NEW YORK – Vittoria Biotherapeutics is in the process of expanding a Phase I clinical trial of its CAR T-cell therapy for lymphoma, VIPER-101. If successful, Vittoria hopes to fast-track the autologous cell therapy to a pivotal Phase II trial and pursue expedited review with the US Food and Drug Administration.
VIPER-101 is a dual population CD5-targeted autologous CAR T-cell therapy that consists of tumor-targeting CAR T cells and regular T cells, both of which have had their CD5 receptors knocked out via CRISPR-Cas9 gene editing. CD5 is an attractive target for CAR T-cell therapies due to its widespread expression on malignant cells. However, it is also expressed on many other T cells, causing CAR T cells to sometimes target each other in what is known as CAR T fratricide.
"One of the current issues with targeting T cells with the CAR T is that not only would we target the malignant cells, but you'll also target the patient's healthy T cells," said Vittoria CEO Nicholas Siciliano. "You can live without B cells for a period of time, but you can't live without T cells." Vittoria's product is unique, Siciliano said, since it "is giving [patients] their own healthy T cells with CD5 deleted so the CAR can't target them."
Buoyed by a recent $25 million investment, Philadelphia-based Vittoria launched an open-label Phase I clinical trial to determine the safety and recommended Phase II dose of VIPER-101 in patients with relapsed or refractory CD5-positive nodal T-cell non-Hodgkin lymphoma.
The trial is currently ongoing at a single site at the University of Pennsylvania. Siciliano said that another trial site is likely to open later this month but declined to disclose at which institution, noting that the trial will continue to expand to even more sites in the first half of 2025 in New York and Boston.
Despite treatment options that include chemotherapy, radiation, targeted therapy, and stem cell transplant, patients with T-cell lymphoma –– and particularly those with relapsed or refractory disease –– often have poor prognoses, and there is, as yet, no approved CAR T-cell therapy in this setting. Given this unmet medical need, Siciliano said that the company sees VIPER-101 as a strong candidate for the FDA's expedited review process. If the Phase I trial is successful, Siciliano said that the company hopes to immediately move to a Phase II pivotal trial to continue to advance its product.
Vittoria designed VIPER-101 using its proprietary Senza5 platform. The platform engineers patients' T cells, eliminating their CD5 surface proteins and adding a CAR that targets tumor cells to a subset of those engineered cells. The process further leads to enhanced T-cell expansion in vivo, better durability, and more stemness, Siciliano explained, while the company's five-day manufacturing process contributes independently to enhanced stemness.
The engineering and manufacturing processes "gets us a very potent product," Siciliano said, and enable the company to administer smaller doses than what patients would typically receive with conventional cell therapies. In the current Phase I trial, participants at the first dose level receive 10 million CAR T cells. Other dose levels being tested in the trial range from 25 million to 125 million CAR T cells. By comparison, patients weighing more than 110 pounds often receive CAR T-cell doses ranging from 10 million to 250 million cells.
The trial aims to recruit up to 30 participants and is estimated to complete in mid-2026, although Siciliano said that the company hopes to release preliminary data sometime in the first half of next year. "One of the interesting things with T-cell lymphoma is that it's such a progressive disease that even near-term durability is going to be a very important clinical marker of efficacy," he said.
Siciliano added that the anticipated data readout from this study should also provide valuable information on the Senza5 platform's performance, which the company hopes to leverage in its search for strategic partnerships.
As it establishes itself as a clinical-stage developer, Vittoria appears to have found a lightly populated niche in the otherwise rapidly evolving field of CAR T-cell therapies. While CD5 is a frequent CAR target, relatively few groups appear to be pursuing strategies of CD5 modulation directly on CARs.
Baylor College of Medicine, for example, recently published the results of a first-in-human Phase I trial of a CD5-directed CAR that also limits fratricide via reduced CD5 protein levels in CAR T cells while retaining strong cytotoxicity against CD5 positive cancer cells.
Further afield, China's Nanjing Iaso Biotherapeutics conducted a Phase I study of CD5-depleted CAR T cells for relapsed/refractory T-cell acute lymphoblastic leukemia, but that trial is currently marked as terminated and the therapy does not appear within the company's pipeline.
Siciliano said that while the company's current financial holdings provide a "strong runway" to complete the Phase I trial, Vittoria plans to initiate another funding round within the next year, so it has the resources to move VIPER-101 quickly to a pivotal Phase II trial and begin clinical testing of other pipeline assets.
Vittoria currently has two other candidate CAR T-cell therapies undergoing investigational new drug (IND) application-enabling studies. Although it hasn't yet disclosed the targets of these therapies, one is designed to treat solid tumors and the other is for B-cell mediated diseases. Vittoria hopes to meet with the FDA next year to discuss the work needed for a submission package for VIPER-102, the solid tumor therapy, and file an IND by either the end of next year or in early 2026.