Natural killers, the new experimental weapon against cancer

Emily Whitehead, Doug Olson or Joan Gel embody the best of cancer research.

They all suffered from blood tumors that should have killed them years ago, but are alive thanks to experimental CAR-T therapies.

This treatment based on an autotransplant of immune cells seemed like science fiction 10 years ago, but today it is used in the clinic and total remissions are being achieved in a large number of patients.

Science is already preparing the next twist of these treatments, known as cell therapies.

Until now, CAR-Ts have reached a small number of patients, partly because cells taken from each patient have to be used, genetically modified so that they learn to destroy their tumor, and reinfused into that same patient and not into any other, since the rejection could kill him.

The new frontier is to achieve similar treatments that can be applied to any patient without fear of side effects.

A few days ago, the pioneers of this type of experimental therapy met to share their latest advances in a symposium organized by the Ramón Areces Foundation in Madrid.

Some of the approaches presented seem even more unreal and fascinating than the CAR-T.

The main conclusion is that generalizing these therapies is possible.

Some of these treatments against tumors with a very poor prognosis could be available in a few years.

German oncologist Evelyn Ullrich from Frankfurt University Hospital is developing a new generation of CAR-T.

That name responds to the English acronym for T lymphocyte with chimeric receptors for antigens.

T lymphocytes are cells of the immune system highly specialized in detecting and eliminating infections.

The genetic modification of CAR also allows them to identify the molecules that characterize a tumor, called antigens, and eliminate it.

But on many occasions the tumors turn off all the molecular signals that could alert the lymphocytes, with which the cancer can advance without being seen.

Ullrich works with another type of immune system cells known as natural killers, NK, in its acronym in English.

These cells form the first line of defense of the immune system and are the first troops to arrive at the scene of an emergency.

Ullrich's team has created lines of genetically modified natural killers not only to detect the molecules that identify the tumor -antigens-, but also with other receptors that increase their effectiveness.

“These cells can be transplanted allogeneically, that is, from a donor to a different recipient, without rejection problems”, explains the researcher.

This cheapens, simplifies and universalizes the use of immune cells against tumors.

These CAR-NK treatments are already being tested in clinical trials with patients suffering from blood cancers.

The new oncological applications developed by Omid Veiseh, a bioengineer at Rice University (USA), also seem to be taken from a futuristic movie.

The researcher recalls that many current drugs are "biological";

natural molecules such as proteins, enzymes or antibodies that are made in cells grown in the laboratory inside large bioreactors.

The process requires a lot of control to prevent the final product from becoming contaminated.

Then you have to inject the product directly into the bloodstream.

Altogether, “it is a cumbersome and expensive manufacture”, sums up Veiseh.

His idea is to inject the patient with microscopic bioreactors that make the drug directly inside the body.

Veiseh is focusing on women with ovarian cancer with a very poor prognosis.

Her tactic is to create synthetic cells whose genomes have been modified to make cytokines, an inflammatory molecule that alerts the rest of the immune system and directs it where it's needed.

The "chassis" of these cytokine factories are cells extracted from the retina of the eye of a single anonymous patient.

It is a cell line widely used in research and biomedical applications.

The advantage is that they can be used widely without fear of immune rejection, Veiseh says.

These cells are covered with a hydrogel that allows oxygen and nutrients to enter and cytokines to exit right at the point where the tumor is, thus reducing the toxicity of the treatment, argues the researcher.

“We want to see if this principle works in these women with ovarian cancer who have not responded to conventional treatments and whose life expectancy is less than a year,” she explains.

“If it does, we will move on to other tumors with a poor prognosis such as mesothelioma, pancreatic and colorectal,” she adds.

This same approach can be used to make many other "biologics," including immunotherapy antibodies.

Currently, the cost of these molecules is around 100,000 euros, but using synthetic cells it could go down to around 1,000 euros, says Veiseh.

This can be very interesting for developing countries where immunotherapy is still an unattainable medicine.

In 2018, the case of Judy Perkins, an American woman who had been given two months to live by her doctors, was known, as she suffered from a breast tumor with metastases in the liver and other organs.

Perkins underwent an experimental treatment: an autotransplant with her own lymphocytes selected for her ability to identify antigens from her tumor.

Oncologist Elena Garralda, director of the Cancer Molecular Therapy Research Unit at the Vall d'Hebrón Hospital in Barcelona, ​​develops this type of therapy in Spain.

At least two other hospitals, the Barcelona Clinic and the Niño Jesús children's hospital in Madrid, are carrying out similar treatments.

The technique consists of taking a small biopsy of the tumor, collecting the lymphocytes that are inside, making them grow and strengthen in culture in the laboratory, and then reinfusing them into the patient.

“We sequence the tumor to find its specific neoantigens and then we select the lymphocytes that react against them to administer them to the patient”, Garralda details.

“If we can improve the ability of lymphocytes to identify these molecules and even attach cytokines to them that help them, we can improve effectiveness,” she adds.

Testing these treatments is challenging, because they are often given to very debilitated patients who have not responded well to other therapies.

The process takes months, so sometimes you have to give "bridging treatments" to make them last.

So far, positive effects have been seen against melanoma, lung and cervical cancer, says Garralda, plus some spectacular isolated cases, such as that of Perkins, who is still cancer-free almost 10 years later.

Luca Biasco, a molecular biologist at University College, works on another of the most complex and promising fronts: gene therapy.

These treatments designed to correct a specific genetic defect have spent decades under suspicion due to the death of a patient in clinical trials.

Even so, Biasco recalls, some of the first patients with genetic immunodeficiencies to be treated with this approach when they were one year old are now healthy 20-somethings, quite a success.

One of the biggest challenges facing this field is the prices of these therapies.

The world's most expensive drug is a hemophilia gene therapy that costs $3 million per patient.

"Gene therapy is very expensive because it requires very complex manufacturing processes," reasons Biasco.

“You have to extract the cells, modify them, multiply them, always in completely sterile environments, then reinfuse them into the patient.

What we're exploring is whether we can give the gene therapy with a viral vector directly to the patient, inject it into the bloodstream.

This will make manufacturing much cheaper.”

Thus, he argues, "we would eliminate the cell component of cell therapy."

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