Targeting exploitable vulnerabilities in T-cell Lymphoma

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Continuing progress has been made on this research during the past year. First of all, the clinical trial "A Phase I Trial of Anti-CC Chemokine Receptor 4 Chimeric Antigen Receptor T cells (CCR4 CAR T cells) for CCR4 expressing T-cell Malignancies including Peripheral T-cell Non-Hodgkin Lymphoma (PTCL) and Cutaneous T-cell Non-Hodgkin Lymphoma (CTCL)" (CCR4 CAR T-cell trial) has matured into its own separate research project with multiple translational aims and progress in this trial will be documented in this separate project from FY25 Annual report forward. We have continued progress in identifying novel therapeutic strategies to treat T-cell Lymphomas. This has included identifying autonomous CD28 signaling as a targetable vulnerability in novel models of Follicular-Helper T-cell Lymphoma (TFHL) in novel cell line models of disease. This has strongly leveraged the model generation infrastructure for PTCL models that was established in the last FY. This work has established CD28 as a genetic vulnerability, CD28 signaling as a targetable vulnerability, and demonstrated the use of CD28 signaling blockade with the biologic abatacept as a feasible means of treated TFHL clinically. Additionally, we have worked in collaboration with the NCI Laboratory of Pathology to how that clinical samples of TFHL demonstrated gene signatures and pathway components that are consistent with active CD28 signaling. These results are the basis of a manuscript that will be submitted imminently. These results have also served as the basis of a Phase 1 clinical trial developed by NCI in the NIH clinical center testing abatacept in combination with the hypomethylating agent azacitidine in PTCL, which has been allowed to proceed by the FDA and which we anticipate should be open by the end of calendar year 2025, which will provide the initial clinical studies to determine whether this might be a safe combination for patients with insight into its preliminary efficacy. From a clinical standpoint, we also have prepared and will imminently submit a manuscript reporting on a phase 1 trial of the RAdR combination targeted therapy combination that explores how genetic drivers of disease might influence differential response to combination therapies. We have continued our work with NCATS to determine other combinations with abatacept that might show improved preclinical efficacy compared to combinations already tested. We continue our work exploring the molecular mechanisms underpinning CD28 addiction in TFHL cell lines as well as the molecular basis for the oncogenic properties of the characteristic TFHL mutation RHOA G17V. We have continued testing whether there is an interaction between TET2 LOF with AITL cell line sensitivity to elements of the Polycomb Repressor 2 (PRC2) complex. Our ongoing exploratory work includes CRISPR screens to gain insight into possible genetic subtype-specific determinants of TCL vulnerabilities using cell line models as well as to determine novel means of targeting upstream regulators of transcription factor complexes we have previously identified as genetic vulnerabilities in TCL lines. Overall, we have continued progress for this work in basic, translational, and clinical study of these diseases.