【Immunity】A new combination of drugs combined with anti-PD-L1! Studies have found that this combination can overcome cancer immunotherapy resistance

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Written by Sophia

Immunotherapy is a way
to treat cancer by reprogramming a patient's immune system to attack tumors.
This advanced approach has greatly influenced the treatment of cancer patients, and there have been cases
of long-term remission.
Although immunotherapy is tumor-selective, it has shown extraordinary therapeutic effects
clinically.

In a new study published Jan.
10 in Immunity led by Douglas Hanahan's group at the Swiss Institute of Experimental Cancer at the Swiss Institute of Experimental Cancer at the Ecole Polytechnique Fédérale de Lausanne, scientists discovered a way to
break down the resistance of neuroendocrine pancreatic cancer mice.
This cancer is very resistant to an immunotherapy called checkpoint blockade, in which patients receive a drug (checkpoint inhibitor) that blocks proteins that normally make the immune response too strong, and also prevents immune cells (T cells) from killing cancer cells
.

https://doi.
org/10.
1016/j.
immuni.
2022.
12.
006

Research background

 01 

The development of cancer immunotherapy has revolutionized the way cancer patients are treated
.
At present, at the forefront of immunotherapy development are immune checkpoint inhibitors, which have been clinically approved
.
Despite abnormalities in remission, most cancer patients either do not respond to immune checkpoint blockade (ICB) or develop resistance to this treatment modality
.
Therefore, immunomodulatory strategies are needed to disrupt this non-reactive mechanism of operation
.

Research progress

 02 

The scientists evaluated an engineered protein-antibody fusion called immune cytokines, which are increasingly used in immunotherapy
.
They focused on the bispecific immune cytokine PD1-IL2v, which can localize tumors, activating killer T cells to attack cancer cells
that drive tumor growth.

Fluorescence microscopy of controlled tumors with PD1-IL2v for the treatment of tumors

The researchers combined the immune cytokine PD1-IL2v with the immune checkpoint inhibitor anti-PD-L1 to enhance anti-tumor immunity against
immunotherapy-resistant tumors.
The authors said that PD1-IL2v is more effective
when combined with immune checkpoint inhibitor anti-PD-L1.
Compared to traditional anti-PD-1 therapies, PD1-IL2v induces stronger anti-tumor T cells by stimulating specific T cell subtypes, and anti-PD-L1 targets and disrupts the barrier established in the tumor microenvironment, namely pre-tumor macrophages and tumor vasculature, which synergistically fight anti-tumor immunity
.

Combining these two molecules improves survival in tumor-bearing mice, producing a longer-lasting therapeutic effect
than the bispecific immune cytokines themselves.
The combination improves treatment outcomes by reprogramming immunosuppressive tumor-associated macrophages and tumor vasculature, making cancers more detectable
by immune cells.

Douglas Hanahan said: "This innovative immunotherapy combination sensitizes PD-1 stem-cell-like T cell-infiltrated immunotherapy-resistant tumors, and PD-1 stem-like T cells have recently been found to be important for maintaining an effective anti-tumor immune response, leading to tumor destruction and thus providing survival benefits
.
" These results provide the rationale for clinical trials designed to evaluate PD1-IL2v and anti-PD-L1 combination therapies
.
”

Research significance

 03 

In conclusion, this study has demonstrated that the delivery of immunostimulatory cytokine IL2v to tumor antigen-expressing CD8 T cells through PD1-IL2v can effectively circumvent the inflammatory barrier and subordinate tumors insensitive to checkpoint inhibitors to immune attack, and this effect can be maintained
by anti-PD-L1.
Notably, the functional effect of anti-PD-L1 is not focused on blocking the PD1 checkpoint
of CD8 T cells.
In contrast, anti-PD-L1 has been shown to target PD-L1 expressed on tumor-infiltrating macrophages and tumor endothelial cells, reprogramming them into pro-inflammatory, antigen-presenting cells that help maintain and enhance dry-sample "resources" and effector CD8 T cell activity triggered by IL2v stimulation delivered by PD1-IL2v, resulting in a combination therapeutic effect
.

Resources:

https://medicalxpress.
com/news/2023-01-drug-combo-cancer-resistance-immunotherapy.
html

https://doi.
org/10.
1016/j.
immuni.
2022.
12.
006

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.

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