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Italian Startup Rigenerand Homes in on Mesenchymal Cells for Pancreatic Cancer Gene Therapy


NEW YORK – Italian startup Rigenerand is hoping to start a first-in-human clinical trial of its autologous, mesenchymal stromal cell (MSC)-based gene therapy in pancreatic cancer patients later this year, once the European Medicines Agency clears its investigational new drug application.

The gene therapy departs from conventional approaches to going after cancer cells. Rather than manipulating immune cells like T cells to target cancer, Rigenerand plans to genetically modify MSCs from stromal tissue in pancreatic cancer tumors' microenvironment — specifically adipose-derived perivascular stromal cells — such that they can home in on cancer cells and then deliver a soluble version of the cancer-killing protein, TNF-related apoptosis-inducing ligand, or TRAIL. To treat patients with this approach, Rigenerand plans to harvest adipose perivascular stromal cells (AD-PCs) by way of a minimally invasive liposuction procedure, engineer them to produce soluble TRAIL, or sTRAIL, expand them ex vivo, then reinfuse them into the patient following a chemotherapy regimen.

"The concept was essentially to use MSCs as a way to deliver anti-cancer agents … a sort of chemotherapy but driven by cells themselves," Massimo Dominici, Rigenerand's scientific founder, said. According to Dominici, validation studies showed that the therapy could be effective for a variety of tumor types, but the most promising to emerge in preclinical studies was pancreatic ductal adenocarcinoma, a cancer that tends to be resistant to conventional treatments and newer targeted therapies alike.

Even though Rigenerand plans to conduct the Phase I trial locally in Italy and is therefore under IND review with the EMA, the therapy, dubbed RR001, has orphan drug designation from the US Food and Drug Administration. Should the local early-phase trials demonstrate the therapy's safety and preliminary efficacy, Rigenerand hopes to launch later-phase studies overseas, including in the US.

Three-pillar focus

Dominici is conservatively optimistic that the EMA will clear Rigenerand's IND for RR001, allowing the firm to begin human studies by year end. If successful, the treatment would be Rigenerand's first treatment to enter clinical trials.  

While moving RR001 into human trials is a major focus at the company, Rigenerand's business is more diverse. The company, which was founded in 2009 as a spinoff of Italy's University of Modena and Reggio Emilia, also develops and markets cell culture technologies for preclinical research, and offers its good manufacturing process (GMP) "cell factory" facility as a contract development and manufacturing organization (CDMO) service to partners in the cell and gene therapy space.

When Rigenerand launched, it was technically a joint venture between the University of Modena and Reggio Emilia and RanD, a biomedical company in the region focusing on bioreactors. Initial financing came from Principa III-Health SGR Fund and other local investors, allowing the company to pour resources into research and development and build its cell therapy facility.

The bioreactor cell culture technology was the initial focus for the Medolla, Italy-based company, and these products, accordingly, have already entered the market. Specifically, Rigenerand's "3D" cell culture technology, dubbed Vitvo, is sold to researchers and drug developers as a way to replicate tumor tissue in the lab and thoroughly evaluate the anti-tumor activity of drug compounds.

According to Dominici, the name "Vitvo" began as somewhat as a joke, but wound up sticking as the product's name. "It's vitro and vivo combined," he explained. "Because the idea was really to have a system to recreate in vitro and in vivo environments … People are buying the technology to recreate organoids to study the interaction between different cell types."

Cells taken from tumor or tissue samples can be loaded onto the bioreactor, and then "treated as though they are the patient" to verify whether there is a response to a given treatment, Dominici said. According to Dominici, the value of the technology is similar to that of using a patient-derived organoid, but it offers a more direct view the cell interactions that can sometimes be difficult to see inside a spherical organoid.

"I would say it's an organoid cage that allows a better observation of the tissue creation in vitro and their dynamics when we treat them with drugs or physical treatments," he said. The "3D" aspect of the technology simulates a cage-like structure, within which researchers can view the cells colonizing inside the bioreactor from different angles.

"For us, it was an incredible way to accelerate the discovery of RR001," Dominici said of the 3D bioreactor. "We filed down the doses and combinations and only selected the one we knew was working to advance to animal models."

From bioreactor to therapies

The company's investigational gene therapy, for which the bioreactor technology was an essential component of early development, became an official focus for the company around 2016, Dominici said. The following year, the researchers working on the therapy, including Carlotta Spano of the University of Modena and Reggio Emilia and Dominici himself, put out a paper in Nature Scientific Reports detailing the science behind the therapy and its preclinical validation.

In this publication, the researchers described how they homed in on the gene encoding sTRAIL by linking different domains and engineered the MSCs using viral vectors. The cells demonstrated anti-tumor activity in the bioreactors and in animal models and did so without harming healthy tissue or damaging the liver in the animal models. In 2019, the researchers published a paper in Theranostics, detailing more of their preclinical findings for the therapy, this time in combination with paclitaxel. Here, they found that the addition of chemotherapy could sensitize resistant cells to sTRAIL, potentially overcoming treatment resistance.

Based on these preclinical studies, Rigenerand is ready to test out RR001's efficacy and safety in humans. The Phase I clinical trial that Rigenerand hopes to begin later this year will be primarily focused on assessing the therapy's safety and maximum tolerated dose, but will also explore its preliminary anti-tumor activity in up to 18 patients with previously untreated, locally advanced pancreatic cancer.

The trial is an important milestone for Rigenerand as a company and a key opportunity to demonstrate the feasibility of MSC-based gene therapy. As of now, Rigenerand's plan is to perform the full process — of harvesting the patients' MSCs, transporting them to the facility, modifying them to deliver sTRAIL, expanding them, and reinfusing them — all without cryopreserving, or freezing, the product.

Without cryopreservation, the product can survive up to two days, Dominici said. This won't present a problem for the European patients who would receive the treatment in this early-phase study, because their cells can be shipped from most regions in the content to Italy within two days. Down the line, should Rigenerand conduct international trials, the firm may have to partner with regional cell or gene therapy developers or CDMOs.

Though the therapy has not yet entered the clinical phase, making global expansion a far-off consideration, Dominici — a past president of the International Society for Cell and Gene Therapy who has been involved in the rapidly advancing field for most of his career — recognized from the start the importance of initiating regulatory dialogues early.

"We wanted to plant a little fruit over there [in the US]," Dominici said, highlighting that Rigenerand has already initiated talks with the FDA and secured orphan drug designation for RR001. "The big answers will come from our early studies, and then if this is positive, it will not be a big issue to identify a partner over there."