T-cell dysregulation informs radiotherapy-immunotherapy response in B-cell lymphoma: results from a Phase I trial

Abstract

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are highly radiosensitive with immune-driven abscopal responses reported. PD-1/PD-L1 inhibitors are relatively ineffective in DLBCL/FL but evidence suggests synergy with radiotherapy (RT), yet no clear biomarkers. This phase I study (NCT03610061) examined safety of escalating RT dose and treated volumes with durvalumab (PD-L1i) in thirty-four adult relapsed/refractory (RR)DLBCL and RRFL and the role of immune-cell subsets on outcomes. Patients received external-beam RT (2.5-30 Gray [Gy], five or ten fractions upto 3 target sites) plus durvalumab from RT day two, until progression. Novel Positron Emission Tomography (PET) biodistribution studies of 89Zr-durvalumab and CD8 T-cell minibody-89Zr-Df-cremirlimab were incorporated. RT recommended phase II dose was 10 Gy/5 fractions and 30 Gy/10 fractions to 3 sites for FL and DLBCL respectively. Most common Grade 3-4 toxicities included anaemia (9%), neutropenia (11%), liver dysfunction (5%). Overall response was 60% in FL (3/5; Complete Response [CR] 40% [2/5]), and 14% in DLBCL (4/27; CR 7% (2/27) Distinct peripheral blood and tumour T cell features, including CD8-PET-determined intratumoral CD8 T cells, correlated with response (p<0.05) RT-Durvalumab with 30Gy/10 fractions of radiotherapy to three disease sites is safe and offers promising responses in FL. Intratumoural and peripheral blood CD8 T cell dysregulation correlate with treatment response.