CAR T-Cell Therapy for Sarcoma

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Disqualifiers: HIV, Severe infection, Pregnant, others

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

Compensation: Varies

Number of Visits: 1

36 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients have a type of cancer called sarcoma. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients. We have found from previous research that we can put a new gene into T cells that will make them recognize cancer cells and kill them. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively. We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials. The purpose of this study is to find the largest safe dose of chimeric T cells, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have recovered from the effects of any prior chemotherapy at least 4 weeks before starting the study. PD1/PDL1 inhibitors can be continued if medically necessary.

What data supports the effectiveness of the treatment CAR T-Cell Therapy for Sarcoma?

Research shows that CAR T-cell therapy, which involves modifying a patient's own immune cells to target cancer, has been effective in treating other cancers like B-cell lymphoma and leukemia. Studies also indicate that HER2-specific CAR T-cells can recognize and kill HER2-positive osteosarcoma cells, suggesting potential effectiveness for sarcoma treatment. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy has shown effectiveness in treating certain cancers, but it can cause serious side effects, including life-threatening reactions like cytokine release syndrome (a severe immune response) and neurologic toxicity. These risks highlight the importance of careful management and monitoring during treatment. ^{1 6 7 8 9}

How is CAR T-Cell Therapy for Sarcoma different from other treatments?

CAR T-Cell Therapy for Sarcoma is unique because it involves genetically modifying a patient's own T cells to specifically target and kill cancer cells expressing the HER2 protein, even at low levels. This approach is different from traditional treatments as it uses the body's immune system to fight cancer, offering a novel option for sarcomas that do not respond well to standard therapies. ^{1 2 3 10 11}

Research Team

Nabil M Ahmed, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Eligibility Criteria

This trial is for patients with HER2-positive sarcoma that's resistant to treatment or has spread, and who've tried at least one therapy before. They should have recovered from previous chemo effects, have a decent quality of life score (Karnofsky/Lansky score), normal heart function, reasonable life expectancy (6 weeks+), stable blood counts and organ functions. They must not be HIV positive, pregnant, breastfeeding, have severe infections or allergies to certain drugs.

Inclusion Criteria

Chest radiograph for baseline evaluation of lungs

Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Bilirubin 3x or less, AST 3x or less, Serum creatinine 2x upper limit of normal or less, Hgb 7.0 g/dl or greater, WBC greater than 2,000/ul, ANC greater than 1,000/ul, platelets greater than 100,000/ul. Creatinine clearance is needed for patients with creatinine greater than 1.5 times upper limit of normal

Exclusion Criteria

I do not have a severe infection at the time of treatment.

At time of Procurement: Known HIV positivity

Known HIV positivity

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive fludarabine or a combination of fludarabine and cyclophosphamide for lymphodepletion before T-cell infusion

5 days

In-patient treatment

T-cell Infusion

Participants receive HER2-CD28 T cells via IV infusion

1 day

1 visit (in-person)

Initial Follow-up

Participants are monitored for toxicity and tumor response after T-cell infusion

6 weeks

Regular clinic visits

Extended Follow-up

Participants are monitored for long-term side effects of gene transfer

15 years

Treatment Details

Interventions

• Autologous CAR Positive T cells
• Autologous HER2-specific T cells
• Cyclophosphamide
• Fludarabine

Trial Overview The study tests genetically modified T cells designed to target and kill cancer cells in advanced sarcoma by introducing a new gene making them recognize the HER2 protein on tumors. It also examines if using chemotherapy (fludarabine alone or with cyclophosphamide) before T cell infusion – known as lymphodepletion – can enhance the treatment's effectiveness.

Participant Groups

Group I: HER2-specific T cells+fludarabine Experimental Treatment 2 Interventions

Autologous HER2-specific T cells+fludarabine: Dose Level 9A: fludarabine followed by 1x10\^8 cells/m\^2

Group II: HER2-specific T cells+fludarab.+cycloph. Experimental Treatment 3 Interventions

Autologous HER2-specific T cells+fludarabine+cyclophosphamide: Dose Level 9B: fludarabine + cyclophosphamide followed by 1x10\^8 cells/m\^2

Group III: CAR Positive cells Experimental Treatment 4 Interventions

Dose Level 9C: fludarabine + cyclophosphamide followed by 1x10\^8 cells/m\^2 CAR positive cells/m\^2

Group IV: Autologous HER2-specific T cells Experimental Treatment 1 Intervention

THIS ARM IS CLOSED Dose Level 1: 1x10\^4 cells/m2 Dose Level 2: 3x10\^4 cells/m2 Dose Level 3: 1x10\^5 cells/m2 (NOT BEING USED) Dose Level 4: 3x10\^5 cells/m2 (NOT BEING USED) Dose Level 5: 1x10\^6 cells/m2 Dose Level 6: 3x10\^6 cells/m2 Dose Level 7: 1x10\^7 cells/m2 Dose Level 8: 3x10\^7 cells/m2 Dose Level 9: 1x10\^8 cells/m2

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Cancer Prevention Research Institute of Texas

Collaborator

Trials

55

Recruited

98,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

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]

CAR T Cell therapy is a promising new treatment for sarcomas, which have seen stagnant survival rates, particularly in recurrent or metastatic cases, highlighting the urgent need for novel therapies.

Recent studies have identified several sarcoma-associated antigens suitable for CAR T Cell targeting, such as HER2 and GD2, showing encouraging results and suggesting that this therapy could improve outcomes for sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. Thanindratarn, P., Dean, DC., Nelson, SD., et al.[2020]

CAR-T cell therapy has shown effective tumor-killing activity in treating B cell-derived hematological tumors and is being explored for solid tumors, indicating its potential as a versatile cancer treatment.

However, the therapy can lead to serious and potentially life-threatening adverse events, highlighting the need for careful monitoring and management strategies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. Chen, X., Li, P., Tian, B., et al.[2023]

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]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

The phase 1 trial showed that NY-ESO-1-specific TCR-T cells are both safe and effective for treating advanced soft tissue sarcomas, marking a significant advancement in adoptive T cell therapy.

This study represents an important step in the clinical application of T cell therapies, potentially offering new hope for patients with this challenging type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pushing forward in sarcoma with a new TCR targeting NY-ESO-1. Al-Marayaty, R., Pollack, SM.[2023]

References

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

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

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

Chimeric Antigen Receptor-modified T cells targeting EphA2 for the immunotherapy of paediatric bone tumours. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. [2020]

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

Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. [2022]

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

Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. [2023]

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

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

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

Toxicity and management in CAR T-cell therapy. [2023]

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

Pushing forward in sarcoma with a new TCR targeting NY-ESO-1. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Cancer therapy in mice using a pure population of CD8+ T cell specific to the AH1 tumor rejection antigen. [2022]

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

Generation of tumor-reactive CTL against the tumor-associated antigen HER2 using retrovirally transduced dendritic cells derived from CD34+ hemopoietic progenitor cells. [2023]