The relationships are complex for the immune system elimination of cancer tumors. When tumors are diagnosed as malignant in an early stage, the body’s immune system is often able to recognize the cancer, target the tumor, and eliminate cancerous cells. In fact, modern immunotherapy protocols can use checkpoint inhibitors to harness this newfound ability. But, as patients who suffer with autoimmunity know all too well, the immune system can also malfunction.
After initially discovering that the body’s immune system is always on the lookout for threats from abnormal cells that could be foreign invaders, it made the process of immune monitoring an appealing study in the mid-1950s. Due to its immunosuppressive effects on some carcinogens, researchers were able to demonstrate that the immune system in mice could reject chemically-induced tumors, which initially laid the groundwork for the theory of immune surveillance.
Although treatments were initially able to eliminate harmful pathogens, spontaneous remissions did not occur in athymic mice that lacked T cells that naturally protect the body, thus the interest in immunotherapy temporarily faded. It wasn’t until the discovery of the body’s natural killer cells in the late 20th century that support for the theory of immune-monitoring resurged. After all, the immune system appeared to prevent new tumors from forming into full-blown cancer by destroying the pre-cancerous cells.
Building on decades of findings, the concept of tumor immunoediting evolved and described the dynamic interplay between the tumors and immunity. Described in three phases, it incorporates the system’s ability to eliminate, maintain equilibrium with, or be escaped by cancer cells. This led to a modern understanding that natural killer and T cells play a key role in controlling tumor growth. Not surprisingly, immunocompromised patients are the ones who are more likely to develop cancer, and T cells can also contribute to autoimmune diseases.
Can adverse immune-related events occur?
Yes they can and they do. Cancer cells may develop an “immune escape” through genetic changes that allow them to avoid immune system detection and control. Plus, some tumors suppress the immune response and co-opt immune cells to actually help cancerous cells grow. Unfortunately, cross-reactivity can also occur where the immune system mistakenly attacks healthy tissues, which can lead to immune-related adverse events that are a form of autoimmunity that can happen following immunotherapy. If the immune system becomes overactive when fighting the cancer, it also can lead to autoimmune paraneoplastic disorder that attacks organs and healthy tissues. So, the relationship between immunotherapy and cancer treatment is complex and our therapeutic goals should continue to aim at reversing a tumor’s ability to evade the body’s immune system.
What is Programmed Cell Death Protein-1?
PD-1 inhibitors are a groundbreaking type of immunotherapy that harness the immune system to activate the body’s anti-tumor responses. So, unlike traditional chemotherapy or radiation, PD-1 does not directly attack cancer cells. However, this unique approach has led to impressive results in the treatment of several cancers. As a checkpoint protein on T cells, this programmed cell death protein-1 also helps regulate responses to prevent unwanted damage to healthy cells.
In August of this year, the general manager of the Dallas Cowboys (Jerry Jones) informed the media that he was a ten-year plus survivor of melanoma. The three-time Super Bowl team owner had previously revealed his diagnosis of the invasive skin disease in 2010 but wanted to credit an experimental drug called PD-1 with helping him to achieve Stage IV remission. Now 82 years old, Jones was highly transparent in sharing details about participating in the drug trial therapy that had already proven successful in over 35 percent of cases.
Over the decade that followed his original diagnosis of melanoma skin cancer, Jones underwent four surgical procedures because the highly-invasive form of skin cancer had metastasized. Two surgeries were performed to remove lymph nodes, as metastatic lymph nodes near the original tumor are the most frequent site for cancer spread. In addition, Jones had two additional surgeries to have cancerous tumors removed from his lungs and joined a clinical drug trial at Houston’s MD Anderson Cancer Center for PD-1 immunotherapy.
History of Today’s Biomarker Revolution
Biomarkers were simply not discovered at a single point in time. In fact, the concept of biochemical markers of disease dates back to the mid-nineteenth century when the Bence-Jones protein was found to be produced by cancerous plasma cells in urine. The term “biomarker” was coined in the mid-70s and the understanding quickly grew with advances in technologies like genomics, proteomics, and metabolomics that enabled complex biological processes to be studied. This has indeed helped to shape precision medicine.
Today, these unique markers help doctors to prescribe more effective treatments as the body can distinguish cancer cells and other abnormalities from normal cells. Biomarkers like PD-1 inhibitors are proteins, but genes and genetic mutations can also be useful indicators. Most often biomarkers are identified using abbreviations like TMB that is short for tumor mutational burden, a measure of genomic instability in cancer cells. TMB-H (high tumor mutational burden) identifies cancer cells that have an elevated number of mutations in their DNA.
TMB-H suggests a greater level of genomic instability, which means there is a higher likelihood of producing neoantigens (tumor-specific) that the body’s T cells can recognize as abnormal cells. Although the TMB-H classification is a relatively new biomarker, it is found in solid tumors in the lungs, liver, bladder, kidneys, and head or neck, as well as certain types of skin cancer like melanoma. While tumor markers are not perfect at predicting outcomes, having a high TMB is seen as a promising indicator that the patient may respond favorably to a PD-1 inhibitor.
PD-1 Inhibitors Are Effective in Treating Cancer Tumors
As discussed, PD-1 is a protein found on T cells that acts as an “off switch” after binding to PD-L1 (programmed death-ligand 1) that naturally blocks the interaction and prevents the body’s immune system from attacking cancer cells. By disrupting the signaling pathway, they combine to restore more aggressive T cell activity that results in a stronger anti-tumor immune system response. Checkpoint inhibitors have shown significant success in treating cancers like melanoma, non-small cell lung cancer, and Hodgkin’s lymphoma.
These inhibitors are monoclonal antibodies used to block the normal interaction between PD-1 and PD-L1 proteins and essentially release the brakes on the body’s immune system. Moreover, they have effectively been used in combination with other treatment protocols, such as chemotherapy or radiation to further enhance the effectiveness. As research continues, it is likely that even more uses for such inhibitors will be discovered, expanding the reach for tomorrow’s doctors to treat a wider range of cancers and improve long-term outcomes for cancer patients.
“Another key area of research is exploring the use of biomarkers to predict which patients will respond best to PD-1 or PD-L1 inhibitors,” says Dr. Hans Wolf the founder of WOLFPACC’s Physician Achievement Concept Course.“ This will help doctors select the most appropriate treatment options for each patient by maximizing their chances of success while avoiding unnecessary side effects. It certainly highlights the challenges medical students will face tomorrow in keeping up with today’s ever-changing medical environment.”
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Ongoing clinical trials will continue to test new and improved versions of PD-1 and PD-L1 inhibitors, as well as investigating their use in eliminating different types of malignant tumors that have not yet been studied extensively. Dr. Hans Wolf devoted decades to developing WOLFPACC’s Power 5 Methodology that helps medical students understand how to apply the basic sciences they learned in medical school to the clinical task at hand. Find out today how WOLFPACC can help you apply the knowledge you’ve gained to ensure a successful career in medicine.
Photo credit Tara Winstead
