Cancer Treatment Breakthrough: New Drug Eliminates Aggressive Forms

An experimental drug has managed to completely eliminate tumors in certain patients with aggressive forms of cancer, according to the results of a phase I clinical study, published on Thursday. The treatment belongs to the CD40 agonist antibody class, but it has an improved design and method of administration, which increase its efficiency and significantly reduce the adverse effects. The results, obtained in patients with types of cancer difficult to treat, such as melanoma and metastatic breast cancer, have aroused the interest of the scientific community and open the way to wider clinical studies.

Over the past 20 years, a class of anticancer drugs, called CD40 agonist antibodies, have shown great potential, but also caused considerable disappointments. CD40 is part of a family of protein involved in regulating the immune response.

The CD40 agonist antibodies are molecules created in the laboratory that bind to the CD40 receiver on the surface of certain cells of the immune system (such as dendritic cells, B and macrophages) and activate it.

When this receiver is activated, it transmits a signal that causes immune cells to become more effective in identifying and destroying abnormal cells, including cancerous ones.

Basically, the CD40 agonist antibodies “press the starting button” of the immune system to fight stronger tumors. As they strongly stimulate the immune response, these antibodies can have beneficial effects in the treatment of cancer, but in their classic forms, they can also cause severe side effects if they activate too many cells.

Although effective in activating the immune system to kill cancer cells in laboratory animals, in patients, their effect has been limited and caused serious adverse reactions, such as systemic inflammation, decreased number of thrombocytes and hepatic toxicity, even at low doses.

Researchers at Rockefeller University have previously demonstrated that they can conceive an improved CD40 agonist antibody, so as to increase its effectiveness and can be administered in a way that limits serious side effects. The results came from research carried out on genetically modified mice to imitate the relevant biological paths.

The next step was to organize a clinical study to observe the impact of the drug on cancer patients.

In the magazine Thursday number Cancer Cell The results of the clinical phase and experimental study 2141-V11, who showed that, of the 12 patients treated, six have registered the reduction of tumors, and in two cases they disappeared completely.

The effect was not limited only to locally injected tumors with the drug, but was also present in other tumors in the body that were reduced in size or were destroyed by immune cells.

“It is remarkable to observe such significant discounts, including complete remission, even in such a restricted group of patients. Such an effect, in which a local injection generates a systemic response, is rarely encountered in clinical practice,” said Dr. Juan Osorio, the main author of the research, oncologist at Memorial Sloan Kettering Center to Ravetch, quoted in a statement.

The role of genetic engineering

CD40 is a cellular surface receptor that is part of the superfamy of the receptors of the tumor necrosis factor, expressed largely by the immune cells. When activated, it triggers the mobilization of the entire immune system, promoting anti -tumor immunity and developing a tumor specific T cell response.

In 2018Ravetch’s laboratory created the experimental molecule 2141-V11, a CD40 antibody that is closely linked to human CD40 receptors and is modified to increase its activity with a specific FC receptor, becoming 10 times more powerful in stimulating an antitumoral immune response.

Antibodies are “Y” molecules with two main regions: FAB part (antigen-banding fragment), which recognize and bind to target antigen, and FC (crystallizable fragment), which act as a “handle” to recruit the cells of the immune system.

The FC part does not recognize antigen, but interacts with FC receptors on immune cells such as macrophages, NK cells or dendritic cells, transmitting the attack signal.

There are several types of FC receptors, each specific for certain antibody classes, and the modification of an antibody to bind stronger or more selectively to a specific FC receiver can amplify the desired immune response, such as the more efficient destruction of tumor cells.

The researchers also changed the method of administration: instead of intravenous infusion, which affects many healthy cells and caused toxicity, injected the drug directly into the tumor, observing only a mild toxicity.

These findings were the basis of the phase I study, which aimed to establish an initial clinical dose and understanding the mechanisms of action.

Induction of remission

The study included 12 patients with various types of metastatic cancer, melanoma, renal carcinoma and different types of breast cancer, and none had serious side effects observed in other CD40 drugs.

Six patients had a systemic reduction in tumors, and two recorded a complete answer, which means total cancer disappearance.

The two patients with full remission had melanoma and breast cancer, both aggressive and high risk of relapse.

The melanoma of the patient manifests through dozens of metastatic tumors in the foot. Although the injection was made only in a tumor on the thigh, after several administrations all the other tumors disappeared.

The situation was similar in the patient with metastatic breast cancer, with tumors to the skin, liver and lung, but treated only by injection in a tumor on the skin, all the other tumors present later.

Tissue analyzes have shown that tumors have been invaded by several types of immune cells, respectively by different types of dendritic cells, T cells and mature B cells, organized in structures similar to lymph nodes, called tertiary lymphoid structures (SLT, in Engl. TLS), associated with a better prognosis.

The slt were also found in uninjected tumors, a sign that once the immune system recognizes cancer cells, immune cells migrate to other affected areas.

Improve immunotherapy

The results led to the initiation of other clinical trials in collaboration with Memorial Sloan Kettering and Duke University, now in phase I or II, which investigates the 2141-V11 effect on difficult to treat, prostate and glioblastoma, with almost 200 registered patients.

These studies will help to understand why some patients respond to treatment, and others do not, and how this can be changed.

For example, in the two patients in the initial study who have entered complete remission, from the beginning, a high cloning of T cells, essential elements in eliminating cancer cells, indicates that, in order for this medicine to be effective, certain pre -existing conditions are required in the immune system.

In general, only 25-30% of patients respond to immunotherapy, and the main challenge remains identifying those who can benefit from this treatment and discovering strategies capable of transforming patients unanswered into patients responding to treatment.