Science sub-journal: New breakthrough in pancreatic cancer treatment!

In order to replicate the success of CAR-T in treating blood cancers, a key direction of solid tumor research is to enable engineered immune cells to better target tumors

Now, researchers from the IRCCS San Rafael Institute of Science in Italy have come up with a way to do just that

They found that a sugar-based structure called N-glycan, expressed on the surface of pancreatic tumor cells, protects the cancer cells from being killed by CAR-T cells

Disruption of the "sugar coating" on the tumor surface with the glucose/mannose analog 2-deoxy-D-glucose (2DG) enhanced the killing ability of CAR-T against different mouse pancreatic cancer models and showed in vitro experiments against other Cancer has a good effect

The findings were published Jan.

Glycosylation, the process by which sugar-based molecules attach and modify proteins, plays an important role in cellular processes

Cancer cells tend to exhibit aberrant glycosylation and more diverse expression of glycoglycan coatings than healthy cells

Of these, an increase in N-glycans is one of the most common alterations found in cancer

Pancreatic cancer has an extremely poor prognosis and limited treatment options

In this study, the team blocked the branched-chain N-glycans of pancreatic tumor cells by disrupting the MGAT5 gene, which encodes a key enzyme in the synthesis of the outer glycosyl membrane, and then targeted CD44v6 (a type of CAR-T cell) hyperglycosylated proteins) to attack cancer cells

CAR-T cells showed significantly enhanced antitumor activity: cytolytic activity and increased production of cytokines IFN-γ and TNF-α

By delving into the mechanisms behind the improved efficacy, the researchers discovered that N-glycans interfere with immune synapse formation

CAR relies on this synapse to activate T cells and perform their functions, that is, CAR-T cells and tumor cells combine to kill tumor cells through the immune synapse

The team then tried to inhibit N-glycosylation with 2DG because it accumulates more easily in tumor cells than in healthy cells

In two mouse models of pancreatic cancer xenografts, the combination of 2DG and CAR-T cells showed the best tumor control, significantly extending the survival time of the mice compared with monotherapy

What's more, in mice that also received 2DG, T cells entering the tumor showed a reduced state of exhaustion, and the expression of some immunosuppressive markers such as TIM-3 and PD-1 was reduced

We know that sustained antigen stimulation and expression of inhibitory receptors may lead to T cell depletion, which is a major obstacle to the efficacy of CAR-T cells against solid tumors
.

These findings suggest that CAR-T binding to 2DG not only enhances tumor clearance, but also allows CAR-T cells to escape immune checkpoint inhibition
.

In addition to pancreatic cancer, the addition of 2DG also helps to improve the killing ability of CAR-T against other hyperglycosylated tumors (CD44v6 CAR-T alone is not effective), including ovarian cancer and bladder cancer
.

In fact, after successfully combating hematological tumors, scientists have been actively seeking effective solutions to overcome the obstacles that prevent CAR-T from working in solid tumors:

To address the lack of CAR targeting of tumor-specific antigens, a research team at Children's Hospital of Philadelphia (CHOP) at the University of Pennsylvania has developed a new type of CAR-T called "peptide-centric" CAR-T (PC CAR-T)
.
) This therapy breaks the limitation that CAR-T can only target tumor cell surface antigens
.

The advantage of CAR-T is that it can target antigens in tumor cells through CAR-T, which is expected to significantly expand the cancer types and patient populations for CAR-T therapy
.

Canadian biotech company Oncolytics Biotech is investigating an oncolytic virus called pelareorep to alter the malignant tumor microenvironment that may suppress T cell activity
.

Research in collaboration with the Mayo Clinic shows that CAR-T cells with an oncolytic virus enhance antitumor activity in mice with solid tumors
.

In this latest study, researchers at the San Rafael Institute of Science believe that breaking the sugar barrier around tumor cells by improving CAR-T cell activation and alleviating CAR-T cell exhaustion is the key to overcoming solid tumor resistance to CAR-T cells.
The key to T resistance
.
A promising strategy for the treatment of drug resistance
.

Collectively, this finding suggests that CAR-T combined with 2DG can combat multiple layers of tumor resistance, including insufficient tumor infiltration and disruption of inhibitory pathways
.

references:

1# Stop sugar coating cancer cells to empower CAR-T therapy in solid tumors (Source: FIERCE Biotech)
2# Beatrice Greco et al.
Disrupting N-glycanexpression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies.
Science Translational Medicine .
2022.

(Source: Internet, reference only)