BMS-986301 / BMS - LARVOL DELTA

Inhibiting B-cell-mediated Immunosuppression to Enhance the Immunotherapy Efficacy in Hepatocellular Carcinoma. (PubMed, Res Sq) - "Established tumors were treated with a STING agonist (BMS-986301) or anti-PD1 ICB, and mice were followed to evaluate safety and efficacy, as well as the mechanisms of treatment resistance by RNA sequencing, flow cytometry, and immunofluorescence, B-cell depletion and T-cell immunoglobulin and mucin domain 1 (TIM-1) ICB...This approach decreased the number of TIM-1+ B cells in the tumor and shifted B cells to higher expression of CD86 and MHC class II, enhancing the antigen presentation capability and further boosting the antitumor efficacy of CD8+ cytotoxic T cells. Conclusion : Our findings demonstrate that B cells are associated with ICB- and STING-mediated therapy resistance, and that depleting B-cells or targeting TIM-1 enhances both innate and acquired therapeutic efficacy in HCC."

IO biomarker • Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • CD8 • CD86 • IL10 • KIM1 • MAGEE1 • STING

Inhibiting B-cell-mediated Immunosuppression to Enhance the Immunotherapy Efficacy in Hepatocellular Carcinoma. (PubMed, bioRxiv) - "Our findings demonstrate that B cells are associated with ICB- and STING-mediated therapy resistance, and that depleting B-cells or targeting TIM-1 enhances both innate and acquired therapeutic efficacy in HCC."

IO biomarker • Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • CD8 • CD86 • IL10 • KIM1 • MAGEE1 • STING

Inhibiting B-cell-mediated immunosuppression to enhance the efficacy of STING agonism in hepatocellular carcinoma (SITC 2024) - "Here, we studied the efficacy of a novel STING agonist (BMS-986301) and revealed how to circumvent its treatment resistance in murine HCC models...Conclusions Our findings demonstrate that targeting B-cell-mediated immunosuppression in HCC can reverse resistance to STING-agonist treatment in murine HCC and that the immune checkpoint TIM-1 is a new target for HCC treatment. Ethics Approval All animal experiments were performed under the Institutional Animal Care and Use Committee (IACUC) at Massachusetts General Hospital–approved protocol (2020N000023)."

Clinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • CD86 • IL10 • KIM1 • MAGEE1 • STING

Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration. (PubMed, J Hematol Oncol) - "Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist...The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Transplantation

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1 | N=54 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=190 ➔ 54

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion • Breast Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration (AACR 2024) - "Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment.Design: Using a transplant murine model with spontaneously formed liver metastasis and also the genetically engineered KPC mouse model that spontaneously develops PDAC, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. For the first time, our study supports the clinical development of innate agonists via systemic administration, instead of local administration, for treating PDAC."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • NLRP3

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1 | N=190 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Nov 2025 ➔ Apr 2024 | Trial primary completion date: Aug 2025 ➔ Apr 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1 | N=190 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Monotherapy • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Jul 2024 ➔ Nov 2025 | Trial primary completion date: Nov 2022 ➔ Aug 2025

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist. (PubMed, J Org Chem) - "These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications."

Journal

Sub/supercritical Fluid Chromatography Purification and Desalting of a Cyclic Dinucleotide STING Agonist. (PubMed, J Chromatogr A) - "More than 40 g of crude API was purified and desalted producing >20 g of pure BMT-390025 as the ammonium salt which was obtained with a chemical purity of >98.5% and met the endotoxin requirement of 80 g of its penultimate prior to the deprotection of the silyl group was purified at a high throughput of 6.3 g/h (0.42 g/day/g SP)."

Journal

Large-scale supercritical fluid chromatography purification of unstable STING agonist intermediates. (PubMed, J Chromatogr A) - "In total, 1028 grams of Intermediate 2 were processed at a high throughput of 12.5 g/h on a Viridis BEH 2-EP column. The regioisomeric purity of the desired isomer was ≥96.8% and the recovery was ≥90.7%."

Journal

A Stereocontrolled Synthesis of a Phosphorothioate Cyclic Dinucleotide-Based STING Agonist. (PubMed, J Org Chem) - "This P(V) approach allows for the complete control of chirality of the P-based linkages and enabled conclusive evidence of the absolute configuration. The new approach offers robust procedures for preparing the stereodefined CDN in eight steps starting from advanced nucelosides, with late-stage direct drop isolations and telescoped steps enabling an efficient scale-up that proceeded in an overall 15% yield to produce multigram amounts of the CDN."

Journal

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1; N=190; Recruiting; Sponsor: Bristol-Myers Squibb; N=75 ➔ 190; Trial completion date: Feb 2023 ➔ Jul 2024

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1; N=75; Recruiting; Sponsor: Bristol-Myers Squibb; Trial primary completion date: Aug 2022 ➔ Nov 2022

Combination therapy • IO Biomarker • Monotherapy • Trial primary completion date

An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers (clinicaltrials.gov) - P1; N=75; Recruiting; Sponsor: Bristol-Myers Squibb

Combination therapy • IO Biomarker • Monotherapy • New P1 trial

"My favorite MedChem Reviews are out! Check out the 2019 Medicinal Chemistry Reviews (Vol. 54), edited by Joanne Bronson from Bristol-Myers Squibb @bmsnews . Happy that we contributed a chapter on STING AGONISTS FOR IMMUNO-ONCOLOGY." (@CKuttruff)