Giving a lymph to patients

Moffitt Cancer Center receives NCI grant to create bioengineered “designer” lymph nodes with Scripps Florida

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TAMPA, Fla.—Dr. James Mulé and his colleagues simply aren't satisfied with the human immune system, and they aim to do something about it by creating lymph nodes. To aid in this effort, Moffitt Cancer Center, in collaboration with researchers at the Scripps Florida campus of The Scripps Research Institute, has been awarded a five-year, nearly $2 million grant from the National Cancer Institute to design lymph nodes for cancer immunotherapy.

"We believe we will no longer be held hostage by what Mother Nature has given us with respect to an immune system," says Mulé, executive vice president of applied research at Moffitt. "We anticipate we will be able to create fully functioning, designer lymph nodes at will in the human body."

The reason for the NCI's interest is clear, Mulé notes, when you consider that a patient diagnosed with cancer has a dysfunctional immune system either because of the tumor or the treatment being used to eradicate the tumor. Designer lymph nodes could help rebuild a patient's immune system to better fight disease and possibly even increase the potency of vaccines.

In this effort, Mulé is partnering with Dr. John Cleveland and Dr. Juliana Conkright, both at Scripps Florida in Jupiter, Fla., who will use high-throughput screening technologies to rapidly select the candidate genes to use in creating the human lymph nodes.

A clinical trial related to melanoma is currently underway at Moffitt using one of the first candidate genes as a primitive lymph node. Twelve patients are presently enrolled.
As Mulé describes it, the gene is introduced into a specialized immune cell that is a potent cell for presenting foreign antigens. These gene-modified antigen presenting cells are exposed to and/or incubated with tumor antigens to "load them up" and then simply injected under the skin. The injected cells then produce the protein from the inserted gene that will form the rudimentary lymph node structure within about seven days after injection.

But that, of course, is just based on a single gene. What are the researchers planning to make a more complete "designer lymph" node that could be used in a patient?

"Upon completion of the initial Phase I trial—evaluating safety and immune response/rudimentary lymph node formation monitoring—we will decide, depending on the results, whether to move the single gene strategy into a Phase II trial evaluating clinical efficacy," Mulé says. "In parallel, we, with our Scripps colleagues, will evaluate in the laboratory which of the remaining 47 or so genes should be employed to improve and further design the optimal lymph node. The results of that screen will determine the selection of the 'next generation' genes to move into the clinic."

As to whether such designer lymph nodes would augment existing lymph nodes or replace faulty or failed ones, Mulé says that both are part of his aims, and other permutations as well.

"The sky's the limit," he maintains. "They would be formed anywhere under the skin where the injected, gene-modified cells are located, and would function independently and specifically against whatever foreign antigen is decided upon, or more than one antigen for that matter."

"Our collaborative efforts hold the real promise of restoring anti-tumor activity to the immune system of cancer patients, and could lead to cures for some cancer types," says Cleveland, chairman of the Department of Cancer Biology at Scripps Florida, looking at the current melanoma focus of their work. "It is also a perfect example of the creative, state-of-the-art science being driven by investigators at Moffitt and Scripps and the power of collaboration between the two institutes in moving biomedical science from the laboratory to the patient."

The creation of these designer lymph nodes is not limited to just cancer, Cleveland and his colleagues emphasize. In fact, Mulé plans to expand their use to other areas to boost immunity against a variety of infectious diseases and possibly to improve the functions of the immune system during aging.

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