Since the advent of chimeric antigen receptor therapy (CAR-T cell therapy) and its successful use in clinical practice, the toxicity and side effects associated with CAR-T cell therapy, including cytokine release syndrome (CRS), neurotoxicity, etc., have become the focus of researchers. The resulting symptoms like fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty in breathing may cause the CAR-T cell therapy to be suspended and, in severe cases, even endanger the patient’s life.

In response to this problem, different companies and research institutes have adopted different strategies to improve the effectiveness of CAR-T cell therapy.

Recently, Poseida's new BCMA CAR-T cell therapy shows better safety, which may benefit from the following two points - Stem memory TSCM cells and unique a non-viral genetic engineering technique called PiggyBac DNA modification.

Known as the largest and most advanced comprehensive medical system in the United States, Mayo Clinic is featured by its continuous innovation of medical education and world-leading medical research. You may wonder what kind of strategy Mayo Clinic has taken to tackle the same problem. Next we will find out.

GM-CSF inhibitor (lenzilumab)

Recent studies have shown that monocytes and macrophages lead to the development of CRS and neurotoxicity following CAR-T cell therapy. Therefore, the idea of the Mayo Clinic researchers is to find out whether inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) can decrease the toxicity associated with CAR-T cell therapy.

In their formal study, the use of the GM-CSF inhibitor lenzilumab in vitro and in vivo did not affect the function of CAR-T19. Receiving patient-derived T-cell xenografts and using lenzilumab, CAR-T19 cells proliferated and control over leukemia was more persistent.

GM-CSF inhibition enhances anti-tumor activity of CAR-T cells in vivo in a xenograft model

In CRS and neuroinflammatory (NI) primary acute lymphoblastic leukemia (ALL) xenograft models, inhibition of GM-CSF reduces myeloid T cell infiltration in the central nervous system, while greatly reducing NI and preventing CRS. Then, they used CRISPR/Cas9 to produce GM-CSF-deficient CAR-T19 cells in an attempt to explore the function of GM-CSFk/o's CAR-T19 cells. As a result, GM-CSFk/o CAR-T19 cells ensured normal function compared to CAR-T19 cells, and enhanced anti-tumor effects in vivo with an improved overall survival rate.

Thus, they demonstrated that inhibition of GM-CSF can possibly eliminate CRS and NI while enhancing CAR-T cell function. This research was published in Blood, entitled “GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts”. A clinical phase 2 study of its CAR-T19 cell therapy in combination with lenzilumab is under planning.

AXL inhibitor (TP-0903)

The response rate of CAR-T cell therapy varies from disease to disease, and increasing the effectiveness of CAR-T cell therapy against tumors has always been an important issue. In response to this problem, a strategy proposed by researchers at the Mayo Clinic is CAR-T cell therapy in combination with TP-0903, which is an oral AXL inhibitor at the clinical stage 1.

As is known, AXL is expressed in tumor cells and adjacent immune cells (including dendritic cells, macrophages, NK cells) and is a key driver of tumor cell immune escape and drug resistance. Thus, TP-0903 enhances the efficacy of CAR-T cells in attacking tumor cells. However, the end result may require more research and clinical trials.

Conclusion
In the face of major diseases such as cancer, life is very small, and the strength of a scientist is weak. But every small, recognized discovery and advancement in life sciences and clinical medicine is a big step in the journey of humans to explore the mysteries of disease and improve health.

Author's Bio: 

With over twenty years of experience, BOC Sciences is a reliable chemical supplier for various research institutions across the globe. By 2018 this year BOC Sciences has reached nearly 5 million customers in 29 countries. Ranking first among its selling list, small molecule inhibitors are a well-established class of potential useful drugs. Over 30, 000 inhibitors are available at BOC Sciences, which can be applied to varied fields of Medical and Pharmaceutical research, such as Neurological Disease, Cancer, Metabolic Disease and so on. Except for inhibitors, BOC Sciences also provides varieties of fluorine compounds, APIs, metabolites and impurities to push forward scientists’ research efforts.