Abstract C076: Evidence of TCR and BCR clonal dynamics with enitociclib monotherapy in patients with MYC+ non-Hodgkin lymphoma (NHL)

Abstract

Abstract Introduction: Enitociclib (VIP152) is a potent and selective CDK9 inhibitor with robust MYC downregulation (Frigault ASH 2021). We have previously reported safety, efficacy and MYC downregulation from 16 patients with B-cell lymphoma treated with enitociclib monotherapy, including 2 patients with double-hit diffuse large B-cell lymphoma (DH-DLBCL) who achieved complete metabolic remissions (CR) for 5.5+ and 4.0+ years (Diamond Clin Can Res 2022, Shadman ASH 2022). DH-DLBCL is characterized by MYC and BCL2/BCL6 rearrangements, and MYC+ NHL patients are known to be refractory to immune-oncology (IO) therapies. Herein, we evaluate the IO effect of enitociclib monotherapy in the blood of MYC+ NHL patients. Methods: Enitociclib is being evaluated in a phase 1 trial in patients with NHL receiving 30 mg i.v. once weekly (NCT02635672). From the previously reported 16-patient cohort (Shadman ASH 2022), 12 have evidence of MYC+ and had whole blood collections taken before and after dosing for at least 2 enitociclib doses (204 samples). RNA was purified from whole blood and bulk RNA seq performed by Illumina stranded total RNA prep with RiboZeroTM plus rRNA depletion and globin reduction RNA library preparation with strand-specific sequencing 50M paired reads (Discovery Life Science, AL, USA). TCR and BCR sequences were reconstructed using the TRUST4 algorithm (Song Nature Methods 2021). TCR beta chain (TRBC) sequences were annotated with antigen specificity data from VDJdb, McPAS-TCR and IEDB databases. Results: Demographics of the 12-patient cohort are described: 11 men; median age 68 (58-84) years; median prior therapy 2.5 (1-7); and includes DH-DLBCL (10; 2 CR, 8 clinical progression [PD]), triple hit-DLBCL (1 PD), and transformed follicular lymphoma (1 stable disease, currently on study). Simpson clonality of TRBC after 2 weeks of enitociclib compared with baseline correlates with response (CR, PD); however, the small sample size in each response category limits generalizability. Assuming BCR disease clones are identified by high frequency IGKC or lambda (IGLC), disease clonal switching occurs in 2 patients: DH-DLBCL (CR) from IGLC to IGKC and DH-DLBCL (PD) in reverse. In the CR patient, clearance of the top IGLC with enitociclib treatment is observed with simultaneous expansion of a high frequency TRBC. Although a viral specific TRBC is present in this patient, this top TRBC is unmapped to publicly known antigens suggesting the possibility of a cancer-specific TRBC. The second CR patient had low frequency TRBC. Tumor immune microenvironment deconvolution to describe dynamics of phenotypes will be presented to complement these findings. Conclusions: These data suggest that an IO mechanism of action may contribute to the durable 5.5 year CR observed in a DH-DLBCL patient treated with enitociclib monotherapy. Analysis in expanded datasets is required to support this preliminary observation including following active patients. Citation Format: Melanie M. Frigault, Joseph Birkett, Xin Huang, Raquel Izumi, Amy J. Johnson, Beatrix Stelte-Ludwig, Arushi Mithal, Ahmed Hamdy, Vanessa D. Jonsson. Evidence of TCR and BCR clonal dynamics with enitociclib monotherapy in patients with MYC+ non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C076.