T-cell dysregulation informs radiotherapy-immunotherapy response in B-cell lymphoma: results from a phase 1 trial

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are highly radiosensitive with immune-driven abscopal responses reported. Programmed cell death 1/programmed cell death ligand 1 (PD-L1) inhibitors are relatively ineffective in DLBCL/FL; however, evidence suggests synergy with radiotherapy (RT), but no clear biomarkers. This phase 1 study examined the safety of escalating RT dose and treated volumes with durvalumab (PD-L1 inhibitor) in 34 adults with relapsed/refractory DLBCL and relapsed/refractory FL, and the role of immune-cell subsets on outcomes. Patients received external-beam RT (2.5-30 Gray [Gy], 5 or 10 fractions up to 3 target sites) plus durvalumab from RT day 2, until progression. Novel positron emission tomography (PET) biodistribution studies of 89Zr-durvalumab and CD8 T-cell minibody-89Zr-Df-crefmirlimab were incorporated. The RT recommended phase 2 dose was 10 Gy/5 fractions and 30 Gy/10 fractions to 3 sites for FL and DLBCL, respectively. The most common grade 3 to 4 toxicities included anemia (9%), neutropenia (11%), and liver dysfunction (5%). Overall response was 60% in FL (3/5; complete response, 40% [2/5]), and 14% in DLBCL (4/27; complete response, 7% [2/27]). Distinct peripheral blood and tumor T-cell features, including CD8 PET-determined intratumoral CD8 T-cells, correlated with response (P < .05). RT-durvalumab with 30 Gy/10 fractions of RT to 3 disease sites is safe, and offers promising responses in FL. Intratumoral and peripheral blood CD8 T-cell dysregulation correlate with treatment response. This trial was registered at www.clinicaltrials.gov as #NCT03610061.