Abstract
Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 821-833 |
| Number of pages | 13 |
| Journal | Leukemia and Lymphoma |
| Volume | 63 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2022 |
Keywords
- TLR4
- follicular lymphoma
- glucopyranosyl lipid A
- immunotherapy
- pembrolizumab
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Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma. / Halwani, Ahmad S.; Panizo, Carlos; Isufi, Iris; Herrera, Alex F.; Okada, Craig Y.; Cull, Elizabeth H.; Kis, Bela; Chaves, Jorge M.; Bartlett, Nancy L.; Ai, Weiyun; de la Cruz-Merino, Luis; Bryan, Locke J.; Houot, Roch; Linton, Kim; Briones, Javier; Chau, Ian; von Keudell, Gottfried R.; Lu, Hailing; Yakovich, Adam; Chen, Michael; Meulen JH, ter; Yurasov, Sergey; Hsu, Frank J.; Flowers, Christopher R.
In: Leukemia and Lymphoma, Vol. 63, No. 4, 2022, p. 821-833.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma
AU - Halwani, Ahmad S.
AU - Panizo, Carlos
AU - Isufi, Iris
AU - Herrera, Alex F.
AU - Okada, Craig Y.
AU - Cull, Elizabeth H.
AU - Kis, Bela
AU - Chaves, Jorge M.
AU - Bartlett, Nancy L.
AU - Ai, Weiyun
AU - de la Cruz-Merino, Luis
AU - Bryan, Locke J.
AU - Houot, Roch
AU - Linton, Kim
AU - Briones, Javier
AU - Chau, Ian
AU - von Keudell, Gottfried R.
AU - Lu, Hailing
AU - Yakovich, Adam
AU - Chen, Michael
AU - Meulen JH, ter
AU - Yurasov, Sergey
AU - Hsu, Frank J.
AU - Flowers, Christopher R.
N1 - Funding Information: This study was supported by research funding from Immune Design Corp., a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Colleen Brown (Mark Consulting, Inc.), a medical writer supported by funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, provided drafts, editorial, and formatting assistance to the authors during the preparation of this manuscript. Funding Information: A.S.H.: Research and travel support from Immune Design (paid to institution) and research support from Genentech (paid to institution). C.P.: Support from Immune Design for the clinical trial reported in this manuscript; consulting fees from Bristol-Myers Squibb and Kyowa Kirin; payments or honoraria from Roche Pharma and Janssen; payment for expert testimony from Celgene; and support for attending meetings and/or travel from Roche Pharma. I.I.: No disclosures related to this study. A.F.H.: Grants/research support from Bristol-Myers Squibb, Merck & Co., Inc., Genentech, Inc./F. Hoffman-La Roche Ltd., Gilead Sciences, Inc., Seattle Genetics, AstraZeneca, and ADC Therapeutics; consultant for Bristol-Myers Squibb, Merck & Co., Inc., Genentech, Inc./F. Hoffman-La Roche, Ltd., Seattle Genetics, Karyopharm Therapeutics, AstraZeneca, Tubulis, Takeda Pharmaceutical Company, and ADC Therapeutics; and support for attending meetings and/or travel from Bristol-Myers Squibb. C.O.: No disclosures related to this study. E.H.C.: Speaker for Bristol-Myers Squibb. B.K.: No disclosures related to this study. J.M.C.: No disclosures related to this study. N.L.B.: Support from Immune Design for the clinical trial reported in this manuscript; advisory board participation for ADC Therapeutics, Roche/Genentech, Seattle Genetics, BTG, and Acerta; and research funding from ADC Therapeutics, Affimed, Autolus, Bristol-Myers Squibb, Celgene Corporation, Forty Seven, Gilead, Immune Design, Janssen, Kite Pharma, Merck & Co., Inc., Millennium Pharmaceuticals, Inc., Pfizer Inc., Pharmacyclics LLC, Roche/Genentech, and Seattle Genetics. W.A.: No disclosures related to this study. L.C-M.: No disclosures related to this study. L.J.B.: No disclosures related to this study. R.H.: No disclosures related to this study. K.L.: Research funding from Genmab, Roche, Celgene Corporation, and Beigene; grants or contracts from Blood Cancer UK and Roy Castle Lung Cancer Foundation; consulting fees from Genmab and Roche; honoraria from Aptitude Health, Hartley Taylor, and Roche; support for attending meetings and/or travel from Janssen and Celgene Corporation; and participation on a Data Safety Monitoring Board or advisory board at Kite, Karyopharm, and Celgene Corporation. J.B.: No disclosures related to this study. I.C.: Advisory board for Eli Lilly and Company, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, and Eisai; research funding from Eli Lilly and Company and Janssen-Cilag Pty Ltd.; honoraria from Eli Lilly and Company and Eisai. G.R.v.K.: Consulting fees from Merck & Co., Inc., Incyte, and Pharmacylics LLC. H.L. Full-time employee of Immune Design with stock options during conduct of the study. A.Y. Full-time employee of Immune Design with stock options during conduct of the study; consulting fees from Merck & Co., Inc. (former employer) paid to assist with manuscript preparation following the end of full-time employment. M.C. Former employee of Immune Design with stock ownership and stock options. J.t.M. Full-time employee of Immune Design with stock options during conduct of the study; patent US20140328904: GLA Monotherapy for Use in Cancer Treatment; stockholder of Merck & Co. F.J.H.: Full-time employee of Immune Design during conduct of the study; stock or stock options and support for attending meetings and/or travel as employee of Immune Design and Oncternal Therapeutics. S.Y.: Former employee of Immune Design with stock options. C.R.F.: Research funding from 4 D, AbbVie Inc., Acerta Pharma, LLC, Adaptimmune, Allogene Therapeutics, Amgen Inc., Bayer, Celgene Corporation, Cellectis, EMD, Gilead Sciences, Inc., Genentech/Roche Pharma, Guardant, Iovance Biotherapeutics, Janssen Pharmaceuticals, Inc., Kite Pharma, MorphoSys AG, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda Pharmaceutical Company, TG Therapeutics, Inc., Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation for Cancer Research, and Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research; consultant for AbbVie Inc., Bayer, BeiGene, Celgene Corporation, Denovo Biopharma LLC, Genentech/Roche Pharma, Genmab, Gilead Sciences, Inc., Karyopharm Therapeutics, Pharmacyclics/Janssen Pharmaceuticals, Inc., Seagen, and Spectrum Pharmaceuticals, Inc. Funding Information: Colleen Brown (Mark Consulting, Inc.), a medical writer supported by funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, provided drafts, editorial, and formatting assistance to the authors during the preparation of this manuscript. Publisher Copyright: © 2021 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
AB - Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
KW - TLR4
KW - follicular lymphoma
KW - glucopyranosyl lipid A
KW - immunotherapy
KW - pembrolizumab
UR - http://www.scopus.com/inward/record.url?scp=85121105171&partnerID=8YFLogxK
U2 - 10.1080/10428194.2021.2010057
DO - 10.1080/10428194.2021.2010057
M3 - Article
C2 - 34865586
AN - SCOPUS:85121105171
VL - 63
SP - 821
EP - 833
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
SN - 1042-8194
IS - 4
ER -