The FDA has granted fast track designation to UB-VV111, an investigational in vivo CAR-T cell therapy developed by Umoja Biopharma, for the treatment of patients with relapsed/refractory large B-cell lymphoma (LBCL) and chronic lymphocytic leukemia (CLL) who have received at least two prior lines of therapy. This milestone represents a significant advancement in the field of in vivo CAR-T cell therapies.
Breakthrough in CAR-T Technology
UB-VV111 is an investigational, third-generation, self-inactivating, replication-incompetent lentiviral vector off-the-shelf treatment that generates CD19-targeted CAR-T cells directly in the patient's body. This approach represents a fundamental shift from traditional ex vivo autologous CAR-T cell therapies, which require extracting a patient's T cells, genetically modifying them in a laboratory, and then reinfusing them.
The therapy is surface engineered with a membrane-bound multidomain fusion protein containing CD58, CD80, and CD3-directed single-chain variable fragment components that provide T-cell tropism, as well as activation signals that may assist in effective CAR-T cell generation. UB-VV111 also has an envelope containing cocal virus fusion glycoprotein.
Addressing Current Treatment Limitations
UB-VV111 was designed to address several limitations of currently approved autologous CD19-directed CAR-T cell therapies, including high manufacturing costs, long wait times, burdensome treatment processes, and limited product availability that restrict broad patient access.
"This Fast Track Designation marks a key milestone in the advancement of in vivo CAR T cell therapies," said Luke Walker, MD, Chief Medical Officer of Umoja Biopharma. "UB-VV111 continues to lead the in vivo CAR T cell field in the U.S., and today's announcement further reinforces its potential to address unmet needs in the treatment of those living with relapsed/refractory B-cell malignancies."
Regulatory History and Clinical Development
In 2024, the FDA cleared the investigational new drug (IND) application for UB-VV111 for the treatment of patients with hematologic malignancies, marking the first FDA clearance of an IND application for an in vivo CAR-T cell therapy. The Phase 1 trial was initiated following this clearance.
Ongoing Phase 1 Clinical Trial
The first-in-human, global, multicenter, dose-escalation and confirmation study (NCT06528301) is currently enrolling patients at least 18 years of age with relapsed or refractory LBCL or CLL who have measurable disease per Lugano 2014 criteria (LBCL) or International Workshop on CLL 2018 criteria (CLL).
Patient Eligibility
Eligible patients must have no serious concomitant diseases or active or uncontrolled infections, an ECOG performance status of 0 or 1, and adequate organ function. Patients who have been previously treated with CD19-directed therapy need to have biopsy-confirmed CD19 expression following completion of that therapy.
Exclusion criteria include pregnancy or breastfeeding; current isolated central nervous system (CNS) involvement; ongoing CNS disease precluding neurologic assessment; previous allogeneic bone marrow transplant, gene therapy, or adoptive cell transfer (except for CAR-T cell therapy); history of or active human immunodeficiency virus; active hepatitis B or C; systemic immunodeficiency or autoimmune diseases (except for well-controlled type I diabetes or thyroid disease); uncontrolled angina or other acute heart disease; or current treatment in another interventional clinical trial.
Treatment Protocol and Endpoints
Patients will receive a single dose of UB-VV111 either alone or followed by rapamycin treatment. UB-VV111 will be administered either intranodally or intravenously, with each route of administration following independent dose-escalation and expansion designs.
The primary endpoints are the safety profile, as well as the maximum tolerated dose, maximum administered dose, and recommended phase 2 dose of UB-VV111 with or without rapamycin. The secondary endpoint is overall response rate. Exploratory endpoints include further preliminary efficacy findings; the pharmacokinetics and immunogenicity of UB-VV111 particles and CAR-T cells; and translational correlative findings regarding biomarkers, safety, and efficacy.
Strategic Partnership
AbbVie retains an exclusive option to license Umoja's CD19-directed in vivo CAR-T cell therapy candidates, including UB-VV111, highlighting the commercial potential of this innovative approach to cancer treatment.
