Non-invasive therapy could remotely kill cancer cells

Scientists have developed a system that can non-invasively and remotely control immune cells so that they recognise and kill cancer cells.

There is a critical need to non-invasively and remotely manipulate cells at a distance, particularly for translational applications in animals and humans, researchers said.

They developed an innovative approach to use mechanogenetics—a field of science that focuses on how physical forces and changes in the mechanical properties of cells and tissues influence gene expression—for the remote control of gene and cell activations.

The team used ultrasound to mechanically perturb T cells, and then converted the mechanical signals into genetic control of cells.

They show how their remote-controlled mechanogenetics system can be used to engineer chimeric antigen receptor (CAR)-expressing T cells that can target and kill cancer cells.

The engineered CAR-T cells have mechano-sensors and genetic transducing modules that can be remotely activated by ultrasound via micro-bubble amplification.

"CAR-T cell therapy is becoming a paradigm-shifting therapeutic approach for cancer treatment," said a Dr.

"However, major challenges remain before CAR-based immunotherapy can become widely adopted. For instance, the non-specific targeting of CAR-T cells against nonmalignant tissues can be life-threatening," said the Dr.

"This work could ultimately lead to an unprecedented precision and efficiency in CAR-T cell immunotherapy against solid tumors, while minimizing off-tumor toxicities," said the Dr.

Researchers found that micro-bubbles conjugated to streptavidin can be coupled to the surface of a cell, where mechanosensitive Piezo1 ion channels are expressed.

Upon exposure to ultrasound waves, micro-bubbles vibrate and mechanically stimulate Piezo1 ion channels to let calcium ions inside the cell.

This triggers downstream pathways, including calcineurin activation, NFAT dephoshorylation and translocation into the nucleus.

The nucleus-translocated NFAT can bind to upstream response elements of genetic transducing modules to initiate gene expression of chimeric antigen receptor (CAR) for the recognition and killing of target cancer cells. 

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Cancer-fighting immunotherapy could treat HIV

Researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a weapon in that fight.

A type of immunotherapy that has shown promising results against cancer could also fight HIV, the virus that causes AIDS, a new study has found. 

Scientists from the University of California, Los Angeles found that recently discovered potent antibodies can be used to generate a specific type of cell called chimeric antigen receptors (CARs), that can be used to kill cells infected with HIV-1. 

CARs are artificially created immune T cells that have been engineered to produce receptors on their surface that are designed to target and kill specific cells containing viruses or tumor proteins.

Chimeric receptors are the focus of ongoing research into how gene immunotherapy can be used to fight cancer. However, they could also be used to create a strong immune response against HIV, said Otto Yang, professor at UCLA. 

Although the human body’s immune system does initially respond to and attack HIV, the sheer onslaught of the virus - its ability to hide in different T cells and to rapidly replicate — eventually wears out and destroys the immune system, leaving the body vulnerable to a host of infections and diseases. 

Researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a weapon in that fight. 

“We took new generation antibodies and engineered them as artificial T- cell receptors, to reprogramme killer T cells to kill HIV-infected cells,” said Yang. 

“Others have used antibodies against cancer antigens to make artificial T-cell receptors against cancer and shown this to be helpful in cancer treatment,” he said. 

While the receptors approach has been in use for almost 10 years to fight cancer, this is the first attempt to use the technique to treat HIV since 15 years ago, when experiments proved unsuccessful.

The new research differs because it takes advantage of new antibodies that have been discovered in the past few years. 

In the previous trials, researchers had used an early type that was not antibody-based. That approach, however, was abandoned because it was clinically ineffective. 

Here the researchers used seven recently discovered .“broadly neutralising antibodies” that have the ability to bind multiple strains of invading viruses, unlike earlier isolated antibodies that tend to bind few strains. 

These antibodies were re-engineered as artificial CAR—T cell receptors to have activity against broad strains of HIV. 

In lab tests, the researchers found that all seven had varying degrees of ability to direct killer T cells to proliferate, kill and suppress viral replication in response to HIV-infected cells.

 The next step is to find strategies to put these receptors into humans.

The research was published in the Journal of Virology. 

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