deal a fatal blow to cancers


A revolutionary treatment in the treatment of cancer will see immune cells injected into patients. There are already five approved therapies that remove T cells from cancer patients, genetically modify them in the lab, and re-inject them to kill cancer cells.

But the procedure for performing cell therapy is complex and typically costs over $ 350,000 (€ 301,000). Approved therapies are for blood cancers only and are not available in Ireland. Businesses and clinician scientists are pushing to target solid tumors and make therapy more affordable.

Cancer occurs when cells get out of control, escaping normal controls. The task of killing unwanted cells falls to natural killer (NK) cells and T cells, which deploy cell-killing enzymes or issue suicide instructions.

Our immune system continually kills cancer cells, but this can eventually fail as the slickest rogue cells destroy the system.

Placing a CAR (chimeric antigen receptor) on an immune cell by deploying DNA editing technology prepares it to attach to cancer cells. Kymriah, developed by Novartis, treats patients with acute lymphoblastic leukemia. It does this by genetically modifying a patient’s T cells in a lab so that they hook up and kill their cancerous B cells.

This can save the lives of patients who have no other treatment options. The commercial and clinical potential of this therapy is evident from some 500 clinical trials using CAR-T cells for the treatment of cancer.

One downside is that T cells sometimes trigger dangerous inflammation. In addition, the cost of CAR-T is extremely high, even for rich countries. “Part of that cost is manufacturing,” says Dr Mary Martin, president of Avectas, an Irish biotech working in this field. “It’s partly the logistics. You are drawing blood from someone and may need to ship it to another country, have the changes made [to their cells] and send it back for administration to the patient, ”she said.

Natural killer cells

A more recent approach is to use NK cells, one of the few cell types that directly kill tumor cells, says Dr David Finlay, a biochemist at Trinity College Dublin: “They can inject poisons into a cell or strike receptors that trigger cell death. Sometimes NK cells are taken from a cancer patient, grown and injected back to help fight the cancer. A future approach – currently in clinical trials – is to modify the DNA of NK cells to improve them.

Cell therapies today mainly contain one or two modifications of the immune cell. But scientists believe multiple modifications of these NK or T cells are the future. “CAR-T cells have the fruit at their fingertips,” says Finlay. Future therapies will need to tackle solid tumors, such as breast, lung and prostate cancers, and will therefore require more sophisticated modifications.

The problem with masses of cancer cells is that they can be easy to penetrate and evolve to manipulate other cells around them. “Cancer has ways of suppressing the immune system, both locally in the solid mass and far away from it,” adds Finlay, who has studied the metabolism of NK cells.

NK cells don’t spend a lot of energy while patrolling the body, but that changes once placed on battle stations. “When you activate NK cells, whether in the lab or in mice, they go through this massive increase in metabolism, which allows them to divide and kill tumor cells,” he says. “But many conditions in the tumor microenvironment have the potential to disrupt this metabolism.”

For example, some tumors ensure that very little glucose is present to fuel NK cells, or they generate a rich fatty medium that leaves NK cells dysfunctional. Also, since NK cells are cellular assassins, the body has various levers to stop their proliferation or to cancel their attacks and prevent autoimmune diseases. Unfortunately, cancer cells can evolve to pull these same levers. By spitting out cholesterol-like compounds that act as switches for NK cells, for example. One solution is to curb NK cells or reduce their sensitivity to tumor defense strategies – by altering their DNA.

It is expected that several modifications will be necessary. “For solid tumors and complex cancers, we’re going to have to do a much more complex engineering than those [immune] cells to attract them to cancer and keep them there, without being destroyed, etc. ”, notes Martin. “One edit will not be enough. ”

New generation therapy

Avectas believes that it has a technology suitable for this new generation of cell therapy. When editing immune cells today, there are two popular options. One is to use viruses to deliver the gene-editing cargo – it’s expensive and poses some security concerns. The second is to electrically zap the cells and cause their membranes to leak. The cell editing machinery then enters the cell.

But white blood cells can be fragile. Such procedures can weaken them, resulting in fewer cells for a patient, and this risk is increased if you have to repeat a procedure for multiple checks. Avectas relies on a proprietary solution, delivered in tiny droplets, that causes an immune cell to transiently open and allows gene editing tools to enter.

Their method isn’t as harsh on fragile immune cells as cell zapping, according to the company. “We aim to excel at making complex cell modifications,” says Dr. Michael Maguire, co-founder and CEO of Avectas. “We can deliver complex payloads to cells while maintaining the health of those cells. “

Hundreds of millions to billions of immune cells constitute a therapeutic dose for cell therapies, so it is crucial that they remain viable and healthy when grown and modified in the laboratory. With existing treatments, it sometimes happens that a patient’s cells are not cultured in sufficient quantity to treat them. Avectas hopes companies will license its technology in their future cell therapy manufacturing processes.

“I think in the not too distant future we will see a CAR-T treatment center here in Ireland,” says Martin. It remains to be seen if, or when, such therapies will be manufactured here, however. Currently there are no such facilities in Ireland, but cell therapy is described by some as the third wave of medicine – after small molecules, which Ireland makes a lot, and biologics, antibody therapies manufactured by some state pharmaceutical companies. . Ireland will need to strengthen its capacities and expertise in terms of researchers, small businesses and ultimately multinationals.

Finlay in TCD has partnered with another Irish start-up in this field, ONK Therapeutics. This Galway-based company is looking to design NK cells for cancer treatment. He is interested in bone marrow, breast and ovarian cancers, and is developing ways to edit NK cells to better target these cancers. Life sciences entrepreneur Séamus Mulligan is a key shareholder of ONK Therapeutics and Avetas.

Despite advances in cancer treatments, we desperately need new therapies. Especially for cancers like glioblastoma, a deadly, extremely aggressive and incurable brain cancer. “This particular tumor microenvironment appears to be very inhibitory,” says Finlay. “We can put NK cells in there, but they are deactivated. ”

He is looking for why and how to stop it. The hope is that the modified NK cells can one day be injected into patients with glioblastoma, travel to the brain, and kill cancer cells.

One advantage of NK cells is that they are easier to move between donor and patient than T cells, which could make them suitable for new standard cell cancer therapies.

This is the futuristic vision that many companies and academics dream of – a patient’s tumor is assessed to allow a clinician to select an appropriate vial of NK cells, genetically engineered to accommodate this type of cancer.

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