Could you imagine if the scientists of today were able to produce a 100% percent effective treatment of all cancers? Researchers at the Children’s Hospital of Philadelphia (CHOP) have made a discovery that brings us one step closer. They had a breakthrough in the treatment of neuroblastoma, an aggressive solid cancer often found in children. When neuroblastoma is discovered in a patient’s nervous system, it is disguised so the immune system won’t attack it. The researchers have found that with the help of engineered CAR-T cells, treatment is possible for some leukemias and solid cancers, and hopefully every cancer in the future. T cells created in your body come from the thymus and have the sole purpose of floating around your body until they recognize a foreign antigen on the surface of a cell. They then get to work killing the host cells and activating other immune cells. Cytokines are released, creating a cell-mediated immunity. But because cancer cells do not appear as foreign to our immune systems, they are able to grow unchecked and can kill the patient. CAR-T cells are made from the patient’s own T cells and are “re-engineered” to see certain proteins on the surface of a cancer cell as foreign. When the CAR-T cells are searching for a cancer cell, they locate fragments of the proteins which are normally used as indicators through peptides on the major histocompatibility complex(MHC). The CAR-T cell then attacks cancer and hopefully kills the cancer cell. Neuroblastoma has proven difficult to cure with immunotherapy due to its low MHC levels. Neuroblastoma is a tumorous cancer that is most commonly found on the adrenal glands, but it is classified as an aggressive tumor due to its ability to metastasize. It is driven by modifications of gene expression that advance uncontrollable tumor growth.
This recent advances in CAR-T therapy have led to breakthroughs in the treatment of leukemia, but the CHOP researchers are focused on neuroblastoma. Neuroblastoma presents a tricky challenge of how to connect CAR-T cells to destroy the cancer cell. The reason for this problem is that most of the proteins that the cell requires for survival and the growth of the tumor are inside the nuclei or the cell itself. After much research, they discovered peptides on the surface of the cell that can be targeted by peptide-centric chimeric antigen receptors (PC-CARS), activating the immune response to destroy the tumor. This is very similar to the receptor-mediated endocytosis we have studied in class. Two cells come together by recognizing indicators on the outside of the cell. Pushing through all the obstacles presented by the difficulty of locating and connecting with a neuroblastoma cell, the researchers at CHOP wanted to ensure that the CAR-T cells they sent into a patient’s body did not attach to similar peptides that exist in normal tissue, to avoid cross-reactivity. To do this, the researchers got rid of the MHC molecules present on the neuroblastoma cell to determine which peptides were present and at what population levels. They used a genomic database to do this. To pinpoint a perfect CAR-T cell, they filtered the peptides against the database of MHC peptides on normal human tissues, thus destroying any CAR-T that targeted a peptide with a parent gene from normal tissues. The final peptide discovery was an unmutated peptide of neuroblastoma cells that comes from the PHOX2B, which is a neuroblastoma dependency gene. They created a PC-CAR that was targeted to attack cells with this peptide on its surface. They discovered that not only does it locate the cancer cell, but it is able to do so with patients of more diverse genetic lineages. After this discovery, the researchers decided to first test their theory on mice, to prove that the PC-CAR can completely destroy the neuroblastoma tumors while not attacking normal cells in the mouse.
This subject is very important to me, as I have had family members pass from cancer. My father’s work in biopharmaceuticals has imparted a deep understanding of cancer. Many long car rides to sports games listening in on conference calls has not only given me a grander understanding of the world of business but also how it can relate to science and beyond. This discovery is vital to the continuation of the world facing all the diseases and struggles that come with life.