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Researchers at Johns Hopkins All Children’s Seek to Adapt Adult Treatments to Fight Pediatric Cancers

Posted on Sep 06, 2019

Jonathan Metts, M.D.

For nearly three decades, doctors have been able to harness dormant immune cells that exist naturally in certain tumors to attack those tumors in adults.

Now, advances in technology are allowing researchers like Jonathan Metts, M.D., pediatric hematology-oncology specialist in the Johns Hopkins All Children’s Cancer & Blood Disorders Institute, and his team, to seek new ways to apply the process to fighting pediatric cancers.

The overall survival rate for pediatric cancers has improved greatly in the past 50 years, but the survival rates for certain kinds of pediatric cancer remain low, according to the National Cancer Institute.

“Overall the treatment rates for localized tumors, or tumors in one spot, are pretty high, but when tumors become metastatic and travel elsewhere in the body, the survival rates drop significantly,” Metts says.

Since the 1990s, scientists have been able to remove immune cells, called lymphocytes, from melanoma tumors in adults. Hormones and cytokines (which are proteins released by immune system cells that signal the immune system to respond to infection or inflammation) are used to expand and grow the lymphocytes, which are then returned to the patient’s body where they start attacking and killing the remaining tumor.

It’s a process that is now being used to treat not just melanoma, but also gynecological and urologic cancers. The process of expanding and growing these immune cells has improved over recent decades, enabling researchers to look at applying it to additional types of cancer. A number of clinical trials have been recently opened with adults, and it has not yet been done in pediatrics.

“It’s called adoptive cellular immunotherapy,” says Metts, which means “expanding and modifying the T-cells (a type of lymphocyte) from the body and then giving them back to the patient as a form of therapy.”

Metts and his team aim to apply it to malignant solid tumors — tumors of the liver, kidney, solid organs, muscle, bone or connective tissue — in children.

Partnering with the lab of John Mullinax, M.D., at Moffitt Cancer Center, Metts and his team are collecting tumor samples from pediatric patients to see if they can recreate the therapy for children — take the lymphocytes, expand them and show that they can attack tumors, and then give them back to the patient as a form of therapy.

The types of solid tumors Metts and the team are working with all have small amounts of naturally occurring lymphocytes. Melanomas, in comparison, “are chock full of lymphocytes — they have tons and tons of them already,” he says. This made melanomas apt candidates for this type of therapy, but it is only recently that advancements in technology are enabling researchers to expand the number of lymphocytes from low-lymphocyte-producing tumors.

“When there’s one big home run, everyone sees that and adapts to that,” Metts says. “But this has been a gradual change over the last 20 years.”

“The expansion process has improved step-by-step with new hormones and new cytokines that you can use to help grow these cells,” he says, “so it’s been more of a gradual shift to an enhanced expansion process that is now allowing this therapy to move into other tumor types.”

In addition to tumor samples, the team is collecting blood and bone marrow samples from select patients. This will help them study not just the immune cells within the tumor, but also how immune cells throughout the whole body respond when a tumor is present.

“We also want to learn more about the body’s systemic response to tumors when there is an active tumor in the body,” Metts says.

Part of Metts’ goal is to develop a therapy that can fight solid tumors without causing collateral damage to other tissues. They think the lymphocytes inside of tumors recognize cancer neoantigens. Antigens are substances that trigger an immune system response — cancer neoantigens are antigens on a tumor the body doesn’t recognize yet.

“Instead of normal proteins, cancer cells are making their own mutated proteins that aren’t found in normal tissues,” Metts says. “We think that the lymphocytes that are already within a tumor are there to attack the neoantigens, so by using these cells we hope to target tumors while leaving normal tissue alone.”

Metts has wanted to be an oncologist since he was 12 years old. His father had a bone marrow transplant to treat non-Hodgkin’s lymphoma and was successfully cured of the cancer. But he died about 20 years later of complications from the transplant.

“My inspiration and my goal is to try to find innovative, curative therapies that have fewer long-term side effects,” Metts says.

“The immunotherapy that we’re working on is a small part of a massive paradigm shift in all of oncology over the last five years,” he says. “We’re harnessing the power of the lymphocytes that are already present. We’re not actually engineering or modifying the cells as much as we’re revving them up, making them angry and increasing their numbers.”

The study commenced in early April, with four patients already enrolled. The team’s goal is to gather about 10 samples a year for three years. They will look at any type of solid tumor, whether localized, metastatic, new or relapsed. After surgery, part of the tumor from the enrolled patient, along with blood and sometimes marrow samples depending on the patient, will be sent to the team at Moffitt for laboratory-based work. When the team is ready to try the therapy in patients, they expect it will likely be in patients with relapsed metastatic cancer.

“At the end of three years, we’ll put that information together, see if there are certain types of tumors that more successfully undergo this expansion than others, and try to figure out if there’s a specific scenario where using this cellular immunotherapy may be beneficial in the future,” Metts says.

Swim Across America helps support this research at Johns Hopkins All Children’s Hospital.


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