HER2 CAR-T Therapy for Advanced Solid Tumors

Recruiting at 16 trial locations

Overseen By Fate Trial Disclosure

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fate Therapeutics

Must not be taking: CNS medications

Disqualifiers: Pregnancy, Cardiovascular disease, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-9 weeks

351 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 study designed to evaluate the safety, tolerability, and antitumor activity of FT825 (also known as ONO-8250) with or without monoclonal antibody therapy following chemotherapy in participants with advanced human epidermal growth factor receptor 2 (HER2)-positive or other advanced solid tumors. The study will consist of a dose-escalation stage, followed by an expansion stage to further evaluate the safety and activity of FT825 in indication-specific cohorts.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, if you are taking medications for non-malignant CNS diseases like stroke or epilepsy, you must not have taken them within 2 years prior to joining the study.

What data supports the effectiveness of HER2 CAR-T therapy for advanced solid tumors?

Research shows that HER2 CAR-T cells can effectively target and kill cancer cells that overexpress HER2, a protein found in some tumors. Studies in mice have demonstrated that these engineered T cells can lead to tumor regression and prolonged survival, even in cases where traditional treatments like trastuzumab are ineffective. ^{1 2 3 4 5}

Is HER2 CAR-T therapy safe for humans?

Research suggests that HER2 CAR-NK cells, a type of immune cell therapy, may be a safer alternative to traditional CAR-T cells for treating solid tumors. Unlike CAR-T cells, HER2 CAR-NK cells do not cause severe side effects like cytokine release syndrome (a dangerous immune reaction) and have shown promising safety profiles in studies. ^{2 6 7 8 9}

How is the HER2 CAR-T treatment different from other treatments for advanced solid tumors?

The HER2 CAR-T treatment is unique because it involves genetically modifying T cells to specifically target and destroy cancer cells that overexpress the HER2 protein, which is a common feature in many solid tumors. This approach allows for precise targeting of cancer cells, potentially overcoming resistance seen with other treatments that do not use this targeted method. ^{2 5 10 11 12}

Research Team

Study Director

Principal Investigator

Fate Therapeutics

Eligibility Criteria

This trial is for adults with advanced HER2-positive or other solid tumors. Participants must have measurable disease and be able to receive chemotherapy. They should not have had previous CAR-T therapy, active infections, or any medical conditions that could interfere with the study.

Inclusion Criteria

Anticipated life expectancy of at least 3 months

My cancer is advanced or has spread, confirmed by tests.

I am using birth control as required by local laws for clinical study participants.

Exclusion Criteria

I am not pregnant or breastfeeding.

My organs are not functioning properly.

I have or had an autoimmune disease or immune deficiency.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive chemotherapy prior to the administration of FT825 or FT825 + Cetuximab

4 weeks

Treatment

Participants receive FT825 or FT825 + Cetuximab in Cycle 1, each cycle is approximately 61 days

8-9 weeks

Retreatment

Based on safety and clinical benefit, participants may receive an additional treatment cycle (Cycle 2)

8-9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 2 years

Treatment Details

Interventions

• Cetuximab
• FT825/ONO-8250

Trial Overview The trial is testing FT825 (ONO-8250), a new type of CAR-T cell therapy, combined with standard chemotherapy drugs. Some participants will also receive monoclonal antibodies. The study has two parts: first to find the right dose and then to see how well it works in specific tumor types.

Participant Groups

Group I: Regimen B: FT825 + Cetuximab Experimental Treatment 7 Interventions

Participants with advanced epidermal growth factor receptor (EGFR)-expressing solid tumors receive FT825 in combination with cetuximab following chemotherapy in Cycle 1 (each cycle is approximately 61 days). Based on the safety, tolerability, and radiographically confirmed clinical benefit to treatment in Cycle 1, participants may be considered for an additional treatment cycle (Cycle 2 retreatment).

Group II: Regimen A: FT825 Experimental Treatment 6 Interventions

Participants with advanced HER2-expressing solid tumors receive FT825 following chemotherapy in Cycle 1 (each cycle is approximately 61 days). Based on the safety, tolerability, and radiographically confirmed clinical benefit to treatment in Cycle 1, participants may be considered for an additional treatment cycle (Cycle 2 retreatment).

Who Is Running the Clinical Trial?

Fate Therapeutics

Lead Sponsor

Trials

22

Recruited

1,200+

Findings from Research

The newly engineered HER2-specific sPD-1-CAR-NK cells enhance the immune response against HER2-positive breast cancer by releasing bioactive soluble PD-1, which improves the cytotoxic activity of these cells against cancer targets.

In mouse models, sPD-1-CAR-NK cells demonstrated superior anticancer efficacy compared to traditional HER2-CAR-NK cells, with increased infiltration and activation of immune cells in tumor tissues and no significant side effects observed, making it a promising treatment for trastuzumab-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy. Xia, W., Chen, J., Hou, W., et al.[2023]

The chA21-4-1BBz CAR T cells demonstrated a strong ability to target and kill HER2 overexpressing gastric cancer cells in laboratory tests, showing a Th1 skewed cytokine response that correlates with HER2 levels on tumor cells.

In animal models, these CAR T cells significantly reduced tumor size and improved survival in mice with HER2 overexpressing tumors, while not affecting tumors with low HER2 expression, indicating a targeted and potentially safer treatment approach for gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. Han, Y., Liu, C., Li, G., et al.[2020]

In a Phase 1 study involving 21 Japanese patients with advanced solid tumors, neratinib was found to have a maximum-tolerated dose of 240 mg daily, with common side effects including diarrhea and fatigue.

The study showed that neratinib led to partial responses in 2 breast cancer patients and stable disease in several others, indicating its potential efficacy in treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study. Ito, Y., Suenaga, M., Hatake, K., et al.[2022]

HER2 positive JIMT-1 breast tumors are resistant to trastuzumab, but T cells engineered with a second-generation CAR targeting HER2 can effectively eliminate these resistant tumors, demonstrating their potential in overcoming trastuzumab resistance.

In SCID mice, even a small number of CAR T cells (as few as 17,500) can lead to complete remission of HER2 positive tumors, suggesting that optimizing CAR T cell dosing could enhance treatment efficacy for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Small Number of HER2 Redirected CAR T Cells Significantly Improves Immune Response of Adoptively Transferred Mouse Lymphocytes against Human Breast Cancer Xenografts. Tóth, G., Szöllősi, J., Abken, H., et al.[2020]

CAR T-cell immunotherapy, which involves genetically modifying T cells to target cancer cells, has shown promising results, especially in treating B-cell malignancies with several patients achieving complete and durable responses.

Current research is expanding CAR T-cell therapy to solid tumors, specifically targeting members of the ErbB family, indicating a potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ErbB-targeted CAR T-cell immunotherapy of cancer. Whilding, LM., Maher, J.[2022]

HER2 CAR-engineered natural killer (NK) cells significantly enhance anti-tumor activity against HER2-expressing cancer cells, showing greater cytotoxicity than traditional CAR-T cells, especially in solid tumors.

Unlike CAR-T cells, HER2 CAR-NK cells do not cause harmful effects on non-cancerous cells, making them a safer option for immunotherapy in treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. Portillo, AL., Hogg, R., Poznanski, SM., et al.[2021]

CAR-engineered NK-92 cells targeting the ErbB2 antigen showed effective tumor cell killing in laboratory tests and maintained their antitumor activity in live models, indicating their potential for cancer treatment.

Using γ-irradiation as a safety measure can prevent the replication of these NK cells while still allowing them to effectively attack tumors, making them a promising candidate for clinical use in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Schönfeld, K., Sahm, C., Zhang, C., et al.[2021]

Chimeric antigen receptor-transduced natural killer (CAR-NK) cells offer a promising cancer immunotherapy option by providing rapid and potent cytotoxicity without the toxic side effects commonly associated with T cell therapies, such as cytokine release syndrome and graft-versus-host disease.

CAR-NK cells can be produced on a large scale as 'off-the-shelf' products, making them a practical solution for widespread clinical use in enhancing immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK cells for cancer immunotherapy: from bench to bedside. Zhang, L., Meng, Y., Feng, X., et al.[2022]

HER2 CAR T-cell therapy shows promise for treating solid tumors, particularly in cancers like breast cancer, but it carries significant risks of severe side effects, such as cytokine release syndrome due to targeting HER2 on non-cancerous tissues.

The review highlights ongoing efforts to enhance the safety of HER2 CAR therapies through novel designs and alternative CAR host selections, aiming to minimize the risk of toxicities while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving better and safer HER2-specific CARs for cancer therapy. Liu, X., Zhang, N., Shi, H.[2019]

HER2 is commonly expressed in osteosarcoma but at low levels, making traditional HER2 monoclonal antibody treatments ineffective; however, genetically modified T cells with HER2-specific chimeric antigen receptors (CARs) can effectively target these tumors.

In mouse models, the adoptive transfer of HER2-specific T cells led to significant regression of established osteosarcoma tumors, demonstrating the potential of CAR T-cell therapy in treating cancers with low antigen expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Ahmed, N., Salsman, VS., Yvon, E., et al.[2021]

The engineered T1E28z chimeric antigen receptor effectively activates T cells against various tumor cells by targeting multiple ErbB receptor combinations, demonstrating its potential for broad application in cancer therapy.

In mouse models with established tumors overexpressing ErbB1/2 or ErbB2/3, T1E28z⁺ T cells showed significant antitumor activity, suggesting this immunotherapeutic approach could overcome resistance seen with traditional ErbB-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Davies, DM., Foster, J., Van Der Stegen, SJ., et al.[2022]

Genetically modified NK-92 cells expressing a chimeric antigen receptor targeting the ErbB2 (HER2/neu) antigen can specifically kill tumor cells that overexpress this marker, which is common in many epithelial tumors.

These NK-92-scFv(FRP5)-zeta cells maintain their safety profile by not affecting normal human cells and demonstrate enhanced cytotoxicity against resistant ErbB2-expressing tumors, indicating their potential for effective cell-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Uherek, C., Tonn, T., Uherek, B., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy. [2023]

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

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A Small Number of HER2 Redirected CAR T Cells Significantly Improves Immune Response of Adoptively Transferred Mouse Lymphocytes against Human Breast Cancer Xenografts. [2020]

5. England pubmed.ncbi.nlm.nih.gov

ErbB-targeted CAR T-cell immunotherapy of cancer. [2022]

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

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. [2021]

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

Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. [2021]

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

CAR-NK cells for cancer immunotherapy: from bench to bedside. [2022]

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

Driving better and safer HER2-specific CARs for cancer therapy. [2019]

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

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. [2022]

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

Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. [2021]