Immunotherapy


 
Troy Randall, PhD works on strategies to fight breast cancer.

Using the Body's Own Defenses to Fight Cancer

This summer the American Society for Clinical Oncology (ASCO) conference in Chicago named immunotherapy its Advance of the Year for 2016. This approach to treatment is being called possibly an even greater breakthrough than chemotherapy.

Three UAB researchers are at the forefront of research in developing immunotherapies to combat some of the most lethal forms of cancer.

Troy Randall, PhD is working on more effective strategies for focusing the immune system to fight triple negative breast cancer.

"When immunotherapy works, it's amazing to see. Patients who respond often respond very well. Some are seeing durable, long-term remission," Randall said. "The challenge is that the percentage of patients who respond is low. We are currently only seeing about a 20 percent response rate in ovarian and triple negative breast cancer patients. The biggest push in research now is turning more patients into responders. The trick is to make the immune system think the cancer cells are an infection. It's good at dealing with that."


Rebecca C. Arend, MD with lab samples.

Rebecca C. Arend, MD, is investigating immunotherapies in ovarian cancer.

"There are several different types of immunotherapy, and it's possible that they may work better in combination or in sequence. However, we have a lot of questions to answer. What is the best timing and dosage, and which type of therapy or combination of therapies works best in a particular type of cancer? The biggest question of all is why some people respond and others do not," Arend said.

Current immunotherapy research ranges from immune cell therapy to immune system modulators and cancer treatment vaccines. One of the most exciting areas of current research is immune checkpoint modulators.

"This is the type of therapy Jimmy Carter credits for remission of his brain cancer," Arend said. "Immune checkpoint modulators take the brakes off the immune system to rev it up to fight cancer cells."

One reason nonresponders may not be responding is that T cells aren't seeing the cancer. Some cancer cells are very good at hiding and masquerading as normal. Sometimes they reduce antigens on their surface or express proteins that inhibit the T cells or induce surrounding cells to inhibit them.

Randall said, "Cancers with the most mutations seem to be the easiest for the immune system to recognize. Melanomas have many mutations and seem to respond better to immunotherapy."

Patients with the same types of cancer may have very different degrees of mutation in their cancer cells. It's possible that patients with the most mutations may be more likely to respond to treatment because their T cells are more likely to see their cancer cells as "other" and attack.

Arend is working to find agents or combinations of agents that can change the epigenetics of ovarian cancer cells to make them more visible to the immune system.

"PDL-1 and CTLA-4 are checkpoints that help the immune system put on the brakes. The immune system needs brakes. Otherwise it would overwhelm the body and damage normal tissues. In cancer, molecules from tumors seem to be blocking T cell response. For example, PDL-1 and a molecule from the tumor are like a lock and key system. If the key goes into the lock, the T cell dies. But if we can prevent that connection with a checkpoint inhibitor, the T cell lives and attacks the cancer," Arend said.

While most immunotherpies are generally considered gentler than other types of cancer treatment, and without the potential long term risks of radiation and chemotherapy, checkpoint inhibitors are not without their side effects.

"Checkpoint inhibitors are very promising, but while they are unmasking cancer cells so T cells can attack, the unleashed immune system could be causing inflammation, bowel problems, eczema and other autoimmune problems," Randall said "However, most symptoms can generally be managed to give the immune system an opportunity to attack the cancer."


Randall S. Davis, MD

One of the earliest and most successful areas of immunotherapy is childhood leukemias, where it has become the standard of care. Randall S. Davis, MD, works with immunotherapies for leukemias and lymphomas.

"We can remove molecules from a malignancy and develop monoclonal antibodies to teach the immune system to recognize malignant cells or tag them to take up a toxin or drug. The antibodies are infused back into the patient. They are highly specific, less toxic than other therapies, and well tolerated by the immune system," Davis said. "Effectiveness depends on how well the malignancy is targeted and how clearly mutations are expressed.

"Unfortunately, adult leukemias are not as responsive. We need more therapies. Researchers are working on antigen disrupter T cells and engineering chimeric molecules so antibodies can signal T cells to recognize malignancies."

In collaboration with HudsonAlpha in Huntsville, UAB researchers are also looking at the T cell receptor repertoire in patients with different cancers and those with the same type of cancer who respond differently to therapies.

"In the future, one of the things we think we will be able to do is to look at the patient's cancer and individual immune system and personalize treatment to the patient," Arend said.

Exciting things are happening in immunotherapy--patients are responding with remissions that would have been unlikely with past treatments--but so much research and hard work lie ahead.

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Tags:
checkpoint modulators, chimeric molecules, CTLA-4, HudsonAlpha, immune receptor repertoire, Immunotherapy, Jimmy Carter, leukemia, lymphoma, ovarian cancer, PDL-1, Randall S. Davis MD, Rebecca C. Arend MD, T cells antigen disrupter T cells, triple negative breast cancer, Troy Randall PHD, UAB

 

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