An experimental drug has managed to shrink metastatic tumors in six patients and make them disappear in two of them.

A new version of the CD40 agonist immunostimulatory antibody, called 2141-V11 and developed by scientists at Rockefeller University (United States), has managed to reduce metastatic tumors in six of 12 patients participating in a phase 1 trial. In two of them, the tumor disappeared completely .

The study, published in Cancer Cell , sought to demonstrate the efficacy in cancer patients of an improved format of CD40 agonist antibodies , which originally showed great potential in animal models, but in humans have had limited impact, with significant adverse effects.

In an initial experiment in 2018 using genetically modified mice, the laboratory of Jeffrey V. Ravetch at Rockefeller University revealed that the new format of the drug they had designed was more effective, with 10 times greater potency in generating an anti-tumor immune response.

They then changed the method of administering the drug, which was traditionally administered intravenously. Because CD40 receptors are widely distributed, too many non-cancerous cells took it up, causing toxic side effects. Instead, they injected the drug directly into tumors, intratumorally. "When we did that, we only saw mild toxicity," Jeffrey V. Ravetch noted.

Encouraging results

Now, the small human trial has revealed promising results for future clinical use. The study included 12 patients with various types of metastatic cancer, specifically melanoma, renal cell carcinoma, and different types of breast cancer. The two patients who experienced complete remission had melanoma and breast cancer, respectively, both notoriously aggressive and recurrent.

"The melanoma patient had dozens of metastatic tumors in her leg and foot, and we only injected the drug into one tumor in her thigh," Ravetch explained. "After multiple injections into that tumor, all the others disappeared. The same thing happened with the patient with metastatic breast cancer, who also had tumors in her skin, liver, and lung. And even though we only injected the tumor into her skin, we saw all the tumors disappear ," she explained.

The 2141-V11 innovation has the capacity to bind in an optimized manner to the inhibitory receptor of the Fc fragment of the antibody, called FcyRIIB, and its direct intratumoral administration allows for a reduction in the systemic toxicity observed with previous formats, in addition to enhancing the local activation of dendritic cells and T lymphocytes, as explained by the head of the Clinical Research Unit in Cancer Immunotherapy at CNIO-HMarBCN, Luis Álvarez Vallina, in statements to SMC Spain.

"The strategy could be applied to different tumor types , especially those accessible for local injection (skin, lymph nodes, bladder, breast)," Álvarez emphasized. However, he emphasized that longer-term follow-up of the drug is necessary to confirm the durability of responses and define biomarkers that allow for better patient selection.

Stimulated immune activity

Tissue samples from the tumors revealed drug-stimulated immune activity , including different types of dendritic cells, mature T cells and B cells, which formed lymph node-like aggregates, said first author Juan Osorio, PhD, a visiting assistant professor in the Ravetch lab and a medical oncologist at Memorial Sloan Kettering Cancer Center.

"The drug creates an immune microenvironment within the tumor and essentially replaces it with these tertiary lymphoid structures," Osorio emphasized, specifying that this is linked to a better prognosis and response to immunotherapy . Furthermore, these tertiary lymphoid structures migrate to non-injected tumor areas when the immune system identifies cancer cells.

Based on these findings, several additional clinical trials have been initiated, in which Ravetch's lab is collaborating with researchers at Memorial Sloan Kettering and Duke University. These Phase 1 and 2 trials are examining the effect of 2141-V11 on specific cancers, such as bladder cancer, prostate cancer, and glioblastoma, with nearly 200 participants.

With this, they seek to clarify what causes the drug to work in some patients and not in others , in order to see how to change this. For example, the two patients in the clinical trial whose cancer disappeared had high T cell clonality at the start of the study, which may be one of the requirements for the drug to be effective.