Work

Determinants of response to T‐cell stimulation by CD27 antibody therapy in lymphoma: The RiVa trial

Year: 2023

Type: article

Abstract: Introduction: T-cell immunostimulatory antibodies invoke potent anti-tumour responses in murine models but their ability to induce T-cell immunostimulation in the immunosuppressive tumour microenvironment (TME) of patients, or induce clinical responses, is lacking. Agonistic CD27 antibody stimulation of T cells enhanced tumour killing by anti-CD20 in murine models led to the RiVa trial (NCT3307746): a phase IIa study of rituximab (ritux) and varlilumab (varli, anti-CD27) in relapsed/refractory B-cell lymphoma. Here, we describe the immunological effects of the combination in pre- and post-treatment biopsies, and their association with clinical responses. Methods: Patients with relapsed/refractory CD20+ B-cell lymphoma were randomised to arms A (ritux on Cycle 1 Day 1 (C1D1)/varli (C1D2)) or B (ritux (C1D1)/ varli (C1D8)). C2-6 are identical in both arms (D1 ritux (C2-6); D2 varli (C3 and C5); Q2W. The primary endpoints were overall response and safety. Intratumoral biopsies were taken pre-treatment and on C1D7/8 post treatment, i.e., post-ritux/varli in arm A, and post-ritux alone in arm B, and processed by bulk and single cell RNA sequencing (scRNAseq) for analysis by CIBERSORTx and gene set enrichment analysis (GSEA). Results: Safety and efficacy data were previously reported (Lim et al ASH 2022). 27 patients were randomised (16 indolent B-cell non-Hodgkin lymphoma cases (NHL) and 11 aggressive B-NHL; median age 71 (range 49–87); median lines of previous treatment were 4 (range 1–13). The overall response rate was 37.5% (90% CI, 17.8–60.9) for indolent B-NHL and 20% (90% CI, 3.7–50.7) for aggressive B-NHL (4 partial responders (PR) (2 aggressive B-NHL, 2 indolent B-NHL; duration 54 days to >1 year) and 4 with stable disease (SD) (all indolent B-NHL; duration >11 days to >1 year)). Comparing pre- vs. post-treatment biopsies by bulk RNAseq, pathways enriched in TCR and costimulatory signalling (normalised enrichment score (NES) 1.97–2.51, q-value = 0.001) were observed in ritux/varli-treated cases, which were absent in ritux only cases. CIBERSORTx analysis showed >100-fold increased CD4 T cell infiltration in responders vs. non-responders (p = 0.027). Pre-treatment samples of responders were enriched in T-cell signalling and Th1 signatures (NES 2.52, q = 0.02). scRNAseq analysis of pre-treatment biopsies (3 PR vs. 3 progressive disease (PD)) showed 2.08–4.24-fold higher CD4 T-cell frequencies and 0.61-fold less CD27-expressing B-cells (p < 0.0001) in PR vs. PD cases (see Figure). Conclusions: T-cell immunostimulatory antibodies can overcome the immunosuppressive TME to produce clinical responses when combined with rituximab. In the case of anti-CD27, clinical responses were associated with higher CD4+ T cell numbers and T-cell signalling activity in the pre-treatment tumours. Further studies to exploit therapeutic T-cell agonistic antibodies in lymphoma are warranted. The research was funded by: Cancer Research UK (CRUKD/17/008), a Cancer Research UK Advanced Clinician Scientist Fellowship to SHL (A27179) and Celldex Therapeutics. Keywords: Combination Therapies, Immunotherapy Conflicts of interests pertinent to the abstract. P. McKay Honoraria: Roche W. Osborne Consultant or advisory role: Roche Honoraria: Roche Educational grants: Roche K. Linton Consultant or advisory role: Roche, Genmab Honoraria: Aptitude Health, Hartley Taylor, Roche Research funding: Genmab, Roche, Celgene, Beigene P. Medd Honoraria: Astellas, Jazz Educational grants: Jazz G. P Collins Honoraria: Roche T. Keler Employment or leadership position: Celldex Therapeutics Stock ownership: Celldex Therapeutics M. Yellin Employment or leadership position: Celldex Therapeutics Stock ownership: Celldex Therapeutics A. Gentles Consultant or advisory role: Cibermed G. Griffiths Honoraria: Celldex Therapeutics S. H. Lim Consultant or advisory role: F-star Therapeutics Honoraria: Astra Zeneca Research funding: Celldex Therapeutics; Bioinvent International

Source: Hematological Oncology

DOI: 10.1002/hon.3164_194