Cancers remain a major cause of significant morbidity and mortality worldwide. While a great deal of challenges is from delays in a presentation at a health facility, a major source of concern is the limitations in treatment protocols for these cancers and the adverse effect profile of the chemotherapeutic agents which in most cases, are quite enormous. Over the years, several scientific studies have focused on developing an effective treatment option for these malignancies. One of the most promising is the CAR T cell immunotherapy.
CAR T cell immunotherapy
T cells are a subset of immune cells referred to as lymphocytes. They are involved in immune surveillance and the destruction of aberrant cellular components as well as foreign bodies. Chimeric antigen receptor T cells (CAR T cells) are T cells that have been isolated from an individual’s blood and genetically modified in a laboratory to express specific receptors on their surface that enable them to effectively seek out and destroy cancer cells. These “supercharged” immune cells attack cancer cells when transfused back into the individual’s system.
Difficulties with CAR T cell immunotherapy
This therapy has shown promising signs in the management of blood malignancies but not so much for the management of solid tumors. Beatrice Greco, a member of the Innovative Immunotherapies Unit at IRCCS San Raffaele Scientific Institute, in a statement in Science Translational Medicine says that this therapy showed great success in patients with B cell cancers that are refractory to conventional treatment but showed poor demonstration of efficacy in human solid tumors. According to her, virtually all solid tumors are resistant to the therapy.
Factors responsible for diminished efficacy in solid tumors
Findings by Greco and his team posit that solid tumors shield themselves in a sugar coating that protects them from the attack of the CAR T cells. Their findings show that multiple malignancies express extracellular N-glycans whose quantity has a negative correlation with susceptibility to CAR T cell attack. N-glycosylation is an enzyme-mediated process that involves the transfer of an oligosaccharide unit to an amino acid receptor. This forms a chain made up of multiple units of N-glycosylated sugars that eventually encase the cancer cells. This is particularly evident in pancreatic cancer.
Sugarcoating is not the only factor responsible for the resistance. It is also known that the environment of these tumors also reduces the effective infiltration of tumors by the CAR T cells. This is in addition to the finding that the tumor cells possess antigens that CAR T cells can readily recognize and move in on.
Current studies aimed at by-passing this hurdle
Animal model studies currently happening show a glimmer of hope towards a lasting solution to this sugar problem. Greco believes that adding anti-sugar moieties – which would serve as torpedoes that will break up the sugar chain, along with the CAR T cells will improve the killing function of the immune cells. This procedure leverages the high metabolic needs of the tumors to inhibit the N-glycan synthesis. The anti-sugar utilized in this process is 2-deoxy-D-glucose and was shown to be quite effective in mice. These findings if correctly deployed will significantly see improvements in the management of solid tumors like bladder, lung, and ovarian cancers.
There appears to be hope at the end of the tunnel for the management of solid tumors using CAR T cell immunotherapy. According to Greco, this therapy when combined with the disruption of tumor N-glycosylation increases the magnitude of response to the therapy.