Cancer Killers

Synthetic killer cells

Maxim Rousseau, Polit.roo

Scientists from Memorial Sloan—Kettering Cancer Center have created a new type of genetically modified immune cells that will be able to fight tumors that remained invulnerable to previous therapies. The researchers gave these cells the name SEAKER cells, that is, synthetic killer cells armed with enzymes (Synthetic Enzyme-Armed KillER cells).

The most promising direction of genetic cancer therapy in recent years is considered to be based on the use of T-lymphocytes with chimeric antigen receptors (chimaeric antigen receptor, CAR). The patient takes his own T-lymphocytes (so-called T—killers) and undergoes genetic modification, during which the gene of a certain protein - the cell surface receptor - is transferred to them. This protein is able to selectively bind to antigens — proteins of cancer cells of exactly the type that this person has. Thus, T-lymphocytes, having returned to the patient's body, are already trained to recognize and destroy the cells of his tumor. The first trials of therapy based on the use of chimeric antigen receptors began in 2011, and since then, the number of successfully cured patients has already reached hundreds. However, the high cost of therapy remains a big problem. In the USA, the Kymriah therapeutic method — the first approved CAR-T therapy method - cost $475,000 in 2018.

There are other limitations of CAR-T therapy. First, CAR-T cells can only kill cancer cells containing a marker that CAR-T cells are able to recognize. But it happens that cancer cells stop producing a protein marker and thus avoid prosecution. The second problem is that CAR-T cells can be "depleted" and even suppressed by cancer cells themselves. Finally, existing CAR-T therapies work well only against blood cancers (leukemias, lymphomas) when CAR-T cells can easily reach their target. They act much worse against dense tumors.

To overcome these obstacles, a team of researchers has developed a completely new type of CAR-T cells that act like microscopic pharmaceutical factories: they can deliver directly to the tumor a substance toxic to tumor cells, killing both cells containing the target marker and nearby tumor cells that do not have this marker.

A substance known as AMS (adenosine-5'-O-monosulfamate), previously discovered in the laboratory of one of the authors of the study, Derek Tan, is used as a weapon of these new cells. It was discovered in the process of searching for new powerful antibiotics and was initially considered as a means of combating the microorganism that causes sleeping sickness. Screenings have shown that this substance also effectively kills tumor cells. But AMS has turned out to be so toxic that it cannot be injected directly into the bloodstream. But if CAR-T cells deliver it directly to the tumor and there it acts locally, it becomes an effective medicine that is safe for the rest of the body. In experiments, this method effectively destroyed cultured tumor cells and tumors in live mice.

The idea of using CAR-T cells to deliver additional therapeutic agents has not been expressed for the first time. Several research groups have shown that it is possible to make them produce immune proteins such as antibodies and cytokines. But getting CAR-T cells to produce a low-molecular—weight cancer drug is a more difficult task. "Human cells usually cannot produce compounds of this type," says Derek Tan. To find a workaround, Tan and his colleagues linked AMS to another chemical that "masks" its function. They then genetically engineered T cells to create an enzyme that cuts off the masking molecule from the drug. "Unlike low-molecular-weight drugs, human cells produce enzymes very well, so CAR—T cells are able to produce them efficiently," adds Derek Tan. When an inactive version of the drug, called a prodrug, is injected into the bloodstream, it circulates through the body. The enzyme produced by CAR-T cells acts like scissors, releasing the active part of the prodrug at the tumor site. Scientists have also demonstrated that SEAKER cells work with several different prodrugs and several different cleavage enzymes.

Now that scientists have shown that SEAKER cells work in mice, this approach has aroused great interest. CoImmune has already received a license to develop cells for human testing. "This is an opportunity to better understand the limitations of CAR-T cells and, in particular, to develop new treatment options that can solve problems with the elimination of tumor masses and toxicity," says CoImmune chief executive Charles Nicolette. "This exciting collaboration allows us to evaluate this completely new approach that could provide a new treatment option for patients with dense tumors."

The technology can be used to fight not only cancer, but also other diseases such as autoimmune and infectious diseases. But for now, the focus of researchers at Memorial Sloan—Kettering Cancer Center and CoImmune will be cancer. The head of the molecular pharmacology program, David A. Scheinberg, suggests that two to three years remain before the start of clinical trials of a new cancer drug.

Article by Gardner et al. Engineering CAR-T cells to activate small-molecule drugs in situ is published in the journal Nature Chemical Biology.

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