MIT’s Reverse Immunotherapy Treats Cancer with Dying Cancer Cells

picture explanationNK cells that prevent metastatic cancer seeds from waking from hibernation

Anticancer immunotherapy stimulates the patient’s own immune system to destroy tumor cells.

When it first appeared, it was expected that it would be a very promising cancer treatment.

However, it was later discovered that there was a crucial weakness. In fact, the types of cancer that can be treated are very limited.

MIT (Massachusetts Institute of Technology) scientists have developed a breakthrough cancer immunotherapy that has a much wider range of efficacy than conventional immunotherapy.

This treatment uses chemotherapy on cancer cells removed from the tumor, and then injects it back into the original tumor along with an ‘immune checkpoint inhibitor’ that activates T cells.

Cancer cells whose DNA has been damaged by chemotherapy played a key role here.

When these cancer cells are introduced into the tumor, it has been shown to stimulate the activation of T cells by inducing the generation of a ‘distress signal’.

The results of this study conducted by Professor Michael Yaffe, director of the MIT Cancer Medical Center, were published as a paper in the journal Science Signaling on the 19th (local time).

He is also a member of MIT’s Koch Institute for Integrated Cancer.

Professor Yap, co-lead author of the paper, said, “When the DNA is damaged and produces cancer cells that do not die, it can send a wake-up signal to the immune system.”

Cancer neoantigens and T-cell responses

picture explanationCancer neoantigens and T-cell responses

‘Checkpoint blockade inhibitors’ are currently widely used drugs for cancer treatment.

Simply put, this drug releases the brakes on T cells, which are exhausted and unable to attack cancer cells, and resume their activity.

This immunotherapy was developed as a novel idea, but so far only works for some types of cancer.

The study began as an attempt to improve the efficacy of immune checkpoint inhibitors.

The research team expected that when administered together with cytotoxic chemotherapy, it would stimulate the immune system to attack more cancer cells.

This combination therapy is based on a phenomenon called ‘immunogenic cell death’.

An already dead or dying tumor cell sends out a signal that draws the immune system’s attention.

There are currently a few clinical trials of this approach, but so far little has been known about the ideal way to do it.

Professor Yap’s team divided the cancer cells isolated from the tumor on several Petri dishes and administered different types of chemotherapy at different doses.

Then, dendritic cells and T cells were sequentially added to each dish at 24-hour intervals, and then the ability of T cells to remove cancer cells was measured.

Surprisingly, most chemotherapy didn’t help much. What helped, however, showed the greatest effect at a low dose, which did not kill many cancer cells.

As it turned out later, it wasn’t the dead tumor cells that stimulated the immune system.

Cancer cells that survived DNA damage due to the action of chemotherapy acted as a key factor.

Professor Yap said, “A new concept has emerged of immunogenic cell damage, not immunogenic cell death, for cancer treatment. It wakes up the immune system.”

Activated T cell response

picture explanationActivated T cell response

In particular, chemotherapy that damages the DNA of cancer cells is the most effective treatment for this type of treatment.

Damage to the DNA of tumor cells activates a cellular pathway that responds to stress, and a ‘danger signal’ that stimulates the resumption of T-cell activity goes out of this pathway.

The T cells that woke up in this way destroyed not only the cancer cells that were damaged by the chemotherapy and sent a danger signal, but also the cancer cells around them.

When the treatment was used in a mouse model of melanoma, the tumor was completely eliminated in about 40%.

A few months later, when cancer cells were injected into the same mice, the T cells they identified were removed before they grew into new tumors.

However, when a chemotherapy that damages the DNA of cancer cells was directly injected into the tumors in mice, the same effect did not appear.

This is because the drug harms not only T cells but also other immune cells around the tumor.

Injecting only damaged cancer cells without the immune checkpoint inhibitor had little effect.

Professor Yap’s team hopes to test the treatment in cancer patients who do not respond to immunotherapy.

However, a lot of research is still needed to determine which drugs are used and in what amount to give the best effect for various types of tumors.

Future research goals also include how DNA-damaged cancer cells injected into tumors elicit a strong T-cell response.

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