Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Drug commonly used as antidepressant helps fight cancer in mice

  • June 16, 2021

Newswise — A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain’s “happiness hormone.”

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

“MAOIs had not been linked to the immune system’s response to cancer before,” said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That’s because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs — phenelzine, clorgyline or mocolobemide — either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven’t tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells’ response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.   “We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

The research was supported by Stop Cancer, the Broad Stem Cell Research Center Rose Hills Foundation Innovator Grant and Stem Cell Training Program, the UCLA Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center Ablon Scholars Program, the Magnolia Council of the Tower Cancer Research Foundation and the National Institutes of Health, including a Ruth L. Kirschstein National Research Service Award.

Covid immunity lasts for a year, vaccine boost helps fight variants, study says

Covid immunity lasts for a year, vaccine boost helps fight variants, study says

  • June 16, 2021
Covid-19 vaccine shot | Representational image | Bloomberg


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New Delhi: Immunity in Covid-recovered patients is long-lasting and gets a 50-fold boost after vaccination, according to a new study.

The study, published in the journal Nature Monday, also said that the mRNA vaccines can sufficiently protect against emerging mutations.

More than a year after the Covid-19 pandemic broke, the emergence of new variants that appear to be more transmissible and resistant to antibodies has added to the challenge of controlling the spread of the disease.

To understand how long the immunity lasts, researchers from the Rockefeller University, Weill Cornell Medicine and California Institute of Technology assessed the blood samples of 63 people who had recovered from Covid-19. The samples were collected 1.3, 6.2 and 12 months after infection.

Of these 63 people, 41 per cent had received mRNA vaccines.

The study found that in Covid-recovered patients, antibodies against the protein known as receptor binding domain (RBD) of SARS-CoV-2 and neutralising activity remain relatively stable from six to 12 months, without vaccination.

A receptor-binding domain is a key part of the virus located on its ‘spike’ protein that allows it to latch onto the cell to gain entry into cells and lead to infection.

Memory B cells — a type of white blood cells that learn to recognise specific viral proteins — was also found to remain stable upto 12 months.


Also read: New atomic-scale 3D map of Covid virus protein could hold clue to preventing lung damage


Antibody levels

In addition, the team found that vaccination increases all components of the antibody response. Antibody levels remained relatively unchanged between six to 12 months after SARS-CoV-2 infection, and that vaccination further boosted this activity by nearly 50-fold.

The study found that the ability of vaccine-induced antibodies to neutralise variants of concern was comparable to or greater than that against the original virus.

Researchers also identified that the broad response against the SARS-CoV-2 virus involves what is known as the antibody somatic mutation — a cellular mechanism using which the body’s immune system adapts to the changing virus during the course of the infection.

This results in antibodies that are exceptionally resistant to mutations in the SARS-CoV-2 RBD — including those found in variants of concern

In addition, B cells that produce a broad range of potent antibodies are retained in the body over time and expand dramatically after vaccination.

The data suggest that immunity in Covid-recovered individuals will be very long-lasting, researchers said. Along with this, Covid-recovered patients who receive mRNA vaccines produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants, the study concluded.

(Edited by Neha Mahajan)


Also read: AY.1 — The new Covid variant on world radar stems from Delta variant, linked to immune escape


 

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