Monday 4 July 2022

Is there no treatment?

A lone cell that broke the rule,
Turned into a mass of no use.
Threatens its own living space,
As it forgets that it is not a race.
Unchecked by the internal defenses,
 who will bring it back into its senses?
Maybe a little help from outside,
to open those internal eyes wide.
Catch hold the ones gone astray,
Immunotherapy saves the day.

The first recorded observation of tumours come from ancient Egyptian texts dating back to the 3000 BC that mention, “There is no treatment.”

In the 21st century, we do have treatment for cancer. Do we really? Yes, if the tumour is detected in time, i.e. the cancer cells have not metastasized throughout the body and are still confined to a tissue that can be surgically removed after chemotherapy (treating with chemical drugs to destroy the cancerous cells). No, we do not have a treatment if the cancer has metastasized. Then there are other cancer types like glioblastoma that do not metastasize (because of the presence of blood brain barrier) but are difficult to treat because of the same blood brain barrier. Surgically removing the cancer from the brain gets difficult as the cancer advances. These are some of the examples where conventional chemotherapy and surgery fail. This is when cancer recurs after our 21st century treatments. And we can hear the same words being said by doctors to cancer patients and their families - there is no treatment.

Are you aware that our own immune system has the potential to kill cancer cells? Had it not been so the mortality due to cancer would have been unfathomable. Although, cancer is still a leading cause of death globally. A type of immune cells called cytotoxic T cells, have the ability to identify cancerous cells and then destroy them. Yet, cancers occur. This is so because the cancer cells gain the ability to evade the immune system and at times create a microenvironment around the tumour that can actively suppress the immune system. So, what if we use this arm of the immune system to treat cancer? It sounds logical, right? Have you heard about immunotherapy?

Immunotherapy is an umbrella term for any therapeutics that uses the immune system or components/cells derived from the immune cells/system to treat cancer. One of the immunotherapy that was in news recently showed a 100% response rate and has been termed as a miracle cure. This particular immunotherapy used what is known as monoclonal antibody (antibody is what B cells, a type of immune cells, produce to neutralise molecules present on the surface / released by the pathogens) to block a cell surface molecule called PD1 (programmed death 1). This therapy was designed and tested for patients that had advanced (but not metastasized yet) rectal cancer which have a specific type of mutation present that makes these cells non responsive to the normal checks and controls of a cell to DNA damage and subsequent death. This study showed the potential that immunotherapy holds as no other conventional therapy (radiation or surgery) was required in these cancer patients.

Different cancers have different types of genetic aberrations and therefore a single treatment would not work for all types of cancers. While great many advances have been made in the field of immunotherapy by the West, some commendable efforts are emerging in India as well. An immunotherapy approach that is being formulated utilises FAT1. Researchers at Dept of Biochemistry, All India Institute of Medical Sciences (AIIMS, New Delhi) are working on FAT1 to explore its role as an immunotherapeutic. They have recently published their work in Frontiers in Immunology. “Immunosuppression is the biggest challenge in treating patients of glioblastoma, pancreatic cancer, liver cancer and cervical cancer. It is due to the evasion of immunity by the tumour cells that standard therapeutic procedures in cancer fail and there is tumour recurrence. So, researchers are now looking for newer therapeutic target molecules which may play a crucial role in immunoregulation of cancer and could be used in immunotherapy approaches so as to harness the body’s own fighting ability.” says Dr. Khushboo Irshad, the lead author of this study.

They first sifted through the publicly available databases to check for the levels of FAT1 in various types of cancers in patients. This in silico analysis revealed that the tumours which had low numbers of immune cells (T cells and monocytes) that inhibit the growth of the tumour had high levels of FAT1 protein. Thus, it appears that FAT1 might be promoting an environment around the tumour that keeps the protective cells away. Dr. Irshad adds, “We wanted to pinpoint the molecular link between FAT1 and immune cell infiltration in tumours. TGF-β cytokines are well-known immunosuppressive cytokines present in the tumours.”

So, they next checked for the levels of TGF-β (a protein molecule that suppresses the immune system) along with FAT1 levels in the publicly available databases of cancer patients. They found that even the levels of TGF-β were increased in cancers where FAT1 levels were increased.

To validate this finding experimentally, glioblastoma samples were collected from the Neurosurgery department, AIIMS, New Delhi and were cultured under lab conditions. These cultured cells were then manipulated so as to not let FAT1 be expressed. What was found after this manipulation was that even the levels of TGF-β went down and the number of protective immune cells in the tumour environment increased.

These findings point towards FAT1 being used to harness the potential of the immune system for fighting cancer. Dr. Irshad adds that, “FAT1 is an attractive immunotherapeutic target which entails further studies that may ultimately benefit the patients of aggressive cancers like glioblastoma, pancreatic cancer, etc.”

With a variety of immunotherapies being developed we hope that soon we will be able to replace ‘there is no treatment’ with ‘THERE IS A TREATMENT”.

Listen to Dr. Khushboo Irshad talk about here recent findings in this video.


References:

https://www.cancer.org/treatment/understanding-your-diagnosis/history-of-cancer/what-is-cancer

https://www.cancer.gov/about-cancer/treatment/types/immunotherapy

https://www.frontiersin.org/articles/10.3389/fimmu.2022.813888/full

https://www.nejm.org/doi/full/10.1056/NEJMoa2201445

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