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

Trial Summary

What is the purpose of this trial?

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 nivolumab), to learn what the side effects are, and to see whether this therapy might help patients with sarcoma. Another goal of this study is to study the bacteria found in the stool of patients with sarcoma who are being treated with HER2 CAR T cells and immune checkpoint inhibitor drugs to see if the types of bacteria influence how well the treatment works. The investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. They now want to see if they can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that the investigators 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. After this new gene is put into the T cell, the T cell becomes known as a chimeric antigen receptor T cell or CAR T cell. In another clinical study using these CAR T cells targeting HER2 as well as other studies using CAR T cells, investigators found that giving chemotherapy before the T cell infusion can improve 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 the patient's lymphocytes first should allow the infused T cells to expand in the body, and potentially kill cancer cells more effectively. The chemotherapy used for lymphodepletion is a combination of cyclophosphamide and fludarabine. After the patient receives the lymphodepletion chemotherapy and CAR T cells during treatment on the study, they will receive an antibody drug called an immune checkpoint inhibitor, pembrolizumab or nivolumab. Immune checkpoint inhibitors are drugs that remove the brakes on the immune system to allow it to act against cancer.

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.

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

Research shows that fludarabine and cyclophosphamide, when used together, can effectively reduce tumor cells and create a favorable environment for T cell activation, which is crucial for CAR T-cell therapy. Additionally, fludarabine has been shown to improve outcomes in CAR T-cell therapy for leukemia, suggesting potential benefits in similar treatments. ^{1 2 3 4 5}

Is CAR T-Cell Therapy with Cyclophosphamide and Fludarabine safe for humans?

Cyclophosphamide and fludarabine, used before CAR T-cell therapy, can cause significant reduction in certain immune cells, but they also create a suitable environment for T-cell activation. Some patients may experience side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), but these risks can be managed with careful dosing. ^{1 5 6 7 8}

How is the CAR T-Cell Therapy + Checkpoint Inhibitors treatment for sarcoma different from other treatments?

This treatment is unique because it uses genetically engineered T cells (a type of immune cell) to specifically target and kill cancer cells by recognizing a protein called HER2 on their surface, which is different from traditional chemotherapy that attacks all rapidly dividing cells. Additionally, the combination with checkpoint inhibitors helps to enhance the immune response against the tumor, offering a novel approach for sarcomas where standard treatments are limited. ^{1 9 10 11 12}

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

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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]

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 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, 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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. [2021]

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

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. [2015]

3. Germany pubmed.ncbi.nlm.nih.gov

Combinations of anticancer drugs and immunotherapy. [2015]

4. Greece pubmed.ncbi.nlm.nih.gov

Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. [2020]

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

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. [2022]

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

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma. [2023]

7. United States 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. [2022]

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

Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

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

Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma. [2021]

12. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cell Based Immunotherapy for Cancer. [2018]