An experimental drug reduces metastatic tumors

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

The study, published in Cancer Cellhe has sought Demonstrate efficacy in cancer patients of a Improved format of CD40 agonist antibodies, which originally revealed great potential in animal models, but that in humans have had a limited impact, with important adverse effects.

In a first experiment in 2018 with genetically modified mice, the laboratory of Jeffrey V. Ravetchfrom the Rockefeller University, it revealed that the new drug format they had designed had greater efficiency, with a 10 times higher power to generate an antitumor immune response.

Then, They changed the way to administer the drugwhich was traditionally performed intravenously and, because CD40 receptors are widely distributed, too many non -cancerous cells captured it, causing toxic side effects. Instead, They injected the drug directly into the tumorsintratumoral. “When we did that, we only saw a mild toxicity,” said Jeffrey V. Ravetch.

Promising results

Now, the small essay in human patients has revealed hopeful results for their future clinical use. The study included 12 patients with various types of metastatic cancerspecifically, melanoma, renal cell carcinoma and different types of breast cancer.

The two patients who experienced a Complete remission They had melanoma and breast cancer, respectively, both notoriously aggressive and recurring.

“The patient with melanoma had dozens of metastatic tumors in the leg and foot, and we only inject the drug into a tumor into the thigh,” Ravetch explained. “After multiple injections in that tumor, everyone else disappeared. The same happened with the patient with metastatic breast cancer, who also had tumors in the skin, liver and lung. And although we only injected the tumor into the skin, we saw how all tumors disappeared, “he detailed.

Innovation 2141-V11 has the capacity to optimize the FC fragment inhibitor of the antibody, called FCyriib, and its direct administration intratumorly allows to reduce 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 Clinical Research Unit in Immunotherapy of Cancer Cnio-hmarbcn, Luis Álvarez Vallinain statements to SMC Spain.

“The strategy could be applied to different tumor types, especially those accessible to local injection (skin, lymph nodes, bladder, breast),” He has highlighted Álvarez. However, it has pointed out that it is necessary to monitor the drug to confirm the durability of the responses and define biomarkers that allow patients to better select.

Tumor tissue samples revealed a immune activity stimulated by the drugincluding different types of dendritic cells, T lymphocytes and mature B lymphocytes, which formed similar aggregates to a lymphatic ganglion, as the first author said Juan OsorioVisitor Assistant Professor at the Ravetch Laboratory and Medical Oncologist at the Sloan Kettering Memorial Cancer Center (USA).

“The drug creates an immune microenvironment within the tumor and, in essence, replaces it with these tertiary lymphoid structures”he has stressed Osoriospecifying that this is linked to a better prognosis and response to immunotherapy. In addition, these tertiary lymphoid structures migrate to unpleasant tumor areas when the immune system identifies cancer cells.

From these findings, Several additional clinical trials have been promoted in which the Ravetch laboratory collaborates with researchers at the Memorial Sloan Kettering and the University of Duke. These investigations, in phase 1 or 2, analyze the effect of 2141-V11 on specific cancers, such as bladder cancer, prostate cancer and glioblastoma, with about 200 participants.

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