Chimeric Antigen Recepter (CAR)-T cell therapy is a personalized immunotherapy that harnesses the patient’s own immune system to combat cancer. It is done by engineering the patient’s T cells to specifically target and attack cancer cells in their body, and it has shown great success in treating various blood cancers such as leukemia.
Treating solid tumors with CAR-T cells, however, has proved much more challenging. This is mainly because solid tumors contain a heterogeneous population of cells, expressing a variety of antigens—many of which are also expressed in healthy cells. Therefore, T cells targeting solid tumors could potentially attack healthy tissue, resulting in serious side effects. In addition, solid tumors create a hostile microenvironment that is difficult for CAR-T cells to infiltrate.
It has been more than 100 years since Dr. William B. Coley, known today as the “Father of Immunotherapy,” made the first recorded attempt to mobilize the immune system as a means of treating cancer (9). Decades later, the discovery of T cells and the vital role they play in the immune system set the groundwork for many new immunotherapy treatments, such as those involving monoclonal antibodies, cytokines, CAR T cells, and checkpoint inhibitors.
The first monoclonal antibody (mAb) was produced in a lab 1975, and the first therapeutic mAb was introduced in the United States to prevent kidney transplant rejection in 1986. The first mAb used in cancer treatment the anti-CD20 mAb, rituximab, was used to treat non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Today therapeutic mAbs have become a mainstay of cancer, autoimmune disease, and metabolic disease therapies and include HERCEPTIN® used to treat certain forms of breast cancer, Prolia used to treat bone loss in post-menopausal women, and Stelara used to treat autoimmune diseases like psoriatic arthritis and severe Crohn disease, among many others. Therapeutic mAbs bind targets with high specificity and affinity and they can recruit effector cells to drive target elimination through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP), making them highly specific, effective therapies.
There are as many different
cancers as there are people with cancer. Unlike infectious diseases, which are
caused by pathogens that are foreign to our bodies (bacteria, viruses, parasites),
cancer cells arise from our body—our own cells gone rogue. Because cancer is a
dysfunction of a person’s normal cells, every cancer reflects the genetic
differences that mark us as individuals. Add to that environmental influences like
diet, tobacco use, the microbiome and even occupation, and the likelihood of
finding a “single” pharmaceutical cure for cancer becomes virtually impossible.
But, while looking for a single cure for all cancers may not be a fruitful activity, defining a best practice for understanding the genetic and protein biomarkers of individual tumors is proving worthwhile.
Bacteria make you sick. The idea that bacteria cause illness has become ingrained in modern society, made evident by every sign requiring employees to wash their hands before leaving a restroom and the frequent food recalls resulting from pathogens like E. coli. But a parallel idea has also taken hold. As microbiome research continues to reveal the important role that bacteria play in human health, we’re starting to see the ways that the microbiota of the human body may be as important as our genes or environment.
The story of how our microbiome affects our health continues to get more complex. For example, researchers are now beginning to understand that the composition of bacteria residing in your body can significantly impact the effects of therapeutic drugs. This is a new factor for optimizing drug response, compared to other considerations such as diet, interaction with other drugs, administration time and comorbidity, which have been understood much longer.
Salmonella. Streptococcus. Shigella. The most well-known bacteria are those that cause disease. Our relationship with them is one of combat. With good reason, we look for ways to avoid encountering them and to eliminate them when we do meet.
But not all bacteria are bad for us. Of course we have known for years that we are colonized by harmless bacteria, but recently, studies on the human microbiome have revealed many surprising things about these bacterial tenants. Studies are showing that the teeming multitudes of organisms living in and on the human body are not just harmless bystanders, but complex, interrelated communities that can have profound effects on our health.
Three studies published last week in Science add more to the growing body of microbiome surprises, showing that certain gut bacteria are not only good for us, but may even be required for the effectiveness of some anti-cancer immunotherapies.
Therapeutic monoclonal antibodies (MAbs) are inherently heterogeneous due to a wide range of both enzymatic and chemical modifications, such as oxidation, deamidation and glycosylation which may occur during expression, purification or storage. For identification and functional evaluation of these modifications, stability studies
are typically performed by employing stress conditions such as exposure to chemical oxidizers, elevated pH and temperature.
To characterize MAbs, a variety of analytical techniques are chosen, such as size exclusion chromatography and ion exchange chromatography. However, due to the large size of the intact MAbs, these methods lack structural resolution. Often, the chromatographic peaks resolved by SEC and IEC methods are collected and further analyzed by peptide mapping to obtain more detailed information. Peptide mapping, in which antibodies are cleaved into small peptides through protease digestion followed by LC–MS/MS analysis, is generally the method of choice for detection and quantitation of site-specific modifications. However sample preparation and lengthy chromatographic separation make peptide mapping impractical for the analysis of large numbers of samples. In contrast to peptide mapping analysis, the middle-down approach offers the advantage of high-throughput and specificity for antibody characterization.
Over the last few years, human microbiome studies have revealed fascinating connections between our colonizing microorganisms and ourselves—including associations between gut bacterial populations and obesity, disease susceptibility, and even mood. The relationship between us and our microbial colonists—once considered completely benign, is now being revealed as an intricate, complicated partnership with the potential to redefine who “we” are in fundamental ways.
Two papers published back-to-back in the November 27 issue of Science add further to this growing body of knowledge—reporting a new and unexpected connection between gut bacterial species and the effectiveness of cancer immunotherapies in mice. The work suggests one reason why such treatments are effective in some circumstances, but not others. Both papers report that the presence of specific bacterial populations may be required for the efficacy of certain treatments, and raise the intriguing question “Could the composition of bacteria in the gut be manipulated to enhance the effectiveness of cancer treatments?” Continue reading “Unexpected connections: Gut bacteria influence immunotherapy outcomes”
Immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4 are promising new immunotherapy targets for the treatment of cancer and autoimmunity. Immune checkpoint reporter-based bioassays provide a simple, consistent, and reliable cell-based assay to measure Ab function throughout the drug development pipeline.
The brief chalk talk below describes the assay principals of the reporter-based bioassay that monitors the functional blockade of PD-1/PD-L1 interactions.
For decades scientists have been trying to harness the power of our immune system to fight cancer cells. It is not impossible to imagine that our immune system, which is sophisticated enough to fight against a multitude of invaders that threaten our health, should be able to tackle a deadly disease such as cancer. This formed the basis of testing a new type of cancer treatment known as immunotherapy. Immunotherapy for cancer means developing treatments to harness your immune system and using your own immune system to fight the cancerous cells.
But in reality it was hard to make this work. Because, as scientists discovered recently, cancer outsmarts the immune system by wearing a kind of “invisibility cloak”. Cancer is able to fool the immune system from recognizing that it is the enemy and in effect keeps the immune system from destroying it.
In a breakthrough discovery scientists have found a way around this treachery.
The breakthrough is in therapies called ‘checkpoint inhibitors’. Checkpoint inhibitors block the mechanisms that allow some tumor cells to evade the immune system. The drugs ensure that cancer cells are no longer be shielded from the immune system defenses, but are instead recognized as “foreign”. Continue reading “Removing Cancer’s Cloak of Invisibility”
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