CAR T-Cell Therapy + Checkpoint Inhibitors for Sarcoma

Overseen By Brandon Garner

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: HIV, Autoimmune disease, Organ transplant, others

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

Compensation: Varies

Number of Visits: 2

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for HER2-positive sarcoma. The treatment combines specially modified immune cells, called HER2-CAR T cells (a type of CAR T-cell therapy), with drugs known as checkpoint inhibitors that enhance the immune system's ability to fight cancer. Researchers aim to determine if this combination is safe and effective in treating sarcoma. They are also examining whether gut bacteria types influence the treatment's effectiveness. Individuals with HER2-positive sarcoma that is worsening or recurring after treatment might be suitable for this trial. 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 protocol does not specify if you need to stop taking your current medications. However, you must be at least 4 weeks from your last cytotoxic chemotherapy and at least 7 days or 3 drug half-lives from your last targeted therapy, and you must have recovered from any acute toxic effects.

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

In a previous study, HER2-CAR T cells remained active for about six weeks without causing noticeable side effects, indicating good safety. Research on pembrolizumab, a checkpoint inhibitor, found it safe and beneficial for people with advanced sarcomas, with most patients tolerating it well. Nivolumab, another checkpoint inhibitor, caused side effects in about half of the patients, though only a few experienced severe reactions.

This trial is in its first phase, primarily assessing the treatment's safety. Early trials focus on safety, but unknown risks may still exist. Both pembrolizumab and nivolumab are already used for other conditions, so their safety profiles are well-established. However, combining them with HER2-CAR T cells is new, making it crucial to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because, unlike standard sarcoma therapies like surgery, chemotherapy, and radiation, HER2-CAR T cell therapy represents a new frontier by harnessing the immune system to specifically target cancer cells. This treatment involves engineering a patient's own T cells to recognize and attack tumor cells that express the HER2 protein, offering a highly targeted approach. Additionally, combining these modified cells with checkpoint inhibitors like pembrolizumab or nivolumab can potentially enhance the treatment's effectiveness by preventing the cancer from evading immune detection. This innovative approach not only promises to be more precise but may also lead to better outcomes with fewer side effects compared to traditional therapies.

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

Research has shown that HER2-CAR T cells, one of the treatments in this trial, hold promise in fighting cancer, including sarcoma. These cells can remain in the body for up to six weeks and have been effective against certain sarcoma cells. In this trial, some participants will receive HER2-CAR T cells combined with pembrolizumab, a PD-1 antibody. Studies have found that pembrolizumab can help patients with soft tissue sarcoma live longer without disease progression. Other participants will receive HER2-CAR T cells with nivolumab, another PD-1 antibody, which has demonstrated good response rates in various types of sarcoma. Combining these treatments might enhance their ability to locate and destroy cancer cells in sarcoma patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Meenakshi Hegde, MD

Principal Investigator

Baylor College of Medicine

Shoba Navai, MD

Principal Investigator

Baylor College of Medicine

Nabil Ahmed, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for young patients aged 1-25 with HER2-positive sarcoma, who have normal heart function and organ health. They must not be pregnant or breastfeeding, agree to use contraception if of childbearing potential, and have no severe allergies to the drugs used in this study. Patients with certain heart conditions, active infections, HIV or tuberculosis are excluded.

Inclusion Criteria

WBC > 2,000/µl

Hgb ≥ 7.0 g/dL (transfusion allowed)

ANC >1,000/ul

Exclusion Criteria

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

Intercurrent infection

My cancer has formed a large tumor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion Chemotherapy

Participants receive cyclophosphamide for 2 days followed by fludarabine for 5 days to prepare for CAR T cell infusion

1 week

Daily visits (in-person)

CAR T Cell Infusion

Participants receive HER2 CAR T cells intravenously, followed by monitoring for up to 4 hours

1 day

1 visit (in-person)

Checkpoint Inhibitor Treatment

Participants receive pembrolizumab every three weeks or nivolumab every two weeks, starting one week after CAR T cell infusion

6 weeks

Bi-weekly or tri-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including blood tests and imaging studies

15 years

Regular visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide and Fludarabine
• HER2-CAR T cells
• Nivolumab
• Pembrolizumab

Trial Overview The trial tests a combination of genetically modified T cells (HER2-CAR T cells) and immune checkpoint inhibitors (pembrolizumab or nivolumab). It aims to see if this mix can safely treat advanced sarcoma by enhancing the body's immune response against cancer after pre-treatment with lymphodepletion chemotherapy.

How Is the Trial Designed?

Group I: Arm A Experimental Treatment 2 Interventions

autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody pembrolizumab

Group II: Arm 2 Experimental Treatment 2 Interventions

autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody nivolumab

Cyclophosphamide and Fludarabine is already approved in United States, European Union for the following indications:

Approved in United States as Cyclophosphamide for:

• Leukemia
• Lymphoma
• Multiple myeloma
• Ovarian cancer
• Breast cancer
• Neuroblastoma
• Retinoblastoma
• Ewing's sarcoma

Approved in United States as Fludarabine for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Approved in European Union as Cyclophosphamide for:

• Malignant lymphoma
• Multiple myeloma
• Leukaemia
• Myeloproliferative diseases
• Autoimmune diseases

Approved in European Union as Fludarabine for:

• Chronic lymphocytic leukaemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Faris Foundation USA

Collaborator

Trials

1

Recruited

30+

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Triumph Over Kid Cancer Foundation

Collaborator

Trials

1

Recruited

30+

St. Baldrick's Foundation

Collaborator

Trials

19

Recruited

9,100+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FC-R) resulted in high objective response rates (83%) and complete response rates (42%) among 76 evaluable patients, demonstrating its efficacy in treating chronic lymphocytic leukemia (CLL) and follicular lymphoma.

Patients with CLL showed particularly impressive results, with 100% objective response and 67% complete response rates when treated as first-line therapy, indicating that FC-R is a potent option for both initial and salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Tam, CS., Wolf, M., Prince, HM., et al.[2015]

Immunotherapy, including cancer vaccines and cytokines, has been combined with chemotherapy to enhance treatment efficacy, with cyclophosphamide (CYC) used to inhibit tumor suppressor influences in both rodents and humans.

While combinations of immunotherapy and chemotherapy can lead to higher response rates in cancers like melanoma, the long-term survival benefits are often marginal and may not justify the associated severe toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinations of anticancer drugs and immunotherapy. Mitchell, MS.[2015]

Doxorubicin, when used in combination with genetically-modified cancer cell vaccines, showed immunostimulatory effects that enhanced cure rates in established CT26 tumors, suggesting a promising approach for advanced cancer treatment.

In contrast, cyclophosphamide was found to be immunosuppressive and did not improve cure rates when combined with the vaccine, indicating that not all antineoplastic drugs are suitable for combination therapy with cancer vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. Nigam, A., Yacavone, RF., Zahurak, ML., et al.[2020]

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

CAR T cell therapy, which uses genetically engineered T cells to target cancer cells, has shown significant success in treating B cell malignancies by specifically targeting the CD19 antigen.

While CAR T cells have proven effective in hematologic cancers, research is ongoing to expand their use in solid tumors, with various targets like GD2 and HER2 currently under investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cell Based Immunotherapy for Cancer. Li, F., Zhang, T., Cao, L., et al.[2018]

CAR T cell therapy shows promise for treating pediatric sarcomas, with early trials indicating positive outcomes for some patients, despite challenges in effectiveness due to the immunosuppressive tumor microenvironment.

Current clinical trials are exploring CAR T cells targeting various tumor antigens like HER2 and GD2, and new strategies are being developed to enhance the efficacy of these therapies against the immunosuppressive effects of the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma. Terry, RL., Meyran, D., Fleuren, EDG., 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]

The combination of fludarabine and cyclophosphamide effectively reduces tumor burden in chronic lymphocytic leukemia, but it also leads to a significant reduction in CD4(+) and CD8(+) T cells, indicating potential immunosuppressive effects.

Despite the depletion of T cells, the surviving T cells exhibit a more mature phenotype and increased responsiveness to stimulation, suggesting that fludarabine/cyclophosphamide therapy may create a favorable environment for subsequent T cell activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. Gassner, FJ., Weiss, L., Geisberger, R., et al.[2021]

In a study of 199 adult patients with aggressive B-cell non-Hodgkin lymphomas, an optimal fludarabine exposure (18-20 mg×hour/L) was associated with the best progression-free survival (66%) and lowest risk of disease relapse compared to lower and higher exposure groups.

Higher fludarabine exposure (>20 mg×hour/L) increased the risk of immune effector cell-associated neurotoxicity syndrome (ICANS) and nonrelapse-related deaths, indicating that careful dosing is crucial for balancing efficacy and safety in patients receiving axicabtagene ciloleucel (Axi-cel).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma. Scordo, M., Flynn, JR., Gonen, M., et al.[2023]

In a study of 129 patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, different CD19 CAR T-cell products showed significant variations in toxicity and efficacy, with JCAR014 associated with lower severity of cytokine release syndrome and neurotoxicity compared to axicabtagene ciloleucel (axicel).

While JCAR014 and tisagenlecleucel (tisacel) had lower odds of complete response compared to axicel, the study highlights that the type of CAR T-cell product can independently influence treatment outcomes, emphasizing the importance of product selection in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL. Gauthier, J., Gazeau, N., Hirayama, AV., et al.[2023]

In a study of 26 patients with relapsed/refractory B-cell acute lymphoblastic leukemia receiving CD19 CAR T-cell therapy, higher cumulative exposure to fludarabine (≥14 mg*h/L) was linked to significantly better leukemia-free survival (12.9 months) compared to lower exposure (<14 mg*h/L, 1.8 months).

Patients with lower fludarabine exposure also experienced a higher rate of CD19-positive relapse (100% vs. 27.4%) and shorter duration of B-cell aplasia, indicating that optimizing fludarabine dosing could improve outcomes in CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Dekker, L., Calkoen, FG., Jiang, Y., et al.[2022]

In a clinical trial involving 32 adults with relapsed B cell non-Hodgkin's lymphoma, CD19 CAR-T cells showed significantly improved efficacy when administered after cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion, achieving a 50% complete remission rate and a 72% overall response rate.

The study identified that the Cy/Flu regimen enhanced CAR-T cell expansion and persistence while minimizing immune responses that could limit efficacy, although it also resulted in severe cytokine release syndrome and neurotoxicity in a notable percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Turtle, CJ., Hanafi, LA., Berger, C., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25800760/

Human Epidermal Growth Factor Receptor 2 (HER2) - PubMed This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04995003

NCT04995003 | HER2 Chimeric Antigen Receptor (CAR) T ... The purpose of this study is to learn whether it is safe to give HER2-CAR T cells in combination with an immune checkpoint inhibitor drug (pembrolizumab or ...

3. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1514994/full

Research progress on HER2-specific chimeric antigen ... This HER2-CAR-T cell construct has demonstrated superior cancer growth inhibition compared to traditional CAR-T cells (35). A research group ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1936523321002199

Effectiveness of 4-1BB-costimulated HER2-targeted ... This is the first study to indicate that HER2-targeted CAR T cells are directly effective against molecularly defined synovial sarcoma cells.

5. ecancer.org ecancer.org/en/news/24633-car-t-cell-therapy-targeting-her2-antigen-shows-promise-against-advanced-sarcoma-in-phase-i-trial

CAR T cell therapy targeting HER2 antigen shows promise ... The HEROS 2.0 trial showed that this therapeutic approach is safe and is associated with clinical benefit.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5747970/

HER2-Specific Chimeric Antigen Receptor–Modified Virus ... For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1–27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2–34.6 ...

7. nature.com nature.com/articles/s41419-021-04100-0

HER2-specific chimeric antigen receptor-T cells ... - Nature Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, ...