Clinical and Biological Effects of Combined CD27 and CD20 Antibody Therapy in Relapsed/Refractory B-Cell Lymphoma: The Riva Trial

Background: CD27 antibody stimulation of T cells has been shown to activate and promote myeloid cell infiltration leading to enhanced antibody-dependent cellular phagocytosis (ADCP) by anti-CD20 in lymphoma preclinical models (Turaj et al Cancer Cell 2017). In this phase IIa study (RiVa NCT03307746), the safety and efficacy of rituximab (ritux) and varlilumab (varli, anti-CD27) was tested in relapsed/refractory B-cell lymphoma. Transcriptional effects of therapy were investigated by RNA sequencing of pre- and post-treatment tumour biopsies and single cell RNA sequencing of in vitro peripheral blood mononuclear cells (PBMC). Methods: Eligible patients with relapsed/refractory CD20 + B-cell lymphoma were randomized 1:1 to arms A: cycle 1 day 1 ritux, day 2 varli; or B: cycle 1 day 1 ritux, day 8 varli. Cycles 2-6 are identical in both arms (day 1 ritux (cycles 2-6); day 2 varli (cycles 3 and 5); 2-weekly cycles. The primary endpoints were overall response and safety. RiVa was funded by CRUK (CRUKD/17/008) and Celldex Therapeutics Inc. Intratumoral biopsies were taken pre-treatment and on cycle 1 day 7/8 post treatment, i.e. post- ritux and varli in arm A, and post-ritux alone in arm B, and subjected to RNA sequencing, deconvolution by CIBERSORTx and Gene Set Enrichment Analysis (GSEA). To gain further insight into how anti-CD27 stimulated T cells activate myeloid cells, PBMC from healthy donors were treated with varli or an isotype control for 48 h and analysed by CITE-seq (10x Genomics). Results: Twenty-seven patients were randomised; 15 indolent B-cell non-Hodgkin lymphoma cases (NHL) (1 mantle cell lymphoma and 14 follicular lymphoma (FL) grade 1, 2 or 3a) and 12 aggressive B-NHL (9 diffuse large B-cell lymphoma, 2 FL grade 3b and one transformed FL). Median age was 71 (range 49-87), median lines of previous treatment were 4 (range 1-13) and 22% were refractory to the last line of treatment. Thirteen patients completed all 6 cycles of treatment, 1 patient was withdrawn after 1 cycle due to a new cancer diagnosis, 3 patient/investigator withdrawals occurred and 10 progressed on treatment. The overall response rate at the end of treatment was 26.9% (7/26; 95% CI, 13.4-44.7) (indolent B-NHL 26.7% (4/15); aggressive B-NHL 27.3% (3/11)). Within responders, 4 had partial response (PR) (3 aggressive B-NHL, 1 indolent B-NHL) and 3 had stable disease (SD) (all indolent B-NHL), with a duration of response between 2 months to >1 year. Amongst the responders with agg