NanoCell's Moonshot Aims To Unlock In Vivo Cell Therapy

A conversation with Maurits Geerlings, M.D., and Jacek Lubelski, Ph.D. — NanoCell Therapeutics

Today’s CAR-T and TCR treatments rely on extracting, engineering, and reinfusing patient cells in a process so expensive and cumbersome it can only be done at select hospitals. It’s a potential cure that few patients can access.

NanoCell Therapeutics thinks it has a way around that. Instead of relying on custom cell manufacturing, the company is developing a targeted lipid nanoparticle (tLNP) platform designed to turn a patient’s own T cells into CAR-Ts inside the body. By pairing a proprietary T cell–binding nanoparticle with a transposon-based integration system, NanoCell is betting it can deliver a one-and-done therapy that’s cheaper, more scalable, and more durable than current approaches.

If the science holds, the implications are substantial: eliminating factory-like cell manipulation, reducing costs, and putting engineered T cell therapies within reach patents virtually anywhere in the world. But novel delivery systems raise big questions around safety, off-target effects, durability, and whether in vivo engineering can really dethrone the entrenched ex vivo model.

We presented NanoCell CEO Maurits Geerlings, M.D., and Chief Technology Officer Jacek Lubelski, Ph.D., with some questions about the platform’s mechanics, early data, and the hurdles they see on the path to the clinic. They collaborated on the answers below.

The ex vivo bottleneck is well characterized, but LNPs as an alternative delivery method are less so. Can you give us an overview of NanoCell’s LNP platform?

NanoCell Therapeutics is developing a targeted gene therapy (NCTx) platform, with the vision to make genetically engineered therapies truly affordable, scalable, and accessible for the general patient population. Our new gene therapy vector has the potential to transform the cell and gene therapy space, such as CAR-T and TCR therapy.

Our platform uses targeted nanoparticles to enable in vivo generation of CAR T cells by combining a proprietary T cell binder–coated lipid nanoparticle with a transposon-based gene integration system. This novel targeted gene delivery vehicle (tLNP) holds the promise to eliminate the need for an extended ex vivo cell manufacturing process, currently the standard practice. Furthermore, it could potentially circumvent the need for specialized hospital-based treatment, thus greatly increasing the accessibility of cell therapies to patients worldwide.

In your data, CD3 or CD7 targeting alone wasn't enough — why does combining them work so much better?

CD3 and CD7 targeting provide both specificity and T cell activation, which are needed for effective generation of CAR T cells in vivo.

Were off-target effects, immunogenicity, or uptake variability assessed?

We are conducting a biodistribution study using multiple methods to track the tLNP particle and its components. Our data to date indicate that functional DNA delivery that results in integration into the host chromosome is specific to T cells. The full biodistribution results will be shared in upcoming conference proceedings. In parallel, immunogenicity and efficacy are being evaluated as part of our ongoing preclinical studies.

LNPs are notorious for liver tropism. How much hepatocyte uptake did you see? Does the tLNP modification truly overcome that bias to favor circulating T cells?

We observed that upon IV administration, the tLNP particle localizes to various organs, including the spleen and liver. However, effective DNA delivery (integration into the genome) appears to be specific to T cells with minor off-target effects, typically comprising macrophages and Kupfer cells.

Once delivered, did the CAR gene integrate stably into the T cell genome?

Yes, we have observed stable integration of the CAR gene, as evidenced in vivo through durable expression lasting for more than 140 days in rodents. We noted that CAR-T expression reduced upon elimination of the tumor and recurred with CAR-T expansion upon rechallenge with tumor cells.

How durable was expression in vivo? Did you observe any signs of T cell exhaustion?

Our rechallenge study in mice showed durable expression, the intensity of which depended on the presence of antigen (in this case, tumor) over many months.

What are the primary safety concerns for translating this platform, particularly around genomic integration?

Given the T cell specificity of our tLNP vector, genomic integration concerns would relate to “on-target” effects rather than “off-target” effects.

The integration profile of Sleeping Beauty (SB) transposase, which we use, has been widely published and clinically tested. When compared to lentivirus vectors, SB transposase shows a (theoretically) safer, less biased integration pattern that tends to avoid exons.

What are the biggest translational bottlenecks you anticipate when scaling NCtx clinically?

We are bringing together different components s into a single tLNP drug product, which is in an unprecedented space. Currently, nothing indicates that it is not feasible, but we expect to learn along the way. Our vision is to make in vivo CAR and TCR therapy accessible to patients around the world by overcoming barriers related to cost and scalability. Our tLNP platform has the potential to provide a single-dose treatment, similar to lentiviral-based therapies, but more affordable and more durable than mRNA-LNP-based therapies.

About The Experts:

Maurits Geerlings, M.D., MBA is CEO and president of NanoCell Therapeutics. Previously, he was cofounder, executive vice president, and chief operating officer at Actinium Pharmaceuticals. Before that, he worked for several companies, including Alexion Pharmaceuticals, Cephalon Inc., Prism Pharmaceuticals, and Infinity Pharmaceuticals. He received his medical degree from the University of Utrecht and an MBA from George Washington University.

Jacek Lubelski, Ph.D., MBA is chief technology officer of NanoCell Therapeutics. Previously, he was the vice president of pharmaceutical development at UniQure NV where he led vector , process, analytical and preclinical development,activities focused on rAAV-based therapies. He holds MBA from Rotterdam School of Management and received Ph.D. in molecular microbiology from the University of Groningen and a master’s degree in biotechnology from Maria Curie-Sklodowska University.