A clinical trial set to launch at the University of Colorado Cancer Center will test a therapy designed to fire the body’s natural defenses against a deadly blood cancer.

The target is acute lymphoblastic leukemia (ALL), a cancer that strikes the lymphocytes, which are immature white blood cells in the bone marrow. It most often is treated with chemotherapy, drugs that target specific genetic mutations, and stem cell bone marrow transplants. Children have the greatest chance of surviving the disease. However, for some ALL patients the available treatments fail.

In the past, these patients had little hope. But the multicenter trial in which the Cancer Center is participating and other efforts around the country could change that. The weapon being tested is a key building block of the body’s immune system: T- cells. Rapidly dividing malignant cells in ALL and other cancers can deceive and overwhelm T-cells and their ability to kill the invaders. In a new stratagem, clinicians harvest T-cells from the patient’s body, genetically modify them to recognize specific proteins produced by the cancer cells, grow them by the millions and infuse them back into the body.

The T-cells, now equipped with disease detectors called CARs (chimeric antigen receptors), set out to search and destroy the cells with the protein they have been programmed to recognize and to signal other T-cells to join the attack. The method is akin to a “smart bomb” that devastates an enemy while minimizing collateral damage, said Brian Freed, PhD, executive director of ClinImmune Labs, a School of Medicine-associated biotech facility on the Anschutz Medical Campus that is building the infrastructure to grow and store genetically modified cells designed to fight cancer and other diseases.

Taking aim

The Cancer Center will recruit patients from anywhere in the country for a trial sponsored by Seattle-based Juno Therapeutics. It targets adult ALL patients whose cells express a protein called CD19 that is very commonly present in B-cell lymphomas, including ALL, said principal investigator Enkhee Purev, MD, PhD, assistant professor with the Division of Hematology in the University of Colorado School of Medicine’s Department of Medicine. The CAR T-cell treatment probably represents the last hope for adult patients who have exhausted the standard treatment options, she said.

“These are patients who have gone through many treatments, including chemo and transplants,” Purev said. She said without therapy they would typically have only two or three months left to live.

Past CAR T-cell studies, though limited to a relatively small number of patients, give reason for optimism. The National Cancer Institute, for example, acknowledges the need for further research, but notes that many ALL patients in the trials have had their cancers disappear entirely and have remained cancer-free after CAR T-cell treatment.

The approach has “enormous potential,” said Jonathan Gutman, MD, a colleague of Purev’s and associate professor in Hematology.

“We’re seeing on the order of 90 percent of patients with complete disease control. That’s an unbelievable thing to see,” Gutman said. He noted that the new treatment offers hope not only for patients with diminishing prospects of recovery – most notably those adults in whom ALL recurs – but also as a possible future alternative for those who now go through difficult rounds of chemotherapy and transplants to eliminate the disease.

There are provisos. Gutman stressed that immunotherapy research is still in its relative infancy. Even if it proves its mettle, he added, it will be challenging to spread it quickly to large numbers of patients because of the complicated technical and infrastructure requirements.

“It’s a complex and sophisticated treatment, and that raises questions about its broad applicability,” Gutman said.

The treatment also demands providers with the experience to manage the most serious side effect of the treatments, such as cytokine release syndrome (CRS) and neurotoxicity. The problem occurs when the cancer-seeking T-cells release storms of cytokines, which are molecules that T-cells use to signal other cells and can trigger inflammation in the body. Providers treat CRS and neurotoxicity with an immunosuppressant medicine, tocilizumab, and with low-dose steroids at the first sign of fever.

Preparing for battle

The therapy itself is at this point “very expensive and labor-intensive,” Purev said. It involves several steps taken over a period of weeks. Clinicians first draw blood from the patient and separate the T-cell lymphocytes, Purev said. These are genetically modified to recognize a specific cancer calling card – in the case of the Juno Therapeutics trial, CD19 – and then grown over a two- to three-week period to build sufficient numbers of attacking forces. At that point, providers infuse the fighting cells into the patient and later perform bone-marrow biopsies to determine if the treatment cleared the body of cancer cells.

Purev said providers will probably recommend a bone marrow transplant for patients following CAR T-cell infusion treatments.

For this trial, Juno Therapeutics will modify and grow the cells at its central facility, Purev said, then ship them back through ClinImmune. She, Gutman and Freed, however, are looking to build a home-grown cell-based therapy operation in the future.

Grow your own

Outside ClinImmune’s facility, which is part of CU’s Gates Center for Regenerative Medicine in the Biosciences 2 building, stands a 15,000-gallon liquid nitrogen tank. It supplies gas to a first-floor room with refrigerated units for storing cell samples. Up one floor are clean rooms, the “closed micro-environments” necessary for growing re-engineered cells by the millions, Freed said.

“We technically can do the work now,” Freed said. But the preparations also require meeting a host of FDA regulatory standards, he added.ClinImmune went through a similar process in 2012 when it became just the second public cord blood bank in the country accorded FDA licensure. The lab again will have to provide documentation of environmental monitoring, training, protocols, and equipment validation, Freed said, adding the regulatory work could be finished by the fall.

Making that happen is a necessity, Freed emphasized, because with sufficient resources, the possibilities inherent in cell-based therapies are limitless. “We can find targets specific to any cell we want to remove,” he said.

Gutman agrees that the opportunities for immunotherapy research and development are widening. “The data has been good enough to get industry involved,” he said.

One doesn’t have to look far to find evidence of that: Children’s Hospital Colorado is part of a separate multicenter trial of a CAR T-cell therapy, sponsored by Kite Pharma, Inc., that also targets CD19. If these and other trials continue to show strong results, Gutman believes pharmaceutical companies will look to find partners like ClinImmune to take over the job of growing and storing reengineered cells. That, in turn, would encourage researchers on the Anschutz Medical Campus to develop their own cell-based therapies.

Purev said the Juno trial is a very important step for UCHealth and its campus partners in strengthening its clinical and biotech base.

“We are excited because this trial could open the door to future studies,” she said. “We look forward to collaborating with other groups and learning to take care of patients on our campus with this new therapy.”