CAR T-Cell Therapy for Thyroid Cancer

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Immune checkpoint inhibitors, High dose corticosteroids

Disqualifiers: Active infections, Cardiovascular disability, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new CAR T-cell therapy for individuals with medullary thyroid cancer (MTC) that current treatments cannot cure. The researchers aim to determine the treatment's safety and whether it can be administered without major issues. Participants will receive varying doses of modified immune cells, known as CART-GFRa4 cells, to assess their effects. Suitable candidates have progressive or recurrent medullary thyroid cancer and have tried at least one unsuccessful treatment. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on high-dose corticosteroids, and certain other treatments like immune checkpoint inhibitors must be stopped 2 months before joining the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that CAR T-cell therapy, such as the CART-GFRa4 cells being tested, holds promise in fighting cancer. Specifically, studies have found that GFRα4 CAR T-cells can effectively kill cancer cells in lab experiments, suggesting potential effectiveness against medullary thyroid cancer (MTC).

However, since this study is in its early stages, detailed safety information for humans is not yet available. Early trials primarily focus on assessing safety, so researchers closely monitor side effects and how well participants tolerate the treatment.

In other studies of CAR T-cell therapies, side effects have included fevers, tiredness, and low blood cell counts. These side effects are usually manageable but require medical attention. Participants should discuss potential risks with their healthcare providers to better understand the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CART-GFRa4 cells for thyroid cancer because they represent a novel approach compared to traditional treatments like surgery, radioactive iodine, or thyroid hormone therapy. This treatment involves CAR T-cell therapy, which means it genetically modifies a patient's own immune cells to better target and attack cancer cells. Unlike standard therapies that often broadly affect healthy cells, CART-GFRa4 cells are designed to specifically target cancerous thyroid cells, potentially leading to more effective results with fewer side effects. Additionally, this therapy is administered via a single intravenous infusion, which could be more convenient compared to ongoing treatments.

What evidence suggests that CART-GFRa4 cells might be an effective treatment for medullary thyroid cancer?

Research has shown that a new treatment using CART-GFRa4 cells might help treat medullary thyroid cancer (MTC). These specially designed immune cells can attack and kill cancer cells with the GFRα4 protein, often found in MTC tumors. In lab tests, these cells successfully targeted and destroyed MTC cancer cells and some leukemia cells with high levels of GFRα4. Similar treatments in animal studies have also shown promise, suggesting this method could help patients live longer. Although this research remains in the early stages, it offers hope that CART-GFRa4 cells could become a new treatment option for MTC. Participants in this trial will receive different doses of CART-GFRa4 cells to evaluate their effectiveness and safety. ^{1 2 3 4 5}

Who Is on the Research Team?

Roger Cohen, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

Adults over 18 with incurable medullary thyroid cancer (MTC) that's worsened after treatment or if they couldn't tolerate the therapy. They must have good organ function, not be on dialysis, and have a stable heart and lung condition. Pregnant women, those with severe allergies to trial drugs' components, active infections like hepatitis B/C, unstable heart conditions or seizures can't join.

Inclusion Criteria

Your heart's pumping ability, measured by ECHO or MUGA, is at least 45%.

My liver tests are within the required limits, except I have Gilbert's syndrome.

I have mild or no shortness of breath and my oxygen level is above 92% without assistance.

Exclusion Criteria

You have a skin rash or allergies that need strong medicine to treat.

I have a seizure disorder or have had seizures that needed medication.

I am not on high-dose steroids for an autoimmune disease like MS or Parkinson's.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of CART-GFRa4 cells via intravenous infusion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

4 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• CART-GFRa4 cells

Trial Overview The study is testing CART-GFRa4 cells in patients with MTC who haven't responded to other treatments. It involves modifying a patient's T cells to target cancer cells more effectively. The safety of this approach combined with Fludarabine and Cyclophosphamide chemotherapy is being evaluated.

How Is the Trial Designed?

Group I: Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion Experimental Treatment 3 Interventions

Group II: Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion Experimental Treatment 3 Interventions

Group III: Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion Experimental Treatment 3 Interventions

Group IV: Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion Experimental Treatment 3 Interventions

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

CAR-T cell therapy, which involves genetically engineering T-cells to target specific cancer antigens, has shown unprecedented response rates in patients with B-cell malignancies, particularly after traditional treatments have failed.

The first successful application of CAR-T cells targeting the CD19 antigen led to the approval of three CAR-T products for B-cell malignancies in the US and Europe by December 2020, highlighting both the efficacy and the potential safety concerns associated with this innovative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells, from principle to clinical applications. Bourbon, E., Ghesquières, H., Bachy, E.[2021]

The TSH receptor (TSHR) is highly expressed in a majority of thyroid cancer cases, making it a promising target for CAR-T therapy, particularly in differentiated thyroid cancer (DTC).

Three novel anti-TSHR CAR-Ts were developed, with the K1-70 CAR-T showing significant antitumor activity in vitro and therapeutic efficacy in a mouse model without apparent toxicity, suggesting its potential for safe application in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer. Li, H., Zhou, X., Wang, G., et al.[2022]

The study introduces a novel Fab-based chimeric antigen receptor (CAR) designed to improve T cell therapy for thyroid cancer, which traditionally has limited success with solid tumors due to issues with T cell affinity and longevity.

This new Fab CAR can recognize tumor antigens without relying on MHC/peptide complexes, potentially enhancing the durability and effectiveness of CAR-engineered T cells in generating long-term clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Antibody Fab Fragment-based Chimeric Antigen Receptor Could Efficiently Eliminate Human Thyroid Cancer Cells. Duan, H., Huang, H., Jing, G.[2020]

Thyroid cancer cases are on the rise, and while standard treatments like surgery and radioactive iodine are effective for most patients, about 5% develop aggressive metastatic disease that does not respond to these treatments.

Targeted therapies, such as Sorafenib, have shown promise in treating differentiated thyroid cancer that is resistant to radioactive iodine, highlighting the need for continued development of new drugs targeting specific genetic mutations and pathways involved in thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapies for dedifferentiated papillary thyroid cancer. Fallahi, P., Mazzi, V., Vita, R., et al.[2021]

Thyroid cancer prognosis varies widely, with some subtypes having a high cure rate of nearly 90%, while others are extremely aggressive and lethal, highlighting the need for effective treatments.

Genetically engineered mouse models that mimic human thyroid cancer mutations are crucial for preclinical testing of new therapies, helping researchers identify potential anticancer agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement. Charles, RP.[2021]

ICAM-1 CAR T cells effectively targeted and killed poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) cells in vitro, demonstrating the potential for this therapy to treat aggressive thyroid cancers.

In mouse models of systemic ATC, a single dose of ICAM-1 CAR T cells led to significant tumor reduction, long-term remission, and improved survival, indicating a promising new treatment approach for patients with advanced thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. Min, IM., Shevlin, E., Vedvyas, Y., et al.[2019]

In a phase-1/2 trial involving 13 adult patients with refractory acute lymphoblastic leukemia, third-generation CAR T cells (CARTs) demonstrated promising efficacy, with 80% of evaluable patients achieving complete remission, including 50% with no detectable residual disease.

The treatment was associated with remarkably low toxicity, as none of the patients experienced severe side effects like neurotoxicity or high-grade cytokine release syndrome, indicating a favorable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. Schubert, ML., Schmitt, A., Hückelhoven-Krauss, A., et al.[2023]

CAR-T cell therapy utilizes genetically modified T cells that express an antibody fragment to specifically target and bind to cancer cells, enhancing the immune response against tumors.

This innovative approach represents a promising advancement in cancer treatment, as it harnesses the body's own immune system to identify and destroy cancer cells more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: From the Bench to the Bedside. Golubovskaya, V.[2020]

Anti-thyroperoxidase autoantibodies (anti-TPO aAbs) from patients' sera showed moderate cytotoxic effects against papillary thyroid cancer cells, utilizing mechanisms like complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).

While recombinant anti-TPO aAbs produced in the lab demonstrated some anti-proliferative effects, they were less effective than those derived from patient sera, indicating that factors like IgG glycosylation play a crucial role in their cytotoxic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human recombinant anti-thyroperoxidase autoantibodies: in vitro cytotoxic activity on papillary thyroid cancer expressing TPO. Rebuffat, SA., Morin, M., Nguyen, B., et al.[2021]

CAR-T cell therapy is highly effective in fighting tumors but can lead to serious side effects, including cytokine release syndrome and neurotoxicity, which require careful management.

As CAR-T therapy expands to treat more patients with various cancers and immune diseases, establishing multidisciplinary teams for safe administration and follow-up is crucial to address both efficacy and potential long-term complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and safety of CAR-T therapy in clinical practice. Serra López-Matencio, JM., Gómez Garcia de Soria, V., Gómez, M., et al.[2022]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

A study of 72 children with thyroid carcinoma (TC) treated between 1991 and 2010 revealed that 40.2% had metastasis at diagnosis, indicating that pediatric TC is often diagnosed at an advanced stage.

The incidence of TC significantly increased in the decade following the Chernobyl nuclear accident, but this trend stabilized after 25 years, highlighting the need for long-term monitoring and tailored treatment strategies for affected children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid cancer in children: a 20-year study at a Romanian oncology institute. Piciu, D., Piciu, A., Irimie, A.[2022]

CD19-targeted CAR T cell therapy has shown remarkable efficacy, achieving complete remission in 70-90% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL), highlighting its potential as a powerful treatment for B cell malignancies.

The ongoing phase I study using a non-viral gene transfer method (piggyBac-transposon system) for CD19 CAR T cell therapy in pediatric and young adult patients indicates a promising direction for expanding treatment options in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies. Nakazawa, Y.[2017]

In a study of 202 patients receiving anti-CD19 CAR-T therapy, those who experienced severe cardiovascular events (SCE) had a significantly higher risk of overall mortality, with a hazard ratio of 2.8, indicating that these events are serious complications that can lead to increased death rates.

Patients who suffered from SCE also showed elevated levels of inflammatory markers like IL-6, CRP, and ferritin, suggesting that monitoring these biomarkers could be important for assessing the risk of mortality in CAR-T therapy recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients. Mahmood, SS., Riedell, PA., Feldman, S., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04877613

NCT04877613 | GFRα4 CAR T Cells in MTC Patients This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells expressing a single-chain scFv targeting GFRα4 with tandem ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11190081/

CAR-T cell therapy in advanced thyroid cancer Further studies showed that the GFRα4 CAR-T had a killing effect on MTC cell lines and leukemia cell lines with high expression of GFRα4 and ...

3. trials.braintumor.org trials.braintumor.org/trials/NCT04877613

GFRα4 CAR T Cells in MTC Patients - Clinical Trial Finder This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells expressing a single-chain scFv targeting GFRα4.

4. withpower.com withpower.com/trial/phase-1-carcinoma-neuroendocrine-7-2021-552e9

CAR T-Cell Therapy for Thyroid Cancer · Info for Participants Research on a similar treatment, ICAM-1 CAR T cells, showed that it effectively killed thyroid cancer cells and improved survival in animal studies. This ...

5. onclive.com onclive.com/view/car-t-cell-therapy-may-represent-a-new-option-in-medullary-thyroid-cancer

CAR T-Cell Therapy May Represent a New Option in ... 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.”