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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).

Titel:	A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.
Autor/in / Beteiligte Person:	Merryman, RW ; Redd, RA ; Freedman, AS ; Ahn, IE ; Brown, JR ; Crombie, JL ; Davids, MS ; Fisher, DC ; Jacobsen, ED ; Kim, AI ; LaCasce, AS ; Ng, S ; Odejide, OO ; Parry, EM ; Isufi, I ; Kline, J ; Cohen, JB ; Mehta-Shah, N ; Bartlett, NL ; Mei, M ; Kuntz, TM ; Wolff, J ; Rodig, SJ ; Armand, P ; Jacobson, CA
Link:	Full Text Finder (Volltext)
Zeitschrift:	Annals of hematology, Jg. 103 (2024), Heft 1, S. 185-198
Veröffentlichung:	Berlin : Springer Verlag ; <i>Original Publication</i>: Berlin ; New York : Springer International, c1991-, 2024
Medientyp:	academicJournal
ISSN:	1432-0584 (electronic)
DOI:	10.1007/s00277-023-05475-0
Schlagwort:	Humans Rituximab Programmed Cell Death 1 Receptor Antineoplastic Combined Chemotherapy Protocols therapeutic use Neoplasm Recurrence, Local drug therapy Antibodies, Monoclonal adverse effects Immunotherapy Tumor Microenvironment Lymphoma, Follicular drug therapy Antineoplastic Agents therapeutic use
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Clinical Trial, Phase I; Journal Article Language: English [Ann Hematol] 2024 Jan; Vol. 103 (1), pp. 185-198. <i>Date of Electronic Publication: </i>2023 Oct 18. MeSH Terms: Lymphoma, Follicular* / drug therapy ; Antineoplastic Agents* / therapeutic use ; Humans ; Rituximab ; Programmed Cell Death 1 Receptor ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Neoplasm Recurrence, Local / drug therapy ; Antibodies, Monoclonal / adverse effects ; Immunotherapy ; Tumor Microenvironment References: Sureda A, Zhang MJ, Dreger P et al (2018) Allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma: a combined analysis on behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR. 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A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.