In an interview now available on Penn Clinical Podcasts (as well as Apple Podcasts), Drs. Roger Cohen and Donald Siegel of the Abramson Cancer Center (ACC) and Penn Pathology and Laboratory Medicine, respectively, discuss an enrolling clinical trial they are coordinating to evaluate chimeric antigen receptor T cell therapy, more commonly referred to as CAR T cell therapy, in recurrent or metastatic medullary thyroid cancer (MTC). Dr. Cohen is the Associate Director of Clinical Research at the ACC; Dr. Siegel is the Director of the Division of Transfusion Medicine and Therapeutic Pathology at Penn.
MTC is a neuroendocrine tumor of the thyroid's parafollicular cells, which express calcitonin. In patients with MTC, calcitonin levels are elevated, and the hormone serves as a sensitive biomarker for the disease. MTC manifests sporadically for the most part, though up to 30 percent of cases have their origin in hereditary forms linked to the multiple endocrine neoplasia type 2 syndromes as a result of germ-line RET mutations. Sporadic forms of MTC can also be caused by RET mutations.
The principal treatment for MTC is thorough and meticulous surgical resection. For patients whose MTC recurs or metastasizes, there is an acute need for efficacious long-term therapies. In MTC, radioiodine (RAI) therapy and thyroid-stimulating hormone (TSH) suppression are ineffective, as are chemotherapy and external beam radiotherapy. For patients whose disease recurs or metastasizes, a few therapies, including the multi-target tyrosine and RET kinase inhibitors, can offer disease stabilization and progression delay in some patients. However, these therapies lose efficacy with time.
The immunotherapies offer a promising alternative. Pembrolizumab is being in studied in recurrent and metastatic medullary thyroid cancer, as is CAR T cell therapy.
CAR T therapy has a limited record of success in solid tumor cancers, largely because tumors tend to offer few targetable tumor-specific antigen receptors, raising the specter of off-tumor immune reactions in healthy tissues. To treat MTC with CAR T therapy, therefore, requires a target antigen specific to the tumor. In their recent interview, Drs. Cohen and Siegel explain their discovery in the literature of GFRa4, a protein expressed only in medullary thyroid cancer cells, and their development of a CAR T cell to target the antigen.
GFRα4 CAR T Cells in MTC Patients, a first-in-human clinical trial is now underway at the Abramson Cancer Center. Patients eligible for the trial include adults with incurable, either locally recurrent, or metastatic medullary thyroid cancer who have received at least one, or have declined to receive, a tyrosine kinase inhibitor, such as cabozantinib.
Full information about the trial is available at www.clinicaltrials.gov, or by calling 855-216-0098. Contact by email is welcome at PennCancerTrials@emergingmed.com.