaps, before the advent of personalized medicine and the revelation of adaptive immunity-based treatments engineered towards precise targets.<\/p>\n

\u201cDespite the centrality of the innate immune response, or perhaps because<\/em> of its centrality, innate immunity has proven difficult to manipulate medically,\u201d writes Siddhartha Mukherjee, cancer biology\u2019s student-turned-unofficial biographer, in his book Song of the Cell.<\/em>6<\/sup><\/p>\n

But there\u2019s never been a more thrilling time to reconsider the simple savvy of the NK cell. The biology is there, the tools for manipulation are there, and the combined potential is incredible.<\/p>\n

\u201cThe field really started with autologous cell therapy, and now we have ten years or so of research in that space,\u201d said Xavier de Mollerat du Jeu, Senior Director of Research and Development in Cell and Gene Therapy at Thermo Fisher Scientific.<\/p>\n

It has given NK cell therapy research and manufacturing a nice head start.<\/p>\n

The cell therapy instrument manufacturing landscape, for example, has had time to improve from the early days of DIY ‘garage workshop’ style setups of individual instruments to factory-scale, fit-for-purpose, integrated manufacturing systems. Many key logistical aspects like cold storage and transportation are also improving in lockstep.<\/p>\n

The R&D team at Thermo Fisher Scientific has been proactive in creating NK-specific protocols for the company\u2019s high-throughput cell therapy instruments to adapt their use beyond T-cell applications. This includes the CTSTM<\/sup> XenonTM<\/sup> Electroporation System<\/a> and CTSTM<\/sup> RoteaTM<\/sup> Counterflow Centrifugation System<\/a> \u2013 both of which have been recognized as needle movers in their own right with major engineering innovation-focused awards like the Edison<\/a> and the R&D100<\/a>.<\/p>\n

 <\/p>\n

\"Thermo<\/p>\n

 <\/p>\n

Even with these tools, scaling up cell therapy production to meet demand is no small task. If autologous therapy is the only option, it may be an insurmountable task. The average autologous CAR-T therapy course requires 3-8 weeks of manufacturing time, multiplied by some 60,000 patients in need annually.<\/p>\n

From the patient\u2019s perspective, that \u2018vein-to-vein’ waiting period between cell collection and infusion can be more time than they have to spare.<\/p>\n

\u201cWe quickly realized that this autologous CAR-T method works fantastically well but it\u2019s extremely difficult to manufacture at scale. Allogeneic cell therapy is an incredible opportunity to streamline. It could also help serve as a \u2018gap filler\u2019 in allowing patients to recover and become ready for autologous therapy,\u201d said de Mollerat du Jeu.<\/p>\n

Thus the urgent need for mass production of reliable allogeneic cell therapy, an \u201coff-the-shelf\u201d alternative. NK fits that bill well.<\/p>\n

\u201cIf we can figure out the off the shelf portion of it, if we can figure out a way to have a bank of these cells cryopreserved and available as a patient needs it? All you\u2019d have to do is thaw and inject the therapy. That\u2019s the big dream,\u201d said Heipertz. \u201cPatients won\u2019t have to wait weeks and weeks for a biotech company to harvest and expand and engineer their own cells to give their treatment. Cell therapy should be something that one day is as readily available as a pill.\u201d<\/p>\n

 <\/p>\n

NK cell expansion innovation <\/strong><\/h2>\n

The Thermo Fisher Scientific cell and gene therapy team \u2013 Heipertz, de Mollerat du Jeu, and hundreds of their colleagues \u2013 are committed as partners to enabling scientists to manufacture next-generation allogeneic cell therapies at a wider scale than ever before.<\/p>\n

For example, Heipertz was the lead scientist in developing the company\u2019s CTSTM<\/sup> NK XpanderTM<\/sup> Medium<\/a> specially developed to accelerate expansion of NK cells from peripheral blood, cord blood, or iPSC-derived sources in a feeder-free system.<\/p>\n

\u201cThis media will help customers move away from feeders while still reaching that clinically relevant number of cells needed,\u201d said Heipertz.<\/p>\n

The use of iPSC-derived NK cells in particular is growing.<\/p>\n