CREATE 'OFF-ROAD' IMMUNE CELLS THAT ATTACK DIFFERENT TYPES OF CANCER IN MICE

 

Genetic engineering of T cells causes these cells to attack different types of solid tumors.

   Cancer immunotherapy is one of the most revolutionary and innovative treatments against this set of more than 200 different diseases, which are the second leading cause of death in the world. The pioneering scientists in this novel branch of medicine received the Nobel Prize in Medicine in 2018 for the discovery of oncology therapies based on inhibition of immune system barriers.

   Under normal conditions, the immune system is able to recognize and destroy normal cells that develop into cancers before they multiply and expand through the body. However, this function is not perfect and sometimes cancer cells manage to evade the response of this defensive system and generate a tumor. What the different immunotherapy strategies are looking for is precisely to strengthen the immune system to selectively attack these cancer cells.

   An option to achieve this goal is to genetically modify T cells (specialized immune cells to destroy tumor cells or infectious agents) to recognize specific tumors. These modified T cells, called CAR-T, are already a reality in clinical practice, where they are given to treat blood cancers such as leukemias and myeloma that do not respond to conventional treatment.

   Unfortunately, there are, for now, no immunotherapies that are actually effective for solid tumors in humans. Unlike blood cancers, lymphocytes modified to attack cancer cells of solid tumors lose their effectiveness for multiple reasons. These tumors are, on the one hand, much less accessible to lymphocytes and, on the other hand, are very heterogeneous, expressing molecules on their surface that can vary greatly from one tumor to another, making it difficult for lymphocytes to recognize them. In addition, solid organ cancers are able to activate mechanisms that inactivate the response of T cells. It is a process called "exhaustion" in which lymphocytes no longer recognize specific molecules of tumors and therefore cease their fight against them.

   Multiple research groups around the world are studying how to overcome the above obstacles to creating effective immunotherapies against solid tumors. Recently, scientists in Virginia , USA, have created genetically engineered T cells that have the ability to attack different types of solid tumors in mice. The results have recently been published in the journal Cancer Research.

   Researchers genetically modified T cells to express gene 7 associated with melanoma differentiation, better known as MDA-7. It is a human tumor suppressor gene involved in cell suicide processes (apoptosis), differentiation and cell growth. Previously, several studies had identified that this gene produces a protein (cytokine) called interleucine 24 (IL-24) that has the ability to induce selective death of very diverse cancer cells, without affecting normal cells.

   This study found that mouse lymphocytes modified with the gene had a greater ability to cause oxidative stress damage and death not only in cells in two types of solid tumors (prostate cancer and melanoma in mice), but also in cancer cells that were in remote metastases (and that cause the majority of deaths in patients). In other words, genetic engineering achieved "off-road" T cells, more effective against tumors with different and heterogeneous characteristics, expressing molecules on the surface of cancer cells that serve the immune system to recognize them. This would reduce the risk of tumors developing strategies to escape T lymphocyte attack, as in phenomena such as "exhaustion."

   As a result, mice with cancer who had been given modified T cells had significantly smaller tumors than those who had received unchanged lymphocytes and also showed more limited metastasis. In addition, these modified lymphocytes were more effective in blocking the formation of blood vessels around tumors, making it difficult to grow, as they need this source of oxygen and nutrients to survive.

   Another additional advantage detected by the researchers is that lymphocytes expressing IL-24 were able to better withstand the harsh conditions of the tumor's microenvironment and managed to multiply over time. Increased cytokine production with antitumor effects such as tumor necrosis factor alpha and gamma interferon, which associated further infiltration into the tumor of different lymphocytes beyond genetically modified ones, such as collaborating lymphocytes (CD4) and cytotoxic lymphocytes (CD8), was observed.

   The authors are aware of the limitations of the results as tumors occur in mice and plan to investigate the anticancer effects of MDA-7/IL24 lymphocytes with human cancers. Currently, other scientists are evaluating the anticancer potential of administering MDA-7/IL-24 directly into tumors by using adenoviral vectors in patients with advanced cancers in clinical trials.