2. Academic Validation
  3. A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma

  • Ann Hematol. 2024 Jan;103(1):185-198. doi: 10.1007/s00277-023-05475-0.
Reid W Merryman 1,  Robert A Redd 2,  Arnold S Freedman 3,  Inhye E Ahn 3,  Jennifer R Brown 3,  Jennifer L Crombie 3,  Matthew S Davids 3,  David C Fisher 3,  Eric D Jacobsen 3,  Austin I Kim 3,  Ann S LaCasce 3,  Samuel Ng 3,  Oreofe O Odejide 3,  Erin M Parry 3,  Iris Isufi 4,  Justin Kline 5,  Jonathon B Cohen 6,  Neha Mehta-Shah 7,  Nancy L Bartlett 7,  Matthew Mei 8,  Thomas M Kuntz 9,  Jacquelyn Wolff 10,  Scott J Rodig 11,  Philippe Armand 3,  Caron A Jacobson 3
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA. Reid_merryman@dfci.harvard.edu.
  • 2 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA.
  • 4 Hematology, Yale University School of Medicine, New Haven, CT, USA.
  • 5 Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
  • 6 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 7 Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.
  • 8 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.
  • 9 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 10 Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 11 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
PMID: 37851072 DOI: 10.1007/s00277-023-05475-0
Abstract

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

Keywords

Follicular lymphoma; Immune checkpoint; Immunotherapy; Rituximab; Stool microbiome; Tumor microenvironment.

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