DUBLIN – Genenta Science Srl raised €13.2 million (US$14.6 million) in new funding to progress its genetically engineered autologous hematopoietic progenitor cell therapy designed to reprogram the immunological milieu within the tumor microenvironment.

The therapy, Temferon, has already started two phase I/II trials, in early relapse multiple myeloma and in glioblastoma multiforme (GBM). The cash injection will enable the Milan-based company to complete those studies and, following discussions with the regulators, determine a possible pathway toward approval.

Temferon employs a population of monocytes that express the angiopoietin receptor Tie2 as a Trojan horse to deliver to the tumor microenvironment a genetic payload that leads to the controlled expression of a transgene encoding interferon-alpha, which results in dendritic cell activation and, subsequently, the initiation of an immune response.

Interferon-alpha therapy has a long history as an experimental cancer treatment, but its use has been limited by dosing and toxicity issues. Tie2-expressing monocytes (TEMs), which are spontaneously recruited by tumors in order to promote angiogenesis, may enable Genenta to deliver targeted, localized doses of interferon-alpha that can boost the immunogenicity of the tumor without compromising healthy tissues. The interferon-alpha gene, which is under the control of the human Tie2 promoter, is delivered to the TEMs ex vivo using a lentiviral vector. An additional layer of control is provided by microRNA species, to further limit its expression.

TEMs were originally identified by gene therapy pioneer Luigi Naldini, of San Raffaele University School of Medicine and the San Raffaele Telethon Institute for Gene Therapy, who is a co-founder of Genenta. Although they are present in peripheral blood and human tumors, they are rarely found in healthy organs. The first inkling of Temferon's safety profile will become apparent shortly – preliminary interim safety data are due to be reported in the coming months, Genenta co-founder, CEO and Chairman Pierluigi Paracchi told BioWorld.

In all, Genenta plans to administer Temferon to 21 GBM patients and to nine myeloma patients. The initial part of the GBM study involves the administration of three escalating doses of the therapy to nine patients, after which 12 patients would then receive the optimum dose.

GBM has proved a difficult cancer to treat. Bristol-Myers Squibb Co. and partner Ono Pharmaceutical Co. Ltd., of Osaka, Japan, have failed to obtain an efficacy signal with the PD-1 inhibitor Opdivo (nivolumab) in two phase III trials, Checkmate-498 and Checkmate-143. The jury is still out on a third study, Checkmate-548. Although it recently failed to demonstrate an effect on progression-free survival (PFS) in newly diagnosed patients, the independent data monitoring committee ruled that the study should continue to allow overall survival data to mature.

Treatment options remain limited. "There is nothing to change the profile of the disease," Paracchi said. "The bar is not very high in terms of efficacy." For example, Avastin (bevacizumab, Roche Holding AG) scraped through the FDA approval process on the basis of a limited improvement in PFS for the VEGF inhibitor plus chemotherapy vs. chemotherapy alone (4.2 months vs. 1.5 months).

From a competitive standpoint, myeloma is a different proposition. There are, Paracchi said, no fewer than 38 trials of CAR T-cell therapies targeting B-cell maturation antigen (BCMA) underway in myeloma, in addition to existing regimens based on Celgene Corp.'s "imid" stable of immunomodulators, several proteasome inhibitors and the CD38-targeting antibody class led by Darzalex (daratumumab), developed by Johnson & Johnson and Genmab A/S. The decision to pursue myeloma was based on Temferon's activity in preclinical models, Paracchi said. Its mechanism of action avoids one of the main pitfalls of CAR T therapy. "CAR T is tumor-specific," he said. "We can prevent tumor antigen escape in the long term."

The new cash takes Genenta's total raise to €30 million, but drug developers get more bang for their buck in Italy, according to Paracchi. "In Europe, and especially in Italy, the cost of development is at least 40 percent less," he said.

The current round was led by the Shanghai-based investment firm Qianzhan Investment Management (QZ) and Fidim, an investment vehicle of the Rovati family, who sold the commercial operations of the over-the-counter drugmaker Rottapharm to Meda AB (now part of Mylan) five years ago for about $3.1 billion in cash and shares. Each has appointed an observer to the Genenta board. Jing Akira Liu will represent QZ, while Lucio Rovati will represent Fidim.

Genenta also may have been a beneficiary of the trade war between the U.S. and China. "For the first time, I've noticed Chinese investors are looking at Europe," Paracchi said.

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