Posted May 5, 2017

Duane Mitchell, M.D., Ph.D., University of Florida, Gainesville, Florida

Malignant brain tumors are the most common cause of cancer-related deaths in children. Today's standard treatment includes surgery, craniospinal radiation, and intense chemotherapy including high-dose chemotherapy coupled with peripheral blood stem cell transplantation. Even after this aggressive treatment regimen up to half of the children with the most common malignant brain tumors - medulloblastoma and primitive neuroectodermal tumors (MB/PNETs) - will still die from recurrent disease. Moreover, following such aggressive treatment, survivors often suffer from lifelong cognitive and motor deficits. Therapies that specifically target tumor cells and minimize toxicity to normal cells are thus critical to the next generation of treatments that promise improved clinical outcomes for children affected by MB/PNETs. In work supported by an FY09 PRMRP Clinical Trial Award, Dr. Duane Mitchell and colleagues at the University of Florida are advancing a new kind of treatment that harnesses the power of the immune system to specifically target and attack tumor cells.

Researchers have been attempting to harness the power of the immune system to fight cancer for decades, but immune-based therapies that have reached testing in clinical trials are rare owing in part to the limited amount of tumor tissue available for tumor cell-based vaccine preparations. Using a novel platform developed by colleagues at Duke University, Dr. Mitchell's team utilizes all of the RNA expressed by a tumor to train the immune system to target the myriad of largely uncharacterized antigens present within the patient's malignant tumor cells. The platform utilizes dendritic cells, the immune cells that process and present tumor antigens to �killer� T cells, thereby programming the T cells to seek out and destroy tumor cells while leaving normal cells alone. Part of what makes this approach so powerful is that by injecting total tumor RNA into the dendritic cells all of the antigens produced by the tumor cell have the potential to be targeted by the T cells, not just antigens identified by researchers. Following programming, the T cell population is then expanded in the lab and then combined with the total RNA-expressing dendritic cells and injected back into the patient as a cellular therapy specifically targeted to the particular tumors in that patient. In addition to the total tumor RNA-based approach being a more comprehensive targeting strategy, Dr. Mitchells� group has demonstrated that sufficient RNA for vaccine preparations can be amplified from as few as 100 pediatric and adult brain tumor cells, thus overcoming the limitation of insufficient tumor tissue amounts from which to develop and test vaccines. With RNA amplification, sufficient numbers of cells for vaccine preparation can be collected during surgical biopsies and even from microdissected archival tumor specimens.

The reprogramming and then reinjection of a patient's own T cells, a technique referred to as adoptive cellular therapy, was developed in the treatment of advanced and refractory melanoma where it has been shown to be remarkably effective: objective responses, such as decreases in tumor size, have been observed in up to 70 percent of treated patients. Dr. Mitchell's group at the University of Florida Brain Tumor Immunotherapy Program (UFBTIP), in collaboration with investigators at Children's Hospital Los Angeles and Children's National Medical Center in Washington, D.C., has nearly completed a study using adoptive cell transfer to treat children and young adults with aggressive meduloblastoma and primitive neuroectodermal tumors in the brain.

During the phase 1 portion of this clinical trial, progression free survival at 12 months (PFS-12) following chemotherapy plus dendritic/T cell adoptive cellular therapy was compared to historical data of PFS-12 following chemotherapy alone, and while historical data showed PFS-12 following chemotherapy alone to be 33%, patients who received the adoptive cellular therapy showed an increase of PFS-12 to 67%. At 24 months PFS for patients receiving adoptive cellular therapy was 33%; for those receiving chemotherapy alone: 0%. Two patients enrolled in the trial are beyond 36 months post-treatment and, remarkably, show no evidence of disease. The phase 2 component of the trial is ongoing, and a remarkable clinical response has been observed in a patient with widespread metastastic brain cancer. This patient had disseminated disease in the brain with spread to the spinal cord, to parts of his rib cage, as well as having penetrated bone marrow. The widespread tumors caused debilitating back pain such that the patient, twenty-one years old, needed a wheelchair for mobilization. This patient received adoptive cellular therapy in October 2015. Just two months after therapy, MRI images showed nearly all of the tumors had disappeared. The patient was also pain-free, to the point of being able to return to daily routines including exercise.

While thus far the results of the study are promising, not all patients respond to therapy in the way this inspiring case did. Finding out why, Dr. Mitchell says, will be a major focus going forward.

"Future research will focus on trying to understand why some patients seem to benefit from immunotherapy while others do not, and to try to overcome current limitations in order to extend benefit to a larger number of patients with brain cancer. One of the strengths of UFBTIP is that we have collaborative preclinical, translational, and clinical research teams that can translate promising laboratory observations into early phase clinical trials and also allow us to learn from our observations in clinical trials to inform ongoing efforts in the laboratory. Thus, we are already witnessing the emergence of our �next generation� immunotherapy approaches from the lab that will be incorporated into future trials. Coupled with the rapid advances currently being made in the cancer immunotherapy field in general, I believe we will see the development of effective new immunotherapy treatments for patients with refractory brain tumors in the very near future."

Publication (from work performed under FY09 Clinical Trial Award):

Nair S, Driscoll T, Boczkowski D, Schmittling, et al. 2015. Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma. J Neurooncol, 125(1): 65-74.

Link:

Public and Technical Abstracts: Adoptive Cellular Therapy Targeting Recurrent Pediatric Brain Cancers during Hematopoietic Recovery from High-Dose Chemotherapy

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