(UroToday.com) Dr. Jeffrey Ravetch, MD, a Professor of Immunology, Virology, and Microbiology at Rockefeller University in New York, NY was awarded the 2020 BCAN Bladder Cancer Research Innovation Award. His work was presented by Dr. David Knorr, MD, PhD, a medical oncologist a Memorial Sloan Kettering Cancer Center.
Cluster differentiation 40 (CD40) is a stimulatory protein found on antigen-presenting cells which have been implicated in targeted cancer immunotherapies. CD40 stimulation drives anti-tumor immunity and is highly expressed on B cells. While extensively studied with small molecular inhibitors in the preclinical setting, little anti-tumor activity of these compounds has been exhibited to date.
Prior work by Dr. Ravetch identified that CD40 receptor FcyRIIB engagement is required for optimal anti-CD40 agonistic activity. Furthermore, mutations in FcyRIIB have been found to further enhance anti-CD40 activity.
The 2141-V11 clone is particularly selective and potent, and intratumoral injection in a mouse colon cancer model has been found to be safe and promotes CD8-dependent T cell immunity. The investigators characterized the therapeutic efficacy of 2141-V11 in the MB49 orthotopic mouse model of bladder cancer to evaluate CD40 agonism as a novel therapeutic strategy for NMIBC. Compared to BCG and control, intravesical V11 exhibited greater tumor reduction and improved survival in this model. In the same study, the investigators used heavily pre-treated BCG populations to simulate BCG unresponsive NMIBC, and intravesical V11 after BCG exposure maintained superior treatment efficacy compared to additional BCG treatment.
Through a partnership with clinicians at Memorial Sloan Kettering, a Phase I/II study of intravesical 2141-V11 in patients with BCG unresponsive NMIBC was initiated. The trial is currently enrolling.
Furthermore, CD40 agonism is currently being studied in combination with IL-15 to induce augmented anti-tumor immunogenicity. While there are several drugs currently being evaluated in single-arm FDA registration trials for BCG unresponsive NMIBC, there has been a paucity of approved drugs in this space. We eagerly await the early phase trial results of this seemingly well-tolerated immunotherapeutic strategy with a strong mechanistic rationale
Presented by: David Knorr, MD, Ph.D., a medical oncologist a Memorial Sloan Kettering Cancer Center
Written by: Patrick Hensley, MD, Urologic Oncologist at the University of Kentucky (@pjhensley11) with Ashish Kamat, MD, Urologic Oncologist at MD Anderson Cancer Center (@UroDocAsh) during the 2022 Bladder Cancer Advocacy Network Think Tank (#BCANTT22) Wednesday, Aug 3 – Friday, Aug 5, 2022References:
1. Li F, Ravetch JV. Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011 Aug 19;333(6045):1030-4. doi: 10.1126/science.1206954. PMID: 21852502; PMCID: PMC3164589.
2. Dahan R, Barnhart BC, Li F, et al. Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement. Cancer Cell. 2016 Jun 13;29(6):820-831. doi: 10.1016/j.ccell.2016.05.001. Epub 2016 Jun 2. PMID: 27265505; PMCID: PMC4975533.
3. Knorr DA, Dahan R, Ravetch JV. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11048-11053. doi: 10.1073/pnas.1810566115. Epub 2018 Oct 8. PMID: 30297432; PMCID: PMC6205479.
4. Garris CS, Wong JL, Ravetch JV, et al. Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer. Sci Transl Med. 2021 May 19;13(594):eabd1346. doi: 10.1126/scitranslmed.abd1346. PMID: 34011627; PMCID: PMC8325152.