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Trial studies immunotherapy drug designed to trigger cascading immune response

Researchers have launched a study on an immunotherapy drug that may add a new tool to the immune system's arsenal against cancer.

Researchers have launched a study on an immunotherapy drug that may add a new tool to the immune system's arsenal against cancer. The immune system needs the extra help, because it does not always recognize cancer as a threat, seeing the cells as the body’s own, not the harmful mutations they’ve become. So when the cancer cells pass by protein molecules called “checkpoints”—so named because they “check” cells to gauge their risk to the body’s health—the cancer cells send deceptive signals mimicking the normal cells they used to be, allowing them to pass by undetected.

A promising class of immunotherapy drugs known as checkpoint inhibitors works by disrupting those signals, exposing cancer cells to the immune system and a potential attack. Immunotherapy drugs now on the market target three checkpoint receptors—PD-1, PD-L1, and CLTA-4. Such checkpoint inhibitors are currently approved for advanced melanoma, non-small cell lung cancer, renal-cell carcinoma, Hodgkin lymphoma, bladder cancer, and/or head and neck squamous cell carcinoma.

Exploring new options

The new phase I trial is studying a drug, currently named TSR-022, that is attempting to block another checkpoint that has not yet been targeted by an approved drug: TIM-3. "We are hoping to achieve several things," says Dr. Glen Weiss, Director of Clinical Research and Phase I & II Clinical Trials at our hospital near Phoenix and the principal investigator in the study.  "We want to be able to investigate new treatment options for our patients with advanced cancers, determine how safe the drug is and how it should be dosed, and see whether it leads to long-term results."

What may make TSR-022 different than approved checkpoint inhibitors is the potential cascading effect that may result if it generates an immune response. According to a 2014 article published by the America Association for Cancer Research (AACR), the TIM-3 receptor is not only found on T cells in tumors, but has been linked to the presence of other cells that may short-circuit the immune system and/or promote tumor growth. So, targeting TIM-3 may not just jumpstart T cells, but create other cell reactions beyond the design of current immunotherapy drugs. For instance:

  • Scientists suspect that TIM-3 may attract regulatory T cells (Tregs) that swarm around the tumor microenvironment and suppress the immune system. Tregs are necessary to the immune system in preventing T cells from running amok.
  • Some research suggests TIM-3 may promote the presence of myeloid-derived suppressor cells. These cells help regulate the immune system, but they may also be responsible for poor responses to cancer therapies.
  • TIM-3 has been found on dendritic cells, possibly blocking them from initiating an immune response. Dendritic cells are like the traffic cops of the immune system, sending T cells in the right direction to attack invaders.

How PD-1 inhibitors work

PD-1 checkpoint inhibitors are designed to work in a cause-and-effect fashion. It blocks the communication between cancer cell and immune cell at the PD-1checkpoint, triggering an attack on the cancer cells. TSR-022 "is designed to be broader in its effect," Dr. Weiss says.  Block TIM-3, and the potential reaction may resemble a line of cellular dominoes falling one after another, opening up the cancer cells for multiple attacks.

The AACR article says TIM-3 is found in patients with melanoma, non-small cell lung cancer, and non-Hodgkin lymphoma, but this trial includes adult patients with solid tumors who meet other specific requirements regarding previous cancer treatments. The trial is studying how TSR-022 performs alone and in combination with a PD-1 inhibitor. Our hospital near Phoenix was the first site in the world to administer TSR-022 as part of a Phase 1 clinical trial. TSR-022 was developed by TESARO Inc. of Waltham, Mass., in collaboration with AnaptysBio Inc. of San Diego. 

Learn more about the science behind immunotherapy.