Human immunity is a beautifully complex system. Students of science around the world groan at the mention of immunology because of its never-ending overlapping cell types and pathways. Those groans are being replaced with genuine interest as immuno-oncology becomes a reality. Excitement exploded in 2017 when two cancer treatments that modify immune cells (CAR-T) were approved by the U.S. Food and Drug Administration (FDA). These approvals have paved the way for over 200 hopeful cancer treatments that modify immune cells to begin clinical testing.
Both of the recent FDA approvals for cancer treatment work in a similar way. White blood cells are extracted from the blood, engineered viruses are used to install additional DNA in the cells that create a cancer-seeking surface protein on the white blood cells, and those modified cells are replaced in the body to seek out and kill cancer. This may sound simple but the immune system is a complex entity that requires subtle variances. Although complex these new treatments are miles ahead of chemotherapy and traditional means of cancer therapy.
Yescarta and Kymriah (the first two FDA approved CAR-T treatments) are miracle treatments but they are not a cure. 59% of patients are estimated to still be in remission at 9-12 months. It should be noted that these treatments were only implemented for patients whose cancer already failed to respond to other therapies, so 100% of these patients were highly likely to pass away from their cancer when they were given a last chance with CAR-T. A nearly 60% response for these patients is remarkable. With time immuno-oncology should become a first-line defense. Scientists and doctors are looking forward to increasing safety and efficacy that will come with second and third-generation therapies.
How CAR-T works:
The immune system is a complex thing and adding one surface antigen to immune cells is not nearly subtle enough to create the levels of safety and efficacy we hope for from a treatment. The predictable thing to do next is to add two surface antigens or three, which require the presence of all the targets to be activated. While much of the clinical pipeline is a repeat of the single antigen strategy focused on different indications a few companies are working on the cutting edge to improve the sector as a whole. Schemes like molecular switches controlled by multiple antigens are emerging to solve issues with delivery, safety, and efficacy.
One of the things we know about cancer is that there is quite often more than one mutation in a single tumor. In fact, as the tumor cells multiply more differentiation can occur. So the characteristics of the exterior of the tumor may not be true about the center or origin of the mass. It is postulated by many scientists that the underpinning of most cancers is a genetic instability or a cell line that has failed genetic machinery leading to mutations in the thousands. Not all of these mutations are targetable but many of them represent subtle opportunities to differentiate normal cells from those which are cancerous. The scientific community does not yet possess the capability of delivering those subtleties within a gene delivery package. To solve this specificity issue a few teams are leaning back on the immune system which evolved over eons for this type of subtle differentiation.
We know the immune system has the inherent ability to differentiate between normal cells and potentially cancerous cells. We also know that cancer can evade that system by making subtle changes, So how do we attack a complex and subtle monster inside a complex system?
American Gene Technologies (AGT) is close to an answer. AGT has developed a way to stimulate and increase the activity of the immune system’s innate cancer clean up system, jump starting an attack on the cells that oncologists identify as cancerous (ImmunoTox program). Injecting a lentiviral vector at the tumor site, AGT upregulates a particular phosphoantigen in the tumor itself. This phosphoantigen is an activation signal for a group of cells which naturally surveil the body for malignancy, gamma delta (𝝲𝞭) T cells. Under normal circumstances, 𝝲𝞭 T cells are activated by the phosphoantigen and query separate stress molecules on the surface of a cell to decide whether or not to kill those cells. Every day 𝝲𝞭 T cells mop up cancerous cells before they can become problematic for the body.
AGT stimulates this subtle and selective process. In animal studies, the technology is demonstrating 85% complete remission with abscopal effect in several solid epithelial tumor types. In the animals, activated by the phosphoantigen, the 𝝲𝞭 T cells surveil the body in an activated “killing state” clearing remote tumors, metastases, and unrelated tumors. Click here to read more about its 𝝲𝞭 T cells program, ImmunoTox.
AGT is honing this subtle process in preclinical studies and is looking forward to entering into clinical trials in the near future. The precise activation of the natural processes of the immune system represents an enormous opportunity for the future of immuno-oncology and cancer treatment in general. Most importantly, the activation of the immune system directly at the site of the tumor offers the ability to use the same treatment across what have traditionally been separate types of cancer. AGT plans to start human trials in hepatocellular carcinoma (liver cancer) as a proof of concept, but will move into other solid epithelial tumors as soon as human safety and efficacy are established.
How AGT’s ImmunoTox 𝝲𝞭 T cells therapy works to kill cancer:
With the arrival of CAR-T, many scientists have gained a new, broadened vision for the future of oncology. While CAR-T is an enormous accomplishment, there is still much that can be accomplished to increase the efficacy and safety with new approaches to immuno-oncology. We will not be satisfied until we can declare cancer a manageable disease.