Immunity: Drug combinations can break cancer resistance to immunotherapy!

Immunotherapy is a treatment
of 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.

Still, many patients still don't respond to immunotherapy, or even if they do, the effects are temporary, illustrating how important it is to better understand the mechanisms that lead cancer to
resist this treatment.

In a new study, scientists have discovered a way to break down drug resistance in mice with neuroendocrine pancreatic cancer
.
This cancer is strongly 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, but also prevents immune cells (T cells) from killing cancer cells
.

The study, led by Douglas Hanahan's group at the EPFL Swiss Institute for Experimental Cancer Research, included the Ludwig Cancer Institute, Lausanne University Hospital (CHUV), the Swiss Institute of Bioinformatics and Roche
.

The scientists evaluated an engineered protein-antibody fusion called an immune cytokine, which is increasingly used in immunotherapy
.
They focused on the bispecific immune cytokine PD1-IL2v, Roche's latest immune cytokine that can enter tumors, where it activates killer T cells to attack cancer cells
that drive tumor growth.

The researchers combined the immune cytokine PD1-IL2v to the immune checkpoint inhibitor anti-PD1-I1, thereby enhancing anti-tumor immunity against immunotherapy-resistant tumors
.
"[PD1-IL2v] is more effective when combined with immune checkpoint inhibitors against PD1-I1," the authors wrote
.

"Compared to traditional anti-PD1-I therapies, PD1-IL2v induces stronger and more specific anti-tumor T cell expansion by stimulating specific T cell subtypes, while anti-PD1-I1 targets and disrupts the barrier established in the tumor microenvironment, namely pro-tumor macrophages and tumor vascular system, which together counteract anti-tumor immunity
.
"

Combining these two molecules improves survival in tumor-bearing mice, producing a longer-lasting therapeutic effect
than using bispecific immune cytokines alone.
This combination improves treatment outcomes by reprogramming immunosuppressive tumor-associated macrophages and tumor vascular systems, making cancer more easily "detected" by immune cells
.

"This innovative immunotherapy combination sensitizes PD-1-infiltrated immunotherapy-resistant tumor^+stem cell-like T cells has recently been found to be important for maintaining an effective anti-tumor immune response, leading to tumor destruction and thus reaping survival benefits," said Douglas Hanahan, "These exciting results provide a theoretical basis for clinical trials aimed at evaluating PD1-IL2v and anti-PD1-I1 combination therapies.
" Perhaps initially used in patients with drug-resistant cancer in immunotherapy with T-cell-infiltrated tumors
.
”