CAR T-Cell Therapy for Sarcoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with sarcoma, a type of cancer, who have not responded to standard treatments. The treatment employs a special type of immune cell, called CAR T-cells (a form of immunotherapy), which are modified to better recognize and attack cancer cells. The goal is to determine the safest dose and assess whether this approach can combat sarcoma. Participants who might be suitable include those with HER2-positive sarcoma that has returned or spread, particularly if previous treatments were ineffective. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that patients with sarcoma have safely received up to 100 million HER2-specific CAR T-cells per square meter of body surface area. Early results suggest that these special T-cells, combined with the chemotherapy drugs fludarabine and cyclophosphamide, are safe for treating sarcoma. These drugs enhance the effectiveness of the T-cells and are well-documented in other studies.

Previous research indicates that using these T-cells, with or without chemotherapy, is safe. Studies suggest that targeting HER2 with CAR T-cells is promising, and patients generally tolerate the treatment well. Although this is early research, the data so far suggest that the therapy is safe at the doses tested. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CAR T-Cell Therapy for sarcoma because it offers a novel approach, unlike traditional treatments such as surgery, chemotherapy, or radiation. This therapy involves using genetically modified T cells, specifically designed to target and attack cancer cells, which can lead to more precise and effective treatment. In particular, the HER2-specific T cells are engineered to recognize and bind to HER2 proteins often overexpressed in sarcoma, potentially making the treatment more targeted. Additionally, combining these T cells with drugs like fludarabine and cyclophosphamide could enhance the body's immune response, offering a unique mechanism compared to the standard therapies. This innovative approach could pave the way for more personalized and effective sarcoma treatments.

What evidence suggests that this trial's treatments could be effective for sarcoma?

Research has shown that CAR T-cell therapy could be a promising treatment for sarcoma. In this trial, participants may receive different treatments involving CAR T-cells. One arm involves Autologous HER2-specific T cells, while another combines HER2-specific T cells with chemotherapy drugs like fludarabine and cyclophosphamide. Studies have demonstrated that patients with sarcoma safely handled high doses of these specially engineered T-cells, which are designed to find and destroy cancer cells. The data revealed that 50% of patients benefited from the treatment, with some maintaining their positive response for over six months. When HER2-specific T cells were combined with chemotherapy, the treatment proved effective, with 21% of patients achieving a complete response and 29% experiencing stable disease. These findings suggest that CAR T-cell therapy might help the body better fight sarcoma by enhancing its ability to attack cancer cells. ^{1 3 6 7 8}

Who Is on the Research Team?

Nabil M Ahmed, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Are You a Good Fit for This Trial?

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

My T cells are modified to target HER2 and show strong activity against HER2 cancer cells.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11588040/

Autologous HER2-specific CAR T-cells after lymphodepletion ... In this study, patients with sarcoma safely tolerated up to 1×108 total T-cells/m2 (~0.8×108 CAR-positive T-cells/m2) of HER2-CART infused after ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9006280/

Fludarabine exposure predicts outcome after CD19 CAR T ... Exposure of fludarabine was shown to be a predictor for leukemia-free survival (LFS), B-cell aplasia, and CD19-positive relapse following CAR T-cell infusion.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00902044

Study Details | NCT00902044 | Her2 Chimeric Antigen ... 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 ...

4. ashpublications.org ashpublications.org/blood/article/138/Supplement%201/3871/481078/Fludarabine-Exposure-Predicts-Outcome-after-CD19

Fludarabine Exposure Predicts Outcome after CD19 CAR T ... Exposure of fludarabine was shown to be a predictor for leukemia free survival, B cell aplasia, and CD19+ relapse following CAR T cell infusion.

5. nature.com nature.com/articles/s41571-023-00754-1

Long-term outcomes following CAR T cell therapy Data from these studies confirm the excellent initial CR rates ranging from 62% to 86%, with the majority of these being deep minimal residual ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38658775/

Autologous HER2-specific CAR T cells after lymphodepletion ... Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov ...

7. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2619711

HER2-Specific Chimeric Antigen Receptor–Modified Virus ... Eight patients had a clinical benefit, with a median overall survival of 11.1 months after T-cell infusion and 24.5 months after diagnosis, and ...

8. curesarcoma.org curesarcoma.org/sarcoma-research/autologous-her2-specific-car-t-cells-after-lymphodepletion-for-advanced-sarcoma-a-phase-1-trial/

Autologous HER2-specific CAR T cells after lymphodepletion ... This study had two objectives.The primary outcome was to assess the safety of one dose of HER2 CAR T cells. The secondary outcome was to determine if this ...