New breakthrough in the treatment of pancreatic cancer with CAR-T
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New breakthrough in the treatment of pancreatic cancer with CAR-T
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New breakthrough in the treatment of pancreatic cancer with CAR-T.
To replicate the success of CAR-T therapy in blood cancers, a key direction in solid tumor research is enabling 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 glycosyl structure called N-glycan, expressed on the surface of pancreatic tumor cells, protects the cancer cells from killing by CAR-T cells.
Disruption of the “sugar coating” on the tumor surface with a glucose/mannose analog, 2-deoxy-D-glucose (2DG ), enhanced CAR-T killing in different mouse models of pancreatic cancer and showed in vitro experiments show good efficacy against other cancers.
The findings were published Jan. 19 in Science Translational Medicine. The discovery could pave the way for designing better CAR-T cell therapy strategies against pancreatic cancer and other solid tumors.
Glycosylation, the process by which sugar-based molecules attach and modify proteins, plays an important role in cellular processes.
Cancer cells tend to exhibit abnormal glycosylation and a more diverse expression of their glycan coat compared to 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. CAR-T therapy is also less effective for its treatment, and more complex strategies need to be developed.
In this study, the team blocked branched-chain N-glycans in pancreatic tumor cells by disrupting the MGAT5 gene, which encodes a key enzyme for synthesizing the outer glycosyl membrane, and then targeted CD44v6, a hyperglycosylated protein) of CAR-T cells to attack cancer cells.
CAR-T cells showed significantly enhanced antitumor activity: cytolytic activity and increased production of cytokines IFN-γ and TNF-α (bottom panel).
Source: Science Translational Medicine
By delving into the mechanisms behind the improved efficacy, the researchers found that N-glycans interfere with immune synapse formation.
CAR relies on this synapse to activate T cells and exert their functions, that is, CAR-T cells and tumor cells combine to kill tumor cells through immune synapses.
The team then attempted to inhibit N-glycosylation with 2DG, which accumulates in tumor cells in preference to healthy cells.
In two pancreatic cancer xenograft mouse models, the combination treatment of 2DG and CAR-T cells showed the best tumor control, significantly prolonging the survival time of mice compared with monotherapy.
Source: Science Translational Medicine
More importantly, in mice also treated with 2DG, T cells entering the tumor exhibited a reduced state of exhaustion and decreased expression of some immunosuppressive markers such as TIM-3 and PD-1 (bottom panel).
We know that persistent 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.
Source: Science Translational Medicine
These findings suggest that the combination of CAR-T with 2DG not only improves tumor clearance but also allows CAR-T cells to escape immune checkpoint inhibition.
In addition to pancreatic cancer, the addition of 2DG also helped to improve the killing ability of CAR-T against other highly glycosylated tumors (CD44v6 CAR-T alone did not work well), including ovarian and bladder cancers.
In fact, following the successful battle against hematological tumors, scientists have been actively seeking effective solutions to overcome the obstacles that hinder the role of CAR-T in solid tumors:
To address the lack of tumor-specific antigens that suitable CARs can target, a research group at Children’s Hospital of Philadelphia (CHOP) at the University of Pennsylvania has developed a novel 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 advantages of CAR-T can achieve the targeting of tumor intracellular antigens by CAR-T, which is expected to significantly expand the cancer types and patient populations that CAR-T therapy can treat.
Canadian biotech 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 showed that CAR-T cells armed with the oncolytic virus enhanced 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 is the key to overcoming solid tumor resistance to CAR-T by improving CAR-T cell activation and alleviating CAR-T cell exhaustion. A promising strategy for the treatment of drug resistance.
Collectively, this finding suggests that CAR-T in combination 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.
New breakthrough in the treatment of pancreatic cancer with CAR-T
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