CD5-deleted chimeric antigen receptor cells (SENZA5 CART5) to enhance immunotherapy against T cell non-hodgkin lymphoma (NHL): a first-in-human phase I clinical trial

The Food and Drug Administration awarded The Trustees of the University of Pennsylvania $6.843 million on September 30, 2025, under the Food and Drug Administration Research program (CFDA 93.103) to conduct a first-in-human Phase I clinical trial evaluating CD5-deleted chimeric antigen receptor T cells (SENZA5 CAR-T5) for the treatment of relapsed or refractory T-cell non-Hodgkin lymphoma. The trial will assess the feasibility, toxicity, and efficacy of this novel immunotherapy approach, which addresses a significant clinical gap: CAR-T therapy has achieved remarkable outcomes in B-cell malignancies but has not translated to most other cancers, and relapsed or refractory T-NHL remains largely incurable with current treatments. The research centers on a technology developed by the University of Pennsylvania team in which CD5, a pan-T-cell antigen present on both normal and malignant T cells, is deleted from CAR-T cells engineered to express anti-CD5 receptors. This deletion circumvents CAR fratricide—the self-destruction problem that has limited T-cell immunotherapy—and simultaneously enhances CAR signaling and T-cell effector function. The trial will also explore whether untransduced CD5-deleted T cells can provide short-term immunity if CAR-T toxicity emerges. Performance occurs in Pennsylvania, with a period of performance through August 31, 2029. Dr. Barta serves as principal investigator and clinical lead; Dr. Ruella is a co-investigator on correlative studies.

Abstract

The long-term goal of this research is to change the prognosis of relapsed or refractory (R/R) T-cell non-hodgkin lymphoma (T-NHL) using next-generation chimeric antigen receptor T-cell (CART) immunotherapy. CART therapy has led to remarkable clinical outcomes in B-cell malignancies, but the needle has not moved for most other cancers. Relapsed or refractory T-NHL are considered mostly incurable with available therapies and present a particular challenge for antigen-specific T-cell immunotherapy since normal and malignant T cells largely express the same surface antigens. Our group developed a novel approach to circumvent CART fratricide by deleting the pan T-cell antigen CD5 in T cells that are transduced to express an anti-CD5 car. Of note, our work demonstrated that the deletion of CD5 also enhances T-cell effector function by enhancing car signaling. The present project seeks to test this discovery in a first-in-human clinical trial to evaluate the feasibility, toxicity, and efficacy of CD5 deleted anti-CD5 chimeric antigen receptor CART for T-NHL. The central hypothesis of this grant is that CD5 deleted anti-CD5 car T cell immunotherapy is safe and can lead to potent and long-term clinical responses against T-cell lymphomas. Moreover, this research will explore whether the CD5 KO untransduced (car-NEGATIVE) T cells from the CD5 KO CART5 product can provide short-term T-cell immunity in case of CART5 toxicity against the normal T cells that express CD5. The feasibility of this proposal is underpinned by our preliminary results and our institution's extensive expertise in translating CART therapies. A dedicated study team was formed with experts with complementary expertise, including the proposal's principal investigator (DR. Barta, clinical lead), CO-PI (DR. Ruella, correlative lead), biostatistician (DR. Hwang), clinical research staff, and laboratory personnel to ensure the timely success of this proposal. Financial support has been secured from vittoria biotherapeutics, INC, who serves trial sponsor. The central hypothesis will be tested by pursuing two specific aims. In aim#1, the phase I clinical trial will be performed to evaluate feasibility, toxicity, and efficacy of autologous CD5-deleted anti-CD5 car T-cells for R/R non-leukemic T-NHL. The trial will utilize an bayesian optimal interval design to establish the recommended phase II dose. In aim#2, two working hypotheses will be tested using clinical samples obtained from aim#1: I. CD5-deleted CART5 can potently expand and infiltrate tumors; and II. CD5-deleted untransduced cells presented in the product can persist in the blood, limiting T-cell aplasia. Several laboratory techniques will be used for the correlative studies, including will flow cytometry, single-cell transcriptomics, cytokine profile and digital spatial profiling to study the T-cell dynamics and function in the blood and tumors. The proposed research is highly relevant to public health because patients with R/R T- NHL have no available cures with standard non-cellular therapies. This study will significantly impact the field of cancer immunotherapies by developing a novel potent anti-T-cell lymphoma immunotherapy and such address an unmet need in a rare disease.