Moffitt Expands Its Cellular Therapeutics Production Facilities
Dressed as if they are on the planet Mars, technicians in the new and expanded Moffitt Cell Therapies Core Facility move easily through the sunlit and spacious glassed-in “clean rooms” where they make cellular therapeutics. On the other side of the glass, writers scribble notes while watching the lab techs - gowned, hooded, and gloved - move about the regimented lines of dozens of large, shining silver tanks that keep cells frozen at minus 350° F.
Having just moved the lab from cramped, inadequate space on the Moffitt main campus to the McKinley campus about a mile away, William E. Janssen, Ph.D., Moffitt senior member and director of the facility, leads journalists on a tour of the new facility’s clean rooms and explaining the science behind their work. “The new facility is four times larger than what we had on the Moffitt campus,” explains Dr. Janssen. “That means we have more space dedicated to making cellular therapies, but it also means that we don’t run the risk of running into each other as we work!”
The expansion allows them to not only take on more work, says Dr. Janssen, but also do varieties of work they could not do in the smaller space. In the 10 separate but linked clean rooms - designed to be free of pollutants such as dust, airborne microbes, aerosol particles, and chemical vapors - technicians manufacture cellular therapeutic products to support Moffitt’s clinical trials. Compliant with U.S. Food and Drug Administration standards and accredited as a “human cell and tissue product manufacturing facility,” the lab develops new cellular products for testing; collects and refines patient self-donated cells (lymphocyte and antigen-presenting cells) to make cell therapy products for immune therapies; provides frozen storage (cryostorage) for cells and products for future use; and provides product quality testing and posttreatment immune monitoring for patients who have received the manufactured therapies.
Some therapies are made from the patients’ own modified cells, explains Dr. Janssen. When cells are collected from patients and then modified in the lab, the cells become “drugs,” and their manufacture is tightly regulated by the FDA. “We are developing technology to bring cellular therapies, such as cell transplantation and antitumor vaccines, to the patient’s bedside,” Dr. Janssen tells the journalists, who are also receiving a short but intense lesson in cell biology.
New cellular therapeutic strategies against cancer involve making anticancer vaccines to boost the patient’s immune system, or transplanting cells derived from bone marrow, umbilical cords, and even fat cells, into patients so that the biologically advantageous properties of the cells can help fight their cancer.
Cell transplantation, explains Dr. Janssen, is not new, but newer strategies of cell manipulation and manufacturing, as well as cell delivery via viruses, are tactics at the leading edge of cancer therapies. For example, workers here make a product using dendritic cells – cells with octopus-like tentacles – that are redesigned so that the tentacles hold small pieces of a protein and, on injection, present the protein “snippets” to the patient’s immune system in such a way that the immune system learns to react to them anytime it finds them, including if it finds them on the surface of a cancer cell.
“In many cancers, the immune recognition function is defective, which means the immune system lacks the ability to recognize what is foreign,” says Dr. Janssen. “We use a simple virus to “load” dendritic cells with proteins that they will then “present” on their tentacles, also known as dendrites. The dendritic cells use the protein that they are “presenting” with their dendrites to stimulate the body’s lymphocytes, a kind of immune cell. Our goals are to prevent the shutdown of the immune system by tumors, and to stimulate the patient’s own immune system’s lymphocytes into action against cancer cells.”
With another procedure, they are also supporting a Moffitt clinical trial in which two genes added to cells in the lab secrete the GM-CSF molecule in order to attract and stimulate dendritic cells. “The game plan with GM-CSF is to use it in combination with a patient’s irradiated tumor cells to make a vaccine that will draw dendritic cells,” explains Dr. Janssen. “Essentially, we are trying to leverage the dendritic cells that are still in the patient.”
Yet another strategy is to use tumor-infiltrating lymphocytes, or TILs. These are lymphocytes that have entered the tumor, but are trapped there, unable to react. “We cut some of the surgically removed tumor into small pieces and put the fragments into Petri dishes along with a special protein called IL-2, and the lymphocytes come popping out of the tumor fragments,” says Dr. Janssen. “We expand the lymphocytes 100 times and transfer them to big blood bags and continue to expand them until we end up with 10 billion (yes, billion) lymphocytes in each bag.” Some of these lymphocytes are reactive against the tumors, and these are infused into patients in an effort to reduce the size of their tumors. Some melanoma tumors have vanished entirely when this therapy has been applied, says Dr. Janssen. The majority of tumors are greatly reduced.
Additional study by the laboratory’s investigators is focused on utilizing umbilical cord blood cells for transplantation because these cells are less mature, less specialized, and immunologically weaker than many stem cells drawn from adult sources. Beneficial yet weaker immunologically, they reduce the patient’s risk of acquiring graft-versus-host disease (GVHD) after cell transplantation. GVHD is a debilitating reaction that can occur following cell transplantation when the transplanted cells are donated by hosts other than “self” and are, subsequently, rejected as “foreign” by the recipient’s immune system.
According to Dr. Janssen, the future in their field is quite bright as cancer therapies other than chemotherapy and radiation are having such success that more and more clinical trials in immunotherapy are being devised.
“This new facility will allow us to increase not only the number of studies we conduct, but also the number of patients on each study,” concludes Dr. Janssen.
The cellular therapeutics production facilities support the work of Moffitt physician-scientists, bringing laboratory discoveries to the clinic through numerous immunotherapy trials, including those listed below.
Use of p53 gene-transduced dendritic cells as vaccine for small cell lung cancer.
(Investigator: Dr. Alberto Chiappori)
Use of p53 gene-transduced dendritic cells as vaccine for breast cancer.
(Investigator: Dr. Hatem Soliman)
Use of GM-CSF-secreting, CD40 ligand-expressing bystander cell in concert with non-small cell lung cancer cell lines, either nontransfected or transfected with CCL-21 the gene.
(Investigator: Dr. Jhanelle Gray)
Use of intratumoral-administered dendritic cells in soft-tissue sarcoma.
(Investigator: Dr. Scott Antonia)
Tumor-infiltrating lymphocytes (TIL) expanded and infused for treatment of melanoma.
(Investigators: Dr. Amod Sarnaik; Dr. Jeffrey Weber)
Use of expanded Treg lymphocytes to reduce graft-versus-host disease following allogeneic hematopoietic progenitor cell transplant.
(Investigators: Dr. Joseph Pidala; Dr. Claudio Anasetti)
Use of tumor lysate-pulsed dendritic cell vaccines following autologous hematopoietic progenitor cell transplant for children with neuroblastoma.
(Investigators: Dr. William Janssen; Dr. Shari Pilon-Thomas, Dr. Gregory Hale [Dr. Hale is a Moffitt member based at All Children’s Hospital])
Clinical trials are essential in helping us find new and better cancer treatments. To search for clinical trials at Moffitt, visit www.MOFFITT.org/ClinicalTrials.