Targeting exploitable vulnerabilities in T-cell Lymphoma

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

This project was initiated at NCI with the start of the lab in July of 2022 near the end of FY2022. Progress on the Goals and Objectives of this project during FY2022 included safe transport of GEMM, PDX, and cell line models to the NCI Bethesda Campus so that this work could be initiated. Much of the progress in this project during FY2022 has also been focused on securing proper regulatory compliance for the many facets of this project. Additional work on onboarding personnel in the standard operating procedures of the laboratory has been a major part of the effort of this project during FY2022. During FY23, this project has continued to develop. We have increased collaboration with Drs. Staudt, Young, and Muppidi all within the lymphoid malignancies branch (LYMB) to explore exploitable vulnerabilities in these many models of T-cell lymphoma. Based on work on genetic dependencies of AITL cell line models, there is one manuscript in preparation that should be submitted by early FY24. We also have established collaboration with industry to determine whether some of the agents with mechanism of action against BCL6 or polycomb repressive complex 2 (PRC2) have activity in T-cell lymphoma models, and we additionally anticipate working with other agents in investigator-initiated exploration of their activity. In FY23, the Ng lab has embarked on a collaborative study of Lymphocytic variant Hypereosinophilic syndreome (LHES), which has cases that are known to be associated with development of TCLs, in some cases years or even decades after the initial diagnosis of LHES. In collaboration with Drs. Charles Anderson and Amy Klion of NIAID, we plan to sequence DNA from serial samples of LHES that they have acquired over several years of following patients and to compare these to TCL samples collected in the LYMB with likely circulating disease. Dr. Klion's team will be performing single-cell RNA-seq analysis of these samples, and the Ng lab will perform exome sequencing from peripheral blood mononuclear cells (PBMCs) as well as paired tumor samples to assess for any clonal evolution that may be associated with development of TCLs in this context. We also anticipate more fully adding clinical projects being developed in the lab in FY24. Additional efforts FY23 have included development of 2 clinical trials that further the goals of this project: 1. A Phase I Trial of Anti-Chemokine Antigen Receptor T-cells (CCR4-CAR T cells) for the Treatment of CCR4 expressing T-cell Malignancies including Peripheral T-cell Non-Hodgkin Lymphoma (PTCL) and Cutaneous T-cell Non-Hodgkin Lymphoma (CTCL), for which Dr. Ng became clinical PI after joining the LYMB. This protocol was previously in development and was pending scientific review committee re-submission based on preclinical safety experiments that had been completed prior to Dr. Ng joining the Lymphoid Malignancies Branch. This study seeks to understand the safety and toxicity profile of administering autologous T-cells engineered to target the CCR4 chemokine receptor that is broadly expressed in T-cell Lymphomas. Dr, Ng has now worked with Dr. Perera and Steve Highfill of the NCI Center for Cellular Engineering to develop this study. The clinical protocol has been resubmitted to the SRC and working it's way to approval. We anticipate opening this trial in FY24, and this project will support all of the correlative research associated with this trial, seeking improved understanding of mechanisms of immune effector cell activity in treating T-cell malignancies, where the same cell type is both the target and effector. Correlative studies of patient samples include assessing features of the product associated with sensitivity or resistance of TCLs to CAR T-cell therapy, assessing features CAR-T cell infiltration into primary tumor sites with on-treatment biopsies, and assessment of features from peripheral blood that are correlated with response to treatment. An additional clinical trial under development is:A frontline study of PRC2 inhibition + CHOP in untreated Peripheral T-cell Lymphoma. This trial is in development with collaborators from Dana-Farber Cancer Institute with anticipated participation from DFCI and NCI. All correlative studies for this trial will be directed by the Ng lab. One major hypothesis for the activity of PRC2 inhibitors in TCLs, particularly Tfh TCLs is that TET2 LOF mutations promote a synthetic lethality when PRC2 is inhibited, and the Ng lab will be directly testing this hypothesis with correlative samples obtained from this trial. In FY23, the Ng lab has has initiated testing this hypothesis in preclinical models of AITL that are described in goals and objectives. Of note, the clinical studies described above are still working through development, and while associated plans including for biospecimen acquisition and storage as well as genomic data sharing have been generated in draft format, there has yet to be formal approval for these. This will occur as the approval process for these becomes finalized. Overall, the Ng lab has further developed the foundation for accomplishing the goals and objectives of this project in future fiscal years.