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

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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).

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Acknowledgements

PA and RWM would like to acknowledge support from the Harold and Virginia Lash Grant Program. PA is supported by a Scholar Award from the Leukemia and Lymphoma Society. RWM would like to acknowledge support from an American Society of Hematology Research Training Award for Fellows, a Lymphoma Research Foundation (LRF) Clinical Investigator Career Development Award, and the LRF Lymphoma Clinical Research Mentoring Program. Multiplex immunofluorescence was performed in the Tissue Biomarker Laboratory of the Center for Immuno-Oncology at DFCI. Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) reviewed this manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.

Funding

Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) provided funding for this investigator-sponsored clinical trial. The authors declare no other sources of funding.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA

    Reid W. Merryman, Arnold S. Freedman, Inhye E. Ahn, Jennifer R. Brown, Jennifer L. Crombie, Matthew S. Davids, David C. Fisher, Eric D. Jacobsen, Austin I. Kim, Ann S. LaCasce, Samuel Ng, Oreofe O. Odejide, Erin M. Parry, Philippe Armand & Caron A. Jacobson

  2. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA

    Robert A. Redd

  3. Hematology, Yale University School of Medicine, New Haven, CT, USA

    Iris Isufi

  4. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    Justin Kline

  5. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Jonathon B. Cohen

  6. Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA

    Neha Mehta-Shah & Nancy L. Bartlett

  7. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA

    Matthew Mei

  8. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Thomas M. Kuntz

  9. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Jacquelyn Wolff

  10. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Scott J. Rodig

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  1. Reid W. Merryman
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Contributions

RWM and CAJ designed the research, performed research, analyzed the data, and wrote the paper; ASF, IEA, JRB, JC, MSD, DCF, EDJ, AIK, ASL, SN, OOO, EMP, II, JK, JBC, NM-S, NLB, and MM performed research and reviewed the paper. RAR, TK, SJR, and PA designed the research, performed research, analyzed the data, and reviewed the paper.

Corresponding author

Correspondence to Reid W. Merryman.

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Conflict of interest

RWM — Consulting: Genmab, Adaptive Biotechnologies, Bristol Myers Squibb, Abbvie, Intellia, Epizyme. Research funding: Bristol Myers Squibb, Merck, Genentech/Roche, Genmab.

RAR — none.

ASF — none.

IEA — Consulting: BeiGene.

JRB — consultant for Abbvie, Acerta/Astra-Zeneca, BeiGene, Eli Lilly, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics; received research funding from BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, TG Therapeutics.

JLC — Consultancy: Karyopharm, Kite, Morphosys, Incyte, ADC Therapeutics, Research Funding: Genentech/Roche, Merck, Abbvie, Bayer.

MSD — consulting fees from AbbVie, Adaptive Biosciences, Aptitude Health, Ascentage Pharma, AstraZeneca, BeiGene, Bio Ascend, BMS, Celgene, Curio Science, Eli Lilly, Genentech, Janssen, Merck, Ono Pharmaceuticals, Research to Practice, Secura Bio, TG Therapeutics, Takeda, and research support from AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics.

DCF — none.

EDJ — Consulting: Syros, Takeda. Research funding: Acerta, Janssen, Novartis, Pharmacyclics.

AIK — none.

ASL — Consulting: Research to Practice. Advisory ad boards: Kite and Seagen.

SN — none.

OOO — none.

EMP — none.

II — consultant for Celgene/Jazz, Kite, Epizyme, Beam Therapeutics, and ADC Therapeutics.

JK — Consulting: Merck, ADC Therapeutics, Gilead, Daiichi Sankyo, BeiGene, SecuraBio. Research support: Merck, SecuraBio. Speakers’ Bureau: Kite/Gilead.

JBC — Advisory Board: Abbvie, Janssen, Astra Zeneca, BeiGene, Kite, ADCT, Hutchmed, Loxo/Lilly. Research Funding: Genentech, Takeda, Lilly/Loxo, Celgene/BMS, Astra Zeneca, HutchMed.

NM-S — institutional clinical trial funding from AstraZeneca, Bristol Myers-Squibb, Celgene, C4 Therapeutics, Corvus Pharmaceuticals, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Secura Bio/Verastem, Yingli Pharmaceuticals and Dizal Pharmaceuticals. She has received compensation for service as a consultant for AstraZeneca, Secura Bio/Verastem, Daiichi Sankyo, C4 Therapeutics, Genentech, Karyopharm Therapeutics, Kyowa Hakko Kirin, and Ono pharmaceuticals.

NLB — Consultancy/Advisory Boards: SeaGen, Roche/Genentech, Kite/Gilead, Foresight Diagnostics. Research funding (Institution): ADC Therapeutics, BMS/Celgene, Kite/Gilead, Merck, Millennium, Pharmacyclics, Roche/Genentech, SeaGen.

MM — Advisory board: Novartis, Seattle Genetics, CTI, Janssen, EUSA; Speaker’s bureau: Seattle Genetics, Monjuvi.

TMK — none.

JOW — none.

SJR — Research fundings: Bristol Myers Squibb and KITE/Gilead. Member of the SAB for Immunitas Therapeutics.

PA — Consultancy: Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor. Research funding: Kite. Research funding (institutional): Merck, BMS, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM. Honoraria: Merck, BMS.

CAJ — Consulting: Kite/Gilead, Novartis, BMS/Celgene, bluebird bio, Epizyme, Ipsen, Instil Bio, ImmPACT Bio, Caribou Bio, Morphosys, Miltenyi, Abintus Bio. Research funding: Kite/Gilead and Pfizer.

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Merryman, R.W., Redd, R.A., Freedman, A.S. et al. A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma. Ann Hematol 103, 185–198 (2024). https://doi.org/10.1007/s00277-023-05475-0

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