CAR T-Cell Therapy for Thyroid Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Roger Cohen, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

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

Trial Summary

What is the purpose of this trial?

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 TCR/CD3ζ and 4-1BB (TCRζ/4-1BB) co-stimulatory domains (referred to as "CART-GFRa4 cells") in patients with incurable medullary thyroid cancer (MTC).

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.

What data supports the effectiveness of the treatment CART-GFRa4 cells for thyroid cancer?

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 suggests that CAR T-cell therapies can be promising for treating aggressive thyroid cancers. ^{1 2 3 4 5}

Is CAR T-Cell Therapy generally safe for humans?

CAR T-Cell Therapy can cause unusual side effects, including severe cytokine release syndrome (a condition where the immune system releases too many proteins into the blood too quickly) and severe neurological toxicities (serious side effects affecting the brain and nerves). These risks vary depending on the type of cancer being treated and the specific design of the CAR T cells used. ^{6 7 8 9 10}

How is the treatment CART-GFRa4 cells different from other treatments for thyroid cancer?

CART-GFRa4 cells are a type of CAR T-cell therapy, which is a novel treatment that uses genetically engineered T-cells to target specific proteins on cancer cells. Unlike traditional chemotherapy, which can have severe side effects, CAR T-cell therapy offers a more targeted approach, potentially leading to fewer side effects and more durable clinical effects. ^{7 11 12 13 14}

Research Team

Roger Cohen, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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.

Trial Timeline

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)

Treatment Details

Interventions

• CART-GFRa4 cells (CAR T-cell Therapy)

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.

Participant Groups

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+

Dr. Joan Lau

University of Pennsylvania

Chief Executive Officer since 2020

PhD in Neuroscience from the University of Cincinnati College of Medicine, MBA from the Wharton School of Business, BS in Bioengineering from the University of Pennsylvania

Dr. Robert Iannone

University of Pennsylvania

Chief Medical Officer since 2019

MD from Yale University, MSCE from the University of Pennsylvania

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Thyroid cancer in children: a 20-year study at a Romanian oncology institute. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Human recombinant anti-thyroperoxidase autoantibodies: in vitro cytotoxic activity on papillary thyroid cancer expressing TPO. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

New therapies for dedifferentiated papillary thyroid cancer. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Monitoring and safety of CAR-T therapy in clinical practice. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

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

12. Australia pubmed.ncbi.nlm.nih.gov

An Antibody Fab Fragment-based Chimeric Antigen Receptor Could Efficiently Eliminate Human Thyroid Cancer Cells. [2020]

13. Japan pubmed.ncbi.nlm.nih.gov

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

14. France pubmed.ncbi.nlm.nih.gov

CAR-T cells, from principle to clinical applications. [2021]