CAR T-Cell Therapy May Represent a New Option in Medullary Thyroid Cancer


Investigators at the Perelman School of Medicine at the University of Pennsylvania have recently initiated a clinical trial evaluating a novel CAR T-cell therapy in an effort to fill an unmet need for systemic treatment for patients with advanced incurable medullary thyroid cancer.

Investigators at the Perelman School of Medicine at the University of Pennsylvania (Penn) have recently initiated a clinical trial evaluating a novel CAR T-cell therapy in an effort to fill an unmet need for systemic treatment for patients with advanced incurable medullary thyroid cancer (MTC).

Roger B. Cohen, MD, associate director of clinical research at Penn’s Abramson Cancer Center and a professor of medicine at their School of Medicine, is leading a pilot study (NCT04877613) assessing the safety and feasibility of autologous chimeric T cells targeting the GFRα4 protein in patients with incurable MTC.

CAR T cells have had limited success in solid tumors to date unlike their emerging utility in “liquid tumors” such as pediatric acute lymphoblastic leukemia and adult chronic lymphocytic leukemia. A key feature of the GFRa4 CAR T cells is that they target a protein unique to the parafollicular cells that have become malignant in MTC. Cohen’s scientific collaborator Donald Siegel, MD, PhD, discovered this protein, GFRα4, was a target unique to MTC.

“If you do studies in the lab to see if GFRα4 is expressed on any other kind of cell in the body, it isn’t,” Cohen said in an interview with OncLive®. “Further, if you ask what proportion of MTCs express GFRα4, as far as we can tell, it’s all of them. Expression of the GFRa4 protein is also independent of tumor RET mutation status. GFRα4 is a target that is universally expressed on medullary thyroid cancer that is not expressed anywhere else. This feature of GFRα4 may offer a unique opportunity for a CAR T-cell therapy to be effective in a solid tumor such as MTC.”

MTC is a rare calcitonin-producing neuroendocrine tumor that originates in the parafollicular C-cells of the thyroid gland. The more common thyroid malignancies, such as papillary and follicular cancer, are derived from follicular cells. MTCs do not respond to thyroid-stimulating hormone, and therapies such as radioactive iodine therapy and thyroid hormone suppressive therapy are ineffective for MTC.

The American Thyroid Association estimates that MTCs make up 1% to 2% of thyroid cancers diagnosed annually.1 An analysis of the Surveillance, Epidemiology and End Results database identified 2197 patients diagnosed with MTC from 1998 to 2016.2

MTC has both indolent and aggressive forms. The 5-year overall survival rate is less than 40% for metastatic disease.1 Surgery is the only curative option and is useful mainly when the cancer is detected early and localized to the thyroid itself and surrounding lymph nodes.2

Most MTCs are sporadic, but approximately 25% of diagnoses are associated with hereditary Multiple Endocrine Neoplasia Type 2 syndrome.2 Point mutations in the RET gene are the most common type of genetic defect in hereditary and sporadic MTC.4 Existing systemic therapies target RET mutations as well as angiogenic pathways important for tumor growth. Oral kinase inhibitors blocking RET are very useful therapies for patients with MTC, but most patients will eventually become resistant to these drugs. In addition, up to 50% of patients with MTC do not harbor a RET mutation, and good options available for those patients are few. GFRα4-targeting CAR T cells are hypothesized to be active regardless of RET mutation status.

“It’s important to recognize that in the MEN2 syndromes, other tumors can develop, which is why it is called multiple endocrine neoplasia,” Cabanillas said. “You don’t want to miss parathyroid adenomas or pheochromocytomas, which can be deadly.”

Pheochromocytomas are a rare, usually benign type of tumor that develops in the adrenal gland. The National Cancer Institute says that about 10% ofpheochromocytomas metastasize. The 5-year survival rate for MTC is 95%, but that drops to 34% to 60% in patients with recurrent pheochromocytoma.5

Physicians have had success treating MTC with the antiangiogenic multikinase inhibitors vandetanib (Caprelsa) and cabozantinib (Cabometyx). Newer selective RETinhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) also show high response rates in MTC. Cabanillas said patients on the selective RET inhibitors require that the tumor carry a RET mutation.

Existing systemic therapies targeting RET mutations and the angiogenic pathways important for tumor growth are useful therapies for patients with MTC. However, most patients will eventually become resistant to these drugs. In addition, up to 50% of patients with MTC do not harbor a RET mutation and these patients have few good treatment options.

Because these CAR T cells attack only the GFRα4 protein which appears only on MTC cells, Cohen and his colleagues hope this treatment can control the cancer while avoiding some of the toxicities commonly associated with CAR T cells such as cytokine release syndrome, acute anaphylaxis, and tumor lysis syndrome.

“The GFRα4 protein is a relatively unique target in the world of solid tumors when you’re trying to develop CAR T cells because of its high degree of selectivity for the cancer itself,” he said. “This selectivity does not guarantee that there will be no toxicity in the clinic when the CAR T cells are administered to patients, but a priori GFRα4 appears to be an extremely attractive, if not unique, target for CAR T-cell treatment of solid tumors.”

Enrolling the Phase 1 Trial

Investigators hope to recruit up to 18 adults for this phase 1 dose finding study. Dose escalation and determination of maximum-tolerated dose will be based on a standard 3+3 phase 1 design exploring 3 possible dose levels: 5 x 107, 2 x 107, and 1 x 108 CAR T GFRα4 cells. All patients will receive fludarabine and cyclophosphamide lymphodepleting chemotherapy prior to receiving their CAR T cells.

The incidence of treatment-emergent adverse events is the primary end point of this small pilot study. Secondary end points include assessments of efficacy including best overall response, duration of response, progression-free survival, and overall survival.

Eligible patients must have incurable recurrent/metastatic MTC that is progressive after at least 1 prior tyrosine kinase inhibitor–containing regimen, or the patient was intolerant of or declined such therapy. Patients must have an ECOG performance score of 0 or 1, and any toxicities from prior therapies must have recovered to baseline or to grade 2 or below.

Cohen said Penn will be recruiting patients nationally and internationally. Penn Global Medicine can provide information on costs for international patients interested in participating. Investigators are also working through various patient advocacy groups and social media.

“We are trying to publicize the existence of this trial, thinking creatively about how to reach as many patients as possible with this very rare disease, as well as their doctors,” he said. “All of this publicity is done to make people aware that the trial exists. MTC patients are a rare population of patients who are cared for typically in centers of excellence across the United States. Therefore, we reach out to these centers, for example, and say, “We have a trial. It might be of interest to you, and we would be more than happy to talk to you about it and screen any potential patients you think might be appropriate for or interested in a study like this.’”

Cohen hopes to have some results regarding safety and efficacy within 3 years, although that could happen sooner depending on accrual and what happens to the cancers in patients enrolled on the trial. If successful, investigators would take CAR T GFRα4 cells into a larger trial.

However, Cohen said the knowledge to be gained from this study will be invaluable, regardless of the trial’s outcome. “The results of the trial are important whether the drug is effective or not,” he said. “The lessons learned from identifying this target, GFRα4, and then turning it into a CAR T cell, are extremely important to advance the field of solid tumor cellular immunotherapy generally.”

Cohen requests that physicians treating patients who may be eligible for the trial to contact him directly at or


  1. American Thyroid Association. Medullary thyroid cancer. Accessed March 28, 2022.
  2. Zhao Z, Yin X, Zhang X, et al. Comparison of pediatric and adult medullary thyroid carcinoma based on SEER program. Sci Rep. 2020;10:13310. doi:10.1038/s41598-020-70439-7.
  3. Thyroid cancer: statistics. Updated February 2021. Accessed March 28, 2022.
  4. Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016;12(4):192-202. doi: 10.1038/nrendo.2016.11
  5. National Cancer Institute Pheochromocytoma. Published February 12, 2020. Accessed March 30, 2022.
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