Bladder Cancer Immunotherapy Response may be Predicted by Genetics

Highlights:

Though bladder cancer is one of the more responsive tumor types, it still has just a 25% durable response rate.
Anti-PD-1/PD-L1 treatment, a sort of cancer immunotherapy, that allows the body's immune system to attack tumor cells, has been successful against various cancer types.
This could ease treatment selection for clinicians and determine whether given patients will likely respond to anti-PD-1/PD-L1 therapy.

Genetic signals discovered by Cedars-Sinai Cancer researchers may be used to predict how immunotherapy would affect tumors in patients with bladder and other malignancies. Their findings, published in the National Cancer Institute's peer-reviewed journal, may someday help physicians choose the best cancer therapies for their patients.

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types. We will continue investigating these biomarkers with the goal of bringing them into clinical use and improving patient outcomes,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair and senior author of the study.

Bladder Cancer – Symptoms, Signs, Diagnosis, Treatment, Prognosis & Prevention
Bladder cancer occurs due to abnormal cell growth in the urinary bladder. The most common kind usually is urothelial cancer or transitional cell carcinoma.

‘Response to immunotherapy in bladder cancer can now be predicted with certain gene signatures.’

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Anti-PD-1/PD-L1 therapy, a type of cancer immunotherapy that opens the door for the body’s immune system to attack tumor cells, has demonstrated effectiveness against many cancer types over the past five years.

Keith Syson Chan, Ph.D., translational scientist, professor of Pathology and co-author of the study, said, “It has proven very effective against melanoma and revolutionized lung cancer treatment. Bladder cancer is considered one of the more responsive tumor types, but still has just a 25% durable response rate, so improvement is still needed.”

When a tumor triggers a host immune response, it is referred to as a ‘hot’ tumour because immune cells frequently invade the tumor’s interior. On the other hand, certain cancers, termed as ‘cool’ tumors, prevent immune cells from penetrating.

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Immunotherapy is a type of treatment method that works by using certain components of a person's immune system to treat the disease.

There are two ways by which these therapies work:

Activation immunotherapies work by enhancing or stimulating the immune system. Examples in this category work to destroy cancer cells.
Suppression immunotherapies work by inhibiting or suppressing the immune system. Examples in this category are used to treat allergies and autoimmune diseases.

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A gene named discoidin domain receptor tyrosine kinase 2 (DDR2) was linked in a previous work by Theodorescu to anti-PD-1 resistance in animal models of several tumor types. This new study used human cancer data sets in distinct tumor types in a partnership between cancer biologists and bioinformatics specialists to better analyze the DDR gene family.

Cancer Immunotherapy
Cancer immunotherapy is a new advancement in cancer treatment that uses certain components of a person's immune system to fight against cancer cells.

As the study's first author, Sungyong You, Ph.D., a computational biologist with experience in urologic oncology, examined information from The Cancer Genome Atlas programme, a freely accessible database with details on hundreds of cancer samples, to examine the relationship between the expression of the related gene DDR1 and the host immune response to a tumor using bladder cancer as a model. He also studied the correlation between the genes controlled by DDR2 and DDR1 (also known as gene signatures). Then, he examined patient data from IMvigor 210, a clinical trial that assessed the effectiveness of immunotherapy in treating bladder cancer, to see whether these outcomes related to the expression of DDR2 and DDR1 or their associated gene profiles.

The investigators concluded

First, while belonging to the same gene family, the DDR1 and DDR2 genes have extremely distinct impacts on cancers. DDR2 expression is often low in tumors with high DDR1 expression and vice versa. Furthermore, while high DDR2 tumors are ‘hot’, high DDR1 tumors are ‘coo’'.

Researchers also discovered four distinct gene profiles strongly correlated with tumor response to immunotherapy and were controlled by DDR1 and DDR2. These genetic markers were also studied in other collections of patient data from various cancer types that were made publicly available.

Cancer Immunotherapy Modulates Tumor Immunophenotype
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“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in multiple patient groups. We also evaluated the signatures in publicly available data on melanoma, glioblastoma and blood cancers, with similar results," said You.

“The next step is to validate these signatures in a prospective clinical trial. This could yield new tools that allow clinicians to determine pre-treatment whether given patients will likely respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy for those patients who will derive the most benefit and offer alternative therapies for patients not likely to respond, improving outcomes for all,” said Theodorescu.

Source-Eurekalert