Rockefeller's Redesigned CD40 Antibody Eliminates Metastatic Cancers in Phase 1 Trial, Sparking Nearly 200-Patient Expansion
An Fc-engineered CD40 agonist injected into a single tumor triggered systemic immune responses that eliminated cancer across the body in two patients, with expanded trials now under way at Memorial Sloan Kettering and Duke.
Overview
A redesigned cancer immunotherapy drug has produced striking results in a small clinical trial, with two patients achieving complete remission after researchers injected a single tumor and watched cancer disappear across the body. The drug, an Fc-engineered CD40 agonist antibody called 2141-V11, was developed at Rockefeller University under the direction of immunologist Jeffrey V. Ravetch and has now entered expanded testing in nearly 200 patients across multiple cancer types.
What Happened
The Phase 1 trial, published in Cancer Cell, enrolled 12 patients with metastatic cancers including melanoma, renal cell carcinoma, and several forms of breast cancer. Researchers administered 2141-V11 by direct injection into accessible tumors at four escalating dose levels ranging from 0.7 mg to 10 mg.
Among 10 evaluable patients, six experienced tumor shrinkage and two achieved complete responses — meaning all detectable cancer disappeared. One complete responder was an 89-year-old woman with recurrent in-transit melanoma who had dozens of metastatic tumors on her leg and foot. Researchers injected just one tumor on her thigh; after multiple treatment cycles, all the other tumors disappeared. The second complete responder was a 67-year-old woman with stage IV breast cancer whose liver and lymph node metastases resolved and tumor markers normalized.
Critically, the drug was well tolerated. No patients experienced dose-limiting toxicities, and the maximum tolerated dose was not reached. Side effects were limited to mild-to-moderate fever (42 percent of patients), injection-site reactions (25 percent), and chills (25 percent). This stands in sharp contrast to earlier CD40 drugs administered intravenously, which caused widespread inflammation, dangerously low platelet levels, and liver damage.
How It Works
CD40 is a receptor on immune cells that, when activated, signals the immune system to mount a stronger response against threats. Previous attempts to exploit this pathway with intravenous CD40 antibodies achieved only modest anti-tumor effects while producing severe systemic toxicity.
Ravetch’s team took a different approach on two fronts. First, they engineered the antibody’s Fc region to enhance binding to the inhibitory receptor FcgammaRIIB, which optimizes CD40 trimerization and downstream signaling. Laboratory studies showed the redesigned antibody was roughly 10 times more effective at triggering anti-tumor immune responses than prior versions. Second, they delivered the drug directly into the tumor rather than into the bloodstream, confining the potent immune activation to the tumor microenvironment and avoiding systemic toxicity.
The mechanism behind the systemic responses observed in the trial centers on tertiary lymphoid structures. According to the study, 2141-V11 transformed injected tumors into immune-rich environments resembling lymph nodes, attracting dendritic cells, T cells, and B cells. Complete responders showed mature tertiary lymphoid structures in post-treatment biopsies along with systemic CD8-positive T cell activation. In preclinical humanized mouse models, the antibody promoted de novo tertiary lymphoid structure formation that facilitated intratumoral T cell responses independent of lymph node priming, generating abscopal effects — meaning tumors distant from the injection site shrank or vanished.
“This effect — where you inject locally but see a systemic response — that’s not something seen very often in any clinical treatment,” said Juan C. Osorio, the study’s first author, as reported by ScienceDaily.
What Comes Next
The findings have prompted a wave of follow-up trials. The Ravetch laboratory is now collaborating with researchers at Memorial Sloan Kettering Cancer Center and Duke University on Phase 1 and Phase 2 studies testing 2141-V11 against bladder cancer, prostate cancer, and glioblastoma. Collectively, nearly 200 patients are enrolled across these studies. The recommended Phase 2 dose has been set at 10 mg administered intratumorally every three weeks.
What We Don’t Know
The Phase 1 trial was small — 12 patients — and lacked a control arm, which is standard for dose-escalation studies but limits the strength of efficacy conclusions. It remains unclear why some patients responded completely while others did not, and whether the approach will prove effective in cancers that are not accessible for direct injection. The expanded trials will need to determine whether 2141-V11 works as a monotherapy across tumor types or whether it will require combination with checkpoint inhibitors or other agents to achieve durable responses in a broader patient population.