Medulloblastomas, the most common malignant brain tumors in children, are usually incurable if they recur. But a clinical trial of a novel therapy in which natural killer (NK) cells are infused directly into the brain is now enrolling young patients with recurrent medulloblastoma and other malignant tumors of the posterior fossa.
Medulloblastomas recur in 20%–30% of pediatric patients after standard treatment with surgery followed by concurrent chemotherapy and radiation therapy and then adjuvant chemotherapy or—for children younger than 3 years—surgery followed by high-dose chemotherapy and stem cell transplant. Less common malignant tumors of the posterior fossa, which include ependymomas and atypical teratoid rhabdoid tumors, also have high recurrence rates and carry poor prognoses.
The current treatment for recurrent medulloblastoma is salvage chemotherapy and, for patients at least 3 years old, re-irradiation. Even with treatment, patients with recurrent medulloblastoma have a 2-year overall survival rate of less than 20%.
“We need to find novel therapies for posterior fossa tumors that can have a meaningful effect on survival,” said Soumen Khatua, M.D., an associate professor and chief of the Pediatric Neurooncology Section in the Division of Pediatrics at The University of Texas MD Anderson Cancer Center.
NK cells for cancer treatment
Dr. Khatua is the principal investigator of a clinical trial (No. 2013-0765) in which autologous NK cells are injected directly into patients’ brains. The trial is currently enrolling patients younger than 22 years with recurrent malignant tumors of the posterior fossa. Dr. Khatua said that most patients in the study so far have undergone at least one failed attempt at salvage therapy.
For each patient in the study, NK cells are harvested from the patient’s blood, expanded, and cryopreserved until the time of infusion. A catheter is placed in the patient’s fourth ventricle, and the autologous NK cells are infused through the catheter. The patient receives three cycles of treatment with NK cells; each cycle comprises three infusions per week for 3 weeks followed by 1 week of rest. Three months after the completion of treatment, the patient will undergo magnetic resonance imaging to assess the tumor response.
“We have performed more than 50 infusions and seen no dose-limiting toxicities,” Dr. Khatua said. “This is a doseescalating trial, and we have gone to the second of three dose levels.”
Preliminary results of the trial are not yet available, but preclinical studies showed that NK cells had antitumor activity against medulloblastoma and atypical teratoid rhabdoid tumor cell lines. Mouse xenograft models of medulloblastoma confirmed this activity.
These studies and the resulting clinical trial were developed by a team that included (in addition to Dr. Khatua) Laurence Cooper, M.D., Ph.D., Vidya Gopalakrishnan, Ph.D., Wafik Zaky, M.D., and Dean Lee, M.D., Ph.D., respectively a visiting scientist, associate professor, assistant professor, and former associate professor in the Division of Pediatrics; and David Sandberg, M.D., and Jeffrey Weinberg, M.D., both professors in the Department of Neurosurgery.
Because the ongoing clinical trial is the first to infuse NK cells directly into the brain, several precautions were taken for safety. One of these was infusing three doses of NK cells per week instead of one large, weekly dose. Because of the proven safety of the initial infusions, the researchers have proposed an amendment to the trial’s protocol so that the entire dose for each week can be given in one infusion instead of three.
Another safety provision was the use of autologous rather than allogeneic NK cells. However, because the preclinical studies that led to the trial used allogeneic NK cells, Dr. Khatua and his colleagues think allogeneic NK cells or “off-the-shelf” NK cell products might be more efficacious than autologous NK cells in clinical use. “Now that the safety of autologous cells appears to be established, and hopefully will be further established, the next step will likely be to use allogeneic or off the- shelf NK cells,” Dr. Khatua said.
Finally, Dr. Khatua and his colleagues would like future trials to investigate whether NK cell infusion will have synergy with chemotherapy drugs against malignant posterior fossa tumors. Dr. Khatua said, “It is imperative that we find novel therapies including biologic agents that can be directly infused into the brain to fight these tumors in close proximity and yet prevent toxicity from systemic chemotherapy.”
For more information, Dr. Soumen Khatua at 713-792-3280.
OncoLog, October 2016, Volume 61, Issue 10