A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature..
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).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:103 |
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| Enthalten in: |
Annals of hematology - 103(2024), 1 vom: 01. Jan., Seite 185-198 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Merryman, Reid W [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.01.2024 Date Revised 03.01.2024 published: Print-Electronic ClinicalTrials.gov: NCT03636503 Citation Status MEDLINE |
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| doi: |
10.1007/s00277-023-05475-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363435948 |
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| 100 | 1 | |a Merryman, Reid W |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma |
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| 500 | |a Date Revised 03.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03636503 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a 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) | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Follicular lymphoma | |
| 650 | 4 | |a Immune checkpoint | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Rituximab | |
| 650 | 4 | |a Stool microbiome | |
| 650 | 4 | |a Tumor microenvironment | |
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| 650 | 7 | |a 4F4X42SYQ6 |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
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| 700 | 1 | |a Freedman, Arnold S |e verfasserin |4 aut | |
| 700 | 1 | |a Ahn, Inhye E |e verfasserin |4 aut | |
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| 700 | 1 | |a Crombie, Jennifer L |e verfasserin |4 aut | |
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| 700 | 1 | |a Fisher, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobsen, Eric D |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Austin I |e verfasserin |4 aut | |
| 700 | 1 | |a LaCasce, Ann S |e verfasserin |4 aut | |
| 700 | 1 | |a Ng, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Odejide, Oreofe O |e verfasserin |4 aut | |
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| 700 | 1 | |a Mehta-Shah, Neha |e verfasserin |4 aut | |
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| 700 | 1 | |a Jacobson, Caron A |e verfasserin |4 aut | |
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