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Nutcracker Therapeutics Aims to Beat HPV-Driven Cancers With Multimodal mRNA Therapeutics


NEW YORK – Now that mRNA technology has been proven in the realm of COVID-19 vaccines, Nutcracker Therapeutics is applying it to oncology, developing precision and n-of-1 personalized mRNA cancer therapies.

Nutcracker's lead compound, NTX-0250, is a multimodal mRNA therapeutic for HPV-driven tumors. Here, multimodal means that the product contains three different RNA molecules: a T cell-eliciting molecule intended to generate a T-cell response against HPV proteins E6 and E7, and two immunostimulatory RNA molecules. All of that is contained in Nutcracker's lipid nanoparticle delivery vehicle, dubbed "nutshell."

The Emeryville, California-based company is aiming to start clinical trials of NTX-0250 early next year. Treatment will begin with testing tumors or precancerous lesions for the specific strain of HPV. Approximately 90 percent of anal and cervical cancers are HPV-driven, as are about 70 percent of head and neck cancers and all precancerous neoplasia. NTX-0250 is being developed for patients whose cancers are driven specifically by HPV16.

"That's a terrible virus," said Geoff Nosrati, Nutcracker's chief business officer. "That's the culprit behind most HPV-driven tumors."

Other strains such as HPV18 and HPV45 also drive the development of cancer, he said, but HPV16 is the most prevalent of the high-risk strains.

Cervical intraepithelial neoplasia is typically treated surgically but has a recurrence rate of 10 percent to 20 percent with an elevated lifetime risk of cancer after surgery. Patients with metastatic head and neck cancer or cervical cancer usually receive a mix of chemotherapy or checkpoint inhibitors plus chemotherapy.

"But those patients do run out of treatment options fairly quickly," Nosrati said. "There's a huge need for those late-stage metastatic patients to have some sort of effective therapy that can slow or stop the growth of their tumor." The five-year survival rate for metastatic cervical cancer that has spread to distant locations in the body is just 17 percent.

That huge need has not gone unnoticed. The field of precision therapies targeting cancers driven by HPV, particularly HPV16, is quite crowded. For instance, Precigen's HPV vaccine PRGN-2009 is entering Phase II clinical studies in advanced HPV-associated cancers. In a Phase I trial that combined PRGN-2009 with Merck KGaA's anti-PD1 therapy M7824, 40 percent of patients responded.

And Repertoire Immune Medicines has two Phase I trials targeting HPV16-positive advanced cancer with two different investigational T-cell therapies, RPTR-147 and RPTR-168. Each product is primed with five antigens associated with HPV16. For RPTR-147, those antigens include HPV16 E6 and E7, the same antigens Nutcracker is targeting with NTX-0250.

Inovio, meanwhile, has an investigational immunotherapy in a Phase III trial for precancerous cervical lesions associated with HPV16 and HPV18 and a Phase II trial in precancerous lesions of the anus, as well as other trials. The company has partnered with Qiagen to develop a companion diagnostic to guide clinical decision-making for the product.

BioNTech has also partnered with Qiagen to develop a companion diagnostic for its mRNA-based HPV16-targeted cancer vaccine, BNT113. Like Nutcracker's NTX-0250, BNT113 primes the immune system against E6 and E7. BioNTech is testing BNT113 in the Phase II trial AHEAD-MERIT in combination with Merck's Keytruda (pembrolizumab) versus Keytruda alone in patients with unresectable recurrent or metastatic PD-1-positive HPV-positive head and neck squamous cell carcinoma. A prior investigator-initiated Phase I/II basket trial, HARE-40, showed that BNT113 induced a potent, antigen-specific T-cell response in patients with HPV16-positive cancers.

In Nosrati's view, mRNA-based cancer therapies have an edge over competitors' small molecule and biologic therapies, particularly now that the mRNA-based COVID vaccines have provided large-scale clinical validation of the concept. "There's a ton of flexibility in what you can do with RNA," Nosrati said, noting that the therapeutic possibilities of mRNA are virtually unlimited because they make use of the cell machinery to produce the therapeutic and elicit both T-cell and B-cell responses. "We can also use the body as a bioreactor for all kinds of other interesting therapeutic proteins that are hard or impossible to access via conventional manufacturing."

Another advantage of RNA is that it's transient, Nosrati said. Because it only persists in the body for a couple of days, dosing can be controlled much more carefully than, for example, a DNA therapy that could remain in the body for years or a gene therapy that permanently modifies the genome and can typically only be dosed once due to the development of immunity against the adenovirus used to deliver the therapy. "With mRNA, you have flexibility with regard to dose and schedule and exposure, and that's very important for safety reasons," Nosrati said.

And even compared with other mRNA vaccine efforts, such as BioNTech's, Nutcracker is hoping its multimodal design will give it an edge. Nosrati said that NTX-0250 doesn't just elicit a T-cell response, but its two mRNAs encoding immunomodulatory proteins also reprogram the tumor microenvironment, setting up the T cells to successfully attack the tumor by blocking myeloid-derived tumor cells and other elements that suppress the immune response, converting an immunologically cold environment to a hot one.

"Our product, NTX-0250, contains three different RNA molecules. One encodes E6/E7, while the other two RNAs encode two different immunostimulatory molecules that boost the efficacy of the therapeutic significantly," Nosrati said. "The products are similar in that they both use RNA to encode E6/E7, but that's where the similarity ends."

According to Nutcracker, NTX-0250 showed "very strong" tumor clearance in a mouse model of HPV in a research collaboration with W. Martin Kast, a professor of molecular microbiology and immunology at the University of Southern California's Norris Comprehensive Cancer Center. "We let [the tumors] grow out pretty big for almost 20 days before [treatment]," said Nosrati. But when researchers then exposed the mice to the drug, "the tumors just melted" without producing any concerning immune-related safety signals, he recalled.

Nutcracker's approach has sparked interest among investors. It recently raised $167 million through a series C financing round led by ARCH Venture Partners.

In preclinical development behind NTX-0250, Nutcracker is developing NTX-0565, a patient-specific multimodal mRNA therapy for cutaneous T-cell lymphoma. That therapy will involve genomic sequencing of patients' tumors, identifying the mutations, and then engineering the n-of-1 therapy so that it goes after the specific tumor mutations. The way it's intended to work is that the tumor cells will take up the customized mRNA and present the antigens, which will generate neoantigen-reactive T cells against the tumor.

The sequencing, Nosrati said, will be for a specific, mutation-rich region of the genome. "This is truly n-of-1," Nosrati explained. "Some of the components like the immune-stimulatory proteins will be common between various therapies. But the antigenic component, the T-cell eliciting component, will be truly patient-specific."

Nosrati noted that there's no off-the-shelf test available that pairs with the NTX-0565 program. Instead, Nutcracker will seek to partner with a sequencing provider to outsource the testing.

And while Nutcracker's management team is confident of the eventual success of their clinical programs, there is some uncertainty around the regulatory pathway with the US Food and Drug Administration. This is why the company recently brought on John Stubenrauch, former VP of commercial operations at Gilead Sciences, as chief operating officer in June.

"What we're doing is totally novel. Our biggest risk factor is bringing a new [manufacturing technique] to the FDA and having them sign off on its acceptability for use in humans," Nosrati said. "So far, the data looks great, but any time you bring something new, there's always a risk attached to that."

That manufacturing process involves the use of a biochip, which Nosrati said is "extremely scalable," meaning that the company can produce very small runs of the product, as little as a few milligrams per patient. But it can also produce very large amounts for off-the-shelf products, which Nosrati said is important because the transient nature of mRNA can make it difficult to manufacture in a controlled and scalable manner. The company plans to use the same platform to produce NTX-0250 and NTX-0565.