Immune System Stimulating Treatment to Reduce Psychological and Physiological Stress Prevents Metastases and Can Save Cancer Patients’ Lives

In a breakthrough research published recently in Nature magazine, Tel Aviv University researchers found that the short time period around the tumor removal surgery (the weeks before and after surgery), is critical for prevention of metastases development, which develop when the body is under stress.

According to the researchers, to prevent development of metastases after the surgery, patients need immunotherapeutic treatment along with treatment to reduce inflammation, and physical and psychological stress. The research was conducted by Prof. Shamgar Ben-Eliyahu from the School of Psychological Sciences and Sagol School of Neuroscience at Tel Aviv University and Prof. Oded Zmora from Assaf Harofe Medical Center.

Immunotherapeutic treatment is a medical treatment activating the immune system. One such treatment, for example, is injecting substances with similar receptors to those of viruses and bacteria into the patient’s body. The immune system recognizes them as a threat and activates itself, thus it can prevent a metastatic disease.

Prof. Ben-Eliyahu explains: Surgery for the removal of the primary tumor is a mainstay in cancer treatment, however the risk of developing metastases after surgery is estimated at 10% among breast cancer patients, at 20%-40% among colorectal cancer patients, and at 80% among pancreas cancer patients.

According to Prof. Ben-Eliyahu, when the body is under physiological or psychological stress, such as a surgery, groups of hormones called prostaglandin and catecholamine are being produced in large quantities. These hormones suppress the immune system cells’ activity, and thus indirectly increase the development of metastases. Additionally, these hormones help tumor cells left after the surgery to develop into life threatening metastases. Thus, exposure to those hormones cause tumor tissues to become more aggressive and metastatic.

“Medical and immunotherapeutic intervention to reduce psychological and physiological stress, and activate the immune system in the critical period before and after the surgery, can prevent development of metastases, which will be discovered months of years later,” stresses Prof. Ben-Eliyahu.

Prof. Ben-Eliyahu adds that anti-metastatic treatment today skips the critical period around the surgery, thus leaves the medical staff to face the consequences of treating progressive and resistant metastatic processes, which are much harder to stop. Prof. Ben-Eliyahu’s research contradicts the assumption, widespread in the medical community, according to which, just like in chemo and radiotherapy, it is not recommended to give cancer patients immunotherapeutic treatment in the month before and after the surgery.

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An international research team, headed by Dr. Tali Ilovitsh from the Biomedical Engineering Department at Tel Aviv University, developed a noninvasive technology platform for gene delivery into cancer cells (breast cancer). The technique combines ultrasound together with tumor-targeted microbubbles. Once the ultrasound is activated, the microbubbles explode like smart and targeted warheads, creating holes in cancer cells’ membranes, and enabling the gene delivery. The two-year research was recently published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS).

Dr. Ilovitsh developed this breakthrough technology during her post doctorate research at the lab of Prof. Katherine Ferrara at Stanford University. The technique utilizes low frequency ultrasound (250 kHz) to detonate microscopic tumor-targeted bubbles. In vivo, cell destruction reached 80% of tumor cells.

Dr. Ilovitsh explains: “Microbubbles are microscopic bubbles filled with gas, with a diameter as small as one tenth of a blood vessel. At certain frequencies and pressures, sound waves cause the microbubbles to act like balloons: they expand and contract periodically. This process increases the transfer of substances from the blood vessels into the surrounding tissue. We discovered that using lower frequencies than those applied previously, microbubbles can significantly expand, until they explode violently. We realized that this discovery could be used as a platform for cancer treatment and started to inject microbubbles into tumors directly.”

Dr. Ilovitsh and the rest of the team used tumor-targeted microbubbles, that were attached to tumor cells’ membranes at the moment of the explosion, and injected them directly into tumors in a mouse model. “About 80% of tumor cells were destroyed in the explosion, which was positive on its own,” says Dr. Ilovitsh. “The targeted treatment, which is safe and cost effective, was able to destroy most of the tumor. However, it is not enough. In order to prevent the remaining cancer cells to spread, we needed to destroy all of the tumor cells. That is why we injected an immunotherapy gene alongside the microbubbles, which acts as a Trojan horse, and signaled the immune system to attack the cancer cell.”

On its own, the gene cannot enter into the cancer cells. However, this gene aimed to enhance the immune system was co-injected together with the microbubbles. Membrane pores were formed in the remaining 20% of the cancer cells that survived the initial explosion, allowing the entry of the gene into the cells. This triggered an immune response that destroyed the cancer cell.

“The majority of cancer cells were destroyed by the explosion, and the remaining cells consumed the immunotherapy gene through the holes that were created in their membranes. The gene caused the cells to produce a substance that triggered the immune system to attack the cancer cell. In fact, our mice had tumors on both sides of their bodies. Despite the fact that we conducted the treatment only on one side, the immune system attacked the distant side as well.”

Potential treatment for brain diseases such as Parkinson’s and Alzheimer’s

Dr. Ilovitsh says that in the future she intends to attempt using this technology as a noninvasive treatment for brain related diseases such as brain tumors and other neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. “The Blood-Brain barrier does not allow for medications to penetrate through, but microbubbles can temporarily open the barrier, enabling the arrival of the treatment to the target area without the need for an invasive surgical intervention.”

Photo: Dr. Tali Ilovitsh

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