Dual Function Virus-A New Trial For Cancer Therapy

Dr. Abhishek Kumar Mishra, Swami Rama Himalayan University, Jolly grant, Dehradun, Uttarakhand

2019-10-30 08:10:39

Credit: pixabay.com

Credit: pixabay.com

Cancer is a leading cause of death worldwide. Globally, scientists are trying to develop newer methods to treat cancer patients.  If we talk about the cancer we can say-Initially it is the loss of control over the cellular system of a particular region in body but sometimes it involves many regions-“Metastasis,” spreading form of cancer. Generally, benign tumors are curable through surgery but initiation of malignancy in these tumors reduces the effect of the treatment type.

Available methods of treatments for cancer patients:

Existing therapy to treat cancer patient are-surgery, radiotherapy, chemotherapy, hormone therapy and/or immunotherapy etc.

  1. Surgery:Surgery is just removal of cancer from body.
  2. Radiotherapy:High dose of radiation (gamma rays) is used to kill cancer cells.
  3. Chemotherapy: Drug based (Doxorubicin, Paclitaxel) killing of cancer cells.
  4. Hormone therapy: In somecancer types such as breast and prostate cancer, presence of a specific hormone is required for the growth of cancer cells. Hormone therapy works to stop or reduce growth of cancer cells by making unavailability of that hormone.
  5. Stem cell therapy: While treating cancer patients, radiotherapy or chemotherapy damage the blood cells. Therefore, if there is a damage, stem cell transplantation is used for the formation of new blood cells.
  6. Chimeric antigen receptor (CAR) T cells therapy: It is a type of immunotherapy that works by the extraction of T cells (a type of immune cells) from patient’s blood and engineering them for attack and killing of cancer cells. Extracted T cells are converted into CAR T cells by adding a specific receptor expressing gene. The receptor binds to a particular protein on the surface of cancer cells.

The type of treatment will receive the cancer patient depends on the type, location and progression of tumor. These factors also determine, whether cancer patient will be treated using any one of the specialized therapy or combination therapy.

Dual function virus:Recently a new report is published for the tumor-killing and immunity boosting capacity of an engineered oncolytic virus, named dual function virus (DFV). This report is a work of Dr. Greg Delgoffe and his team and published in "Immunity" on September 17, 2019. The work describes-an engineered dual-function virus (DFV) and it's potential to shrink and remove tumors in mice with melanoma-a type of skin cancer, than a regular oncolytic virus. The study was conducted at the Pittsburgh Medical Center.

Engineered oncolytic viruses have also been successfully used before to kill cancer cells in Melanoma, but this time a second function (addition of a hormone expressing gene) is introduced.

Oncolytic viruses (OV) are used to kill tumor cells. These viruses may occur naturally or can be constructed in laboratories by the engineering of other viruses. The most important property of OV is that they can infect and lyse (break) cancer cells only, without harnessing the normal cells. Adenovirus, Herpes simplex virus and, Vaccinia viruses are generally used as oncolytic viruses. DFV can kill cancer cells and recruit functional immune cells to the tumors, therefore, the function of oncolytic viruses can be further improved to heighten immune response against tumors. In addition to the killing of tumors, DFV also relieves immunosuppression. The creation of the dual function virus was inspired by the pre-established fact that oncolytic viruses can kill individual cancer cells and can boost the immune system's ability to recognize and kill a tumor. The mechanism involves the specific entry and replication of viruses into tumor cells and eventually breaking the cells apart along with the release of specific immune recognition tumor cell proteins-"tumor antigens". These proteins get released into the bloodstream and attract T cells into a tumor to start killing of cancer cells, and potentially may even trigger them to recognize metastatic cancer elsewhere in the body.

Migration of T cells and entry to the tumor cells are very challenging as the tumor environment by its nature is toxic. When T cells get in, they experience a harsh, low-oxygen, desert-like landscape. This environment can render immune cells unable to function.

When an oncolytic virus enters to the tumor site, the interaction between tumor and immune cells is dramatically changed. The virus not only lyses the tumor cells but also recruits a substantial number of T cells inside the tumor bed.

Generally newly arrived T cells at tumor bed, appear healthy and vigorous. But soon, they lose their tumor-killing capacity, transforming them from powerful destroyers to depleted bystanders with limited potential to harm cancer cells—a phenomenon often referred to as "Exhaustion".

Inside the body, DFV not only killed the cancer cells but also prevented the exhaustion of T cells.In the second part of the study, the team focused on a hormone called "leptin" as a possible supportive molecule. It supports the body to regulate hunger, therefore indirectly involved in weight control of the individual. Besides the hunger regulation, leptin also boosts immunity. The remarkable fact about leptin is tumor cells have a very low concentration of it whereas T cells in tumors have high levels of the receptor for this hormone. This is also true for exhausted T cells.

The impact of this hormone on the killing of tumor cells in animal tissue culture system showed that high levels of leptin enhance the ability of T cells to kill tumor cells. Therefore, earlier, researchers tried to deliver high doses of leptin directly into the bloodstream of mice bearing melanoma tumors. But the strategy could not find useful to improve the potential of T cells within tumors.

In the current study, the oncolytic virus was reengineered to insert the gene for the expression of the leptin hormone. When DFV was injected directly into tumors in melanoma tumor mice, leptin concentration increased significantly inside the tumor microenvironment. It could be possible because of the expression of leptin producing gene. As a result of DFV injection, the tumors shrank substantially and one-fourth population of mice gets completely recovered, i.e., no traces of tumors were seen. A prolonged life span was seen in these mice in comparison to the mice injected only with the control virus (virus without the leptin gene).

The leptin-expressing virus also improved survival in a mouse model of aggressive pancreatic cancer. Injection with the leptin-expressing virus also seemed to serve as a cancer vaccine in some mice with melanoma. When the team injected the same tumor cells into mice that had experienced a complete response to the leptin-engineered virus, the immune systems of most of these mice prevented tumor regrowth. In some of these mice, regrowth of tumor seen but at a very slow rate which indicates that the engineered virus had primed the immune system to remember and recognize the tumor cells (memory response). Therefore the study expanded the brighter perspective towards the prevention of tumor recurrence.

The overall summary is-a dual function virus was prepared by adding a leptin gene to an engineered oncolytic virus. The dual function virus was designed to-(I) Kill tumor cells and (II) to support and enhance the power of immune cells.

Oncolytic viruses are already known for targeting and killing of tumor cells, but the addition of leptin producing gene significantly enhanced the potential of the virus.

This study is in initial phase of trial. If found successful, it may provide new horizons in cancer therapy.