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Drug: SA-4-1BBL

Magazine: Cancer Research

Highlights: A new immunotherapy that promises to prevent multiple cancers


T cells play an important role in the defense against cancer, and their activation is regulated by ligand-receptor interactions on macrophages in T cells, dendritic cells, tumor cells, and tumor microenvironments. . These receptor-ligand pairs are called immunological checkpoints. Figure 1 summarizes the immunological checkpoint molecules involved in the regulation of anti-tumor immune responses.


Among them, CTLA-4, PD-1, TIM-3, LAG-3 and the like are inhibitory receptors, and the action is to inhibit the anti-cancer reaction of T cells. Currently, some antibody drugs targeting such receptors or their ligands have been approved for marketing, such as the well-known PD-1/PD-L1 antibody.


Opposite to inhibitory receptors are “activating receptors”, including 4-1BB, GITR, OX40, etc., which act to enhance the anti-tumor activity of T cells.


Among them, 4-1BB, also called CD137 or TNFRSF9, belongs to the TNF receptor family and is mainly expressed on the surface of activated lymphocytes, including T cells, B cells and NK cells. A number of preclinical studies have demonstrated the efficacy of antibodies targeting 4-1BB, and some drugs are already in clinical trials.

4-1BB The currently known natural ligand 4-1BBL belongs to type II transmembrane protein and is mainly expressed on antigen-presenting cells such as dendritic cells, macrophages, and B cells. Activation of 4-1BB with ligands also increases the body’s level of anti-tumor immune response.

On February 15th, the latest study published in the Journal of Cancer Research, scientists from the University of Louisville in the United States designed a recombinant chimeric protein SA-4-1BBL based on 4-1BBL, which contains small The extracellular domain of murine 4-1BBL and a modified version of the core streptavidin.


Animal experiments have shown that the use of SA-4-1BBL alone can prevent the development of a variety of cancers.


Specifically, the researchers allowed mice that had never had cancer to receive SA-4-1BBL alone, and then challenged the mice to “challenges” cervical and lung cancer cells at different time intervals. The results showed that after two weeks of treatment with SA-4-1BBL, the mice received the “challenges” of tumor cells, and the mice received the most significant protection. The cancer immunoprophylaxis effect produced by SA-4-1BBL can last for more than 8 weeks.


This is a very surprising finding because, in general, the immune system recognizes the risk of a tumor after it has formed a certain “scale” of the tumor, and then produces an adaptive tumor-specific response to destroy the identified tumor. .


So, how does SA-4-1BBL play a role in cancer prevention?


Studies have shown that this molecule produces tumor immune surveillance systems by activating CD4+ T cells and innate NK cells, thereby protecting mice from a variety of cancers that have never been seen before. This indicates that SA-4-1BBL has cancer immune prevention function.


Confocal microscopy images show that SA-4-1BBL (green) binds to receptors on immune cells (red), thereby initiating an immune activation cascade against cancer.

Scientists believe that the novelty of the study is that they demonstrate that SA-4-1BBL is capable of producing a specific immune response, ie, “patrolling” in the body, looking for the presence of rare tumor cells, and in cancer in the body ” Destroy it before rooting.


“Only SA-4-1BBL administration can prevent the formation of tumors in animal models. This is very exciting. As far as we know, this is the first study to prove that an immune checkpoint stimulator can be administered alone. Activate the immune surveillance system to protect the body from a variety of tumors,” said Professor Haval Shirwan, who led the study.


Professor Shirwan et al also believe that although the study only tested cervical cancer and lung cancer in mice, it may be effective in preventing multiple tumor types because the protective effect of SA-4-1BBL does not involve specific tumor antigens. .


They plan to further test the cancer prevention function of SA-4-1BBL. However, despite the appeal of this concept, the design of clinical trials poses a challenge to the target population. Scientists hope that advances in cancer screening technology and genetic tools can help identify high-risk individuals with cancer and then test the effects of SA-4-1BBL in these individuals and in people who have detected precancerous lesions.


A company called FasCure Therapeutics in the United States also participated in the study. Dr. Esma S. Yolcu of the company said: “We are very excited about the possibility of SA-4-1BBL producing cancer immune prevention. On the one hand, its effectiveness is not only for certain types of tumors; on the other hand, as a A natural ligand that does not cause toxicity; in addition, because SA-4-1BBL activates innate immune cells, concerns about its own immunity are greatly reduced.”


Cancer prevention seems to sound more predictable than cancer treatment. Will immunotherapy really open up new horizons again?


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