Researchers identify drug that could overcome tumor resistance

Scientists from the Jonsson Comprehensive Cancer Center at the University of California-Los Angeles Health Sciences have discovered that a drug that stimulates the body’s natural defenses by acting like a virus may also make some sneaky melanoma tumors perceptible to the immune system, enabling them to be better targeted by immunotherapy.

Researchers identify drug that could overcome tumor resistance
Dr. Anusha Kalbasi (left) and Dr. Antoni Ribas. Image Credit: University of California-Los Angeles Health Sciences.

Published recently in the Science Translational Medicine journal, the findings may offer new possibilities of using drugs that imitate viruses to resolve immunotherapy resistance in tumors with faulty interferon signaling and help develop more personalized treatments for people suffering from hard-to-treat cancers.

Most immunotherapy approaches rely on the ability of T cells to recognize and kill tumor cells. But in some patients, tumors escape the immune system through mutations in genes involved in the interferon signaling pathway. This is a critical pathway because it normally allows tumors to increase their antigen presentation, intricate machinery that makes tumors visible to T cells.”

Dr Anusha Kalbasi, Study Lead Author and Assistant Professor of Radiation Oncology, David Geffen School of Medicine, University of California-Los Angeles Health Sciences

Dr Kalbasi is also the study’s corresponding author and member of the Jonsson Cancer Center.

Interferons are cellular proteins that respond to viral infection by inhibiting the ability of the virus to replicate and warning the immune system to assemble its forces. When interferon signaling in tumors is activated, the tumors divide slowly and molecules are released that recruit more number of immune cells to the tumor.

This coordinated effort as a result of interferon signaling can help the immune system better identify and kill tumor cells.”

Dr Anusha Kalbasi, Study Lead Author and Assistant Professor of Radiation Oncology, David Geffen School of Medicine, University of California-Los Angeles Health Sciences

Initially, the team tried to defeat the faulty interferon signaling by employing adoptive T cell therapy—a kind of immunotherapy in which T cells are extracted from a patient and subsequently engineered in the laboratory to identify and destroy cancer cells. The team observed that these T cells stayed ineffective against tumors with faulty interferon signaling.

The researchers then engineered mouse melanoma tumor cells using a gene known as NLRC5. NLRC5 increased the presentation of antigens even in the nonexistence of interferon signaling and restored the effectiveness of the T cells. But while this method was demonstrated to be effective in mice, it was not so easy to engineer tumor cells in humans.

Instead, Dr Kalbasi and his collaborators focused on a virus-mimicking drug known as BO-112 that stimulates virus-sensing pathways in tumors. Upon injecting the drug directly into the tumor in a laboratory setting, the researchers found that the activation of virus-sensing pathways boosted the presentation of antigens even when interferon signaling was faulty. Consequently, these tumors could be detected and killed by T cells.

This study helps us understand the interdependence between interferon signaling and antigen presentation, which gives us important insights into how tumor cells are recognized by the immune system.”

Dr Antoni Ribas, Study Senior Author and Professor of Medicine, Geffen School of Medicine, University of California-Los Angeles Health Sciences

Dr Ribas is also the director of the Tumor Immunology Program at the Jonsson Cancer Center.

Dr. Ribas continued, “New strategies to promote antigen presentation to make tumors more visible to the immune system will allow immunotherapy to be effective for even more tumor types.”

The study also emphasizes the prospect of other potential clinical methods that bypass tumor interferon signaling as well as antigen presentation, such as CAR, or chimeric antigen receptor–based T cell therapy, which can detect and destroy tumor cells even when there is no antigen presentation.

At present, Dr Kalbasi is leading a human clinical trial of the combination treatment of an immune checkpoint blockade drug called nivolumab, and BO-112 in patients with specific types of sarcoma who are undergoing radiation therapy followed by surgery. The concept is to stimulate the immune system against the patient’s tumor while the tumor still remains in the body.

Source:
Journal reference:

Kalbasi, A., et al. (2020) Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Science Translational Medicine. doi.org/10.1126/scitranslmed.abb0152.

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