Tumor immunotherapy is expected to break through
Release date: 2018-03-09
In adoptive cell transfer, immune cells called killer T cells are purified from the blood of patients and genetically modified to provide excellent tumor recognition ability, which is induced to proliferate in vivo. These genetically modified T cells are then perfused back into the patient's circulatory system where they are capable of efficiently and selectively destroying the tumor.
However, after instilling these modified T cells back into the patient, they are unable to survive, proliferate, and target kill for a sufficient period of time, which makes the method more limited. This is because these modified T cells often require a protein called IL-2 that is essential for booster injection into the body, as natural T cells do.
IL-2 is a major regulator of the immune system and, in particular, it is a major T cell growth factor. It is responsible for T cell production, proliferation and activation.
Many types of immune cells naturally secrete IL-2 when responding to multiple threats. It promotes these T cell activations when it binds to receptors on the surface of T cells, including receptors on the surface of T cells that secrete it. Once deprived of IL-2, once activated T cells are inhibited and become exhausted.
Dr. Christopher Garcia, a professor of molecular and cellular physiology and a professor of structural biology at the Stanford University School of Medicine, and a researcher at the Howard Hughes Medical Institute, said the situation applies to genetically modified T cells that are infused into cancer patients. He said that these genetically engineered T cells require IL-2 to survive, function and proliferate.
This is good when these genetically modified T cells are present outside the patient's body. However, there are major limitations in the strategy of intravenous IL-2 to enhance the efficacy of adoptive cell transfer after T cell perfusion, due to the side effects caused by high-dose injection of this potent protein—especially Pulmonary edema - so severe that it outweighs the benefits of this treatment.
The problem is that receptors for IL-2 are not only present on the surface of T cells, but also on the surface of immune cells that are best inactivated during cancer treatment, such as so-called regulatory T cells, whose role is Inhibiting the immune response produced by mobilizing the immune system against tumors or invading pathogens. Prolonged activation of the immune system can lead to persistent inflammatory and autoimmune diseases that can damage tissue. Many other types of cells in the body, such as lung cells, also contain IL-2 receptors, so IL-2 is able to induce destructive inflammation in tissues containing these cells.
However, in a new study, Garcia and his team found a workaround that would allow for the progression of adoptive cell transfer therapy, but would not cause T cell exhaustion and would not cause IL-2 damage. Sexual side effects. The results of the study were published in the March 2, 2018 issue of Science, entitled "Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes".
The Garcia team made a slight adjustment to a subunit of IL-2 by genetic modification so that receptors containing this subunit could no longer bind to IL-2, ie they produced a slightly regulated IL-2 molecule. The molecule is not able to bind to its normal receptor. In response to this slightly regulated IL-2, its receptor is also modified correspondingly such that the modified IL-2 and the modified receptor bind only to each other with high affinity.
Using laboratory methods to modify mouse T cells to express this modified receptor, the Garcia team confirmed in a series of experiments that these modified T cells responded to this modified IL-2. Just as natural T cells are expected to respond to normal IL-2. However, unmodified T cells do not respond to this modified IL-2.
Next, the Garcia team collaborated with Dr. Jeffrey Bluestone, an immunologist at the University of California, San Francisco, and Dr. Antoni Riba, a cancer expert at the University of California, Los Angeles. In the Bluestone and Riba laboratories, these researchers conducted further disease-based experiments, some of which were conducted in mice that were induced to have a well-described melanoma. Mice carrying this highly aggressive tumor usually die very quickly. In undergoing adoptive cell transfer - genetically engineered T cells from the mouse itself to target them to this particular tumor, and then infuse these modified T cells back into these mice - afterwards Normal IL-2 injections can prevent this melanoma from growing, but IL-2 causes many unpleasant side effects, reflecting the side effects of injections in the body: weight loss, limited mobility, hypothermia Spleen enlargement, swollen lymph nodes and possible death. (In this study, mice are euthanized if they become ill and may die.)
However, T cells from mice were similarly genetically engineered to attack this melanoma and allowed to express modified receptors that only respond to this regulated IL-2, which were subsequently modified. The T cells are perfused back into these mice, followed by a normal dose of this adjusted IL-2, which also causes the tumor to shrink, but without side effects. The survival rate of these mice was significantly improved whether compared to untreated mice or to mice that received these adoptive cell transfer therapies but did not receive IL-2 injection.
Garcia said his team has now produced a human version of this modified IL-2/modified receptor that binds to each other only. He is seeking to collaborate with academic or industry partners to conduct clinical trials based on this new technology.
He said he believes that this method can also be used to activate regulatory T cells rather than killer T cells, and in principle should be effective against autoimmune diseases.
Source: Bio Valley
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