CARv3-TEAM-E T Cells for Glioblastoma

Overseen By William Curry, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Marcela V. Maus, M.D.,Ph.D.

Must not be taking: Immunosuppressants, Investigational agents

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 8

Duration: 6 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this research study is to determine the best dose of CARv3-TEAM-E T Cells for treating participants with glioblastoma. The name of the treatment intervention used in this research study is: -CARv3-TEAM-E T Cells (or Autologous T lymphocytes).

Do I need to stop taking my current medications for the trial?

Participants must stop taking certain medications before joining the trial. Specifically, they need to be 4 weeks from their last dose of alkylating therapy or immunotherapy and must wait for at least 5 half-lives from another investigational agent. However, no washout period is required for radiation therapy.

What data supports the effectiveness of the CARv3-TEAM-E T Cells treatment for glioblastoma?

Research shows that CAR T-cell therapy, which involves modifying a patient's own T cells to better target cancer cells, has shown promise in treating glioblastoma by activating the immune system and potentially improving the tumor environment. Although still in early stages, studies have observed some signs of effectiveness in patients with glioblastoma, suggesting that this approach could help in fighting this challenging cancer. ^{1 2 3 4 5}

Is CARv3-TEAM-E T Cells therapy safe for humans?

CAR T-cell therapy, including versions like CARv3-TEAM-E T Cells, has shown feasibility and safety in clinical studies for glioblastoma, although it can create an immunosuppressive environment in the brain. ^{1 3 6 7 8}

How is the CARv3-TEAM-E T Cells treatment different from other treatments for glioblastoma?

The CARv3-TEAM-E T Cells treatment is unique because it uses genetically modified T cells to specifically target and attack glioblastoma cells, potentially overcoming the challenges of the tumor's location and immune evasion. This approach is different from traditional treatments as it aims to enhance the body's immune response directly against the tumor. ^{3 5 9 10 11}

Research Team

William Curry, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults with recurrent glioblastoma, a type of brain tumor. Participants must have had prior radiation, measurable disease, and be able to undergo an MRI. They should not have other ongoing serious illnesses or a history of certain cancers within the last 5 years (with some exceptions). Adequate organ function and agreement to use contraception are required.

Inclusion Criteria

My cancer has returned for the first time and I've had radiation before.

My cancer has returned or worsened for the first time and I've had radiation before.

I expect to take 4 mg or less of dexamethasone daily at the start of my CAR-v3-TEAM-E treatment.

Exclusion Criteria

I have received treatments targeting EGFRvIII before.

I've completed most of my radiation therapy without using temozolomide before getting CARv3-TEAM-E Infusion.

I am breastfeeding and receiving CARv3-TEAM-E treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Safety Run-In

Participants receive 1 infusion of CARv3-TEAM-E, with staggered enrollment and evaluation for dose-limiting toxicities

Up to 6 months

1 visit (in-person)

Treatment

Participants receive CARv3-TEAM-E T Cells weekly for 6 doses

6 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Regular follow-up visits

Long-term Follow-up

Participants are monitored for long-term safety and survival outcomes

Up to 15 years

Treatment Details

Interventions

• CARv3-TEAM-E T Cells

Trial Overview The study is testing CARv3-TEAM-E T cells to find the best dose for treating glioblastoma. These are modified immune cells designed to target and destroy cancer cells in patients who've seen their cancer return after initial treatment.

Participant Groups

Group I: Safety Run-In Phase Experimental Treatment 1 Intervention

* Participant enrollment will be staggered by 30 days for up to 3 participants. * Participants will receive 1 infusion of CARv3-TEAM-E. * Phase will be expanded up to 6 participants if any Dose-Limiting Toxicities DLTs occur. * After all participants have been enrolled, there will be an evaluation made by the Data Safety Monitoring Board (DSMB) and the FDA to determine the safety of enrollment into additional arms.

Group II: Arm 3: Recurrent GBM, EGFRvIII Negative Experimental Treatment 1 Intervention

* Participants will undergo a leukapheresis procedure, or collection of mononuclear T cells via peripheral blood draw. * CARv3-TEAM-E will be administered 1x weekly for 6 doses on Days 0, 7, 14, 21, 28, and 36. * Participants will be followed for 2 years post-treatment.

Group III: Arm 2: Newly Diagnosed GBM, EGFRvIII Positive Experimental Treatment 1 Intervention

* Participants will undergo a leukapheresis procedure, or collection of mononuclear T cells via peripheral blood draw. * CARv3-TEAM-E will be administered 1x weekly for 6 doses on Days 0, 7, 14, 21, 28, and 36. * Participants will be followed for 2 years post-treatment.

Group IV: Arm 1: Recurrent Glioblastoma (GBM), EGFRvIII Positive Experimental Treatment 1 Intervention

* Participants will undergo a leukapheresis procedure, or collection of mononuclear T cells via peripheral blood draw. * CARv3-TEAM-E will be administered 1x weekly for 6 doses on Days 0, 7, 14, 21, 28, and 36. * Participants will be followed for 2 years post-treatment.

Who Is Running the Clinical Trial?

Marcela V. Maus, M.D.,Ph.D.

Lead Sponsor

Trials

6

Recruited

110+

Findings from Research

CAR-T cell therapy is now an approved treatment for relapsed/refractory B-cell malignancies and is gaining attention for its potential application in solid tumors, particularly those that are immunologically 'cold' like glioblastoma.

This therapy works by genetically engineering a patient's own T cells to target tumor-associated antigens, which may help overcome the challenges posed by the hostile tumor microenvironment, although research in solid tumors is still in its early stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma. Brown, MP., Ebert, LM., Gargett, T.[2021]

CAR T-cell therapy not only targets tumors directly but also activates the body's own immune system, enhancing the response against glioblastoma (GBM) by promoting T-cell memory and activating myeloid cells.

The effectiveness of CAR T-cell therapy in GBM is significantly linked to IFNγ signaling, which helps remodel the tumor microenvironment to support stronger antitumor immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. Alizadeh, D., Wong, RA., Gholamin, S., et al.[2022]

CAR T-cell therapy, which involves modifying a patient's own T cells to target cancer cells, has shown promising safety and feasibility in treating glioblastoma, a type of brain cancer, despite the challenges associated with this disease.

Some patients with glioblastoma have experienced signs of efficacy from CAR T-cell therapy, indicating potential for this treatment approach, even though significant barriers to effective T-cell function remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Bagley, SJ., Desai, AS., Linette, GP., et al.[2019]

EphA2-redirected CAR T-cells were administered to three patients with recurrent glioblastoma, showing preliminary tolerability with transient clinical efficacy, including tumor reduction in one patient.

While two patients experienced grade 2 cytokine release syndrome, which was effectively managed with dexamethasone, there were no other significant organ toxicities, indicating a relatively safe profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose. Lin, Q., Ba, T., Ho, J., et al.[2022]

Chimeric antigen receptor (CAR) T cell therapy shows promise for treating glioblastoma, with initial studies indicating an acceptable safety profile, but the antitumor effects have not met expectations due to challenges like tumor heterogeneity and an immunosuppressive environment.

Ongoing research is exploring novel target antigens and combinations with other therapies to enhance the effectiveness of CAR T cells in glioblastoma, suggesting potential for improved clinical outcomes as our understanding of the disease and CAR technology advances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells for Glioblastoma: Current Concepts, Challenges, and Future Perspectives. Karschnia, P., Teske, N., Thon, N., et al.[2021]

CAR T-cell therapy appears to be a relatively safe treatment for patients with recurrent glioblastoma, with only 9.5% of patients experiencing mild cytokine release syndrome and 25.4% having non-critical neurological events.

However, the therapy shows marginal efficacy, with a pooled objective response rate of only 5.1% and a median overall survival of 8.1 months, indicating that more research is needed to improve its effectiveness in treating this type of brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis. Jang, JK., Pyo, J., Suh, CH., et al.[2023]

In a trial involving 10 patients with glioblastoma, a single dose of CAR T cells successfully eliminated tumor cells expressing the target antigen, EGFR variant III.

Despite the initial success in clearing tumor cells, the CAR T cells also created an immunosuppressive environment, and the inconsistent expression of the target antigen in tumors may limit the treatment's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells Infiltrate Brain, Target Tumors. [2018]

Adoptive T cell immunotherapy using CAR T cells targeting the glioma-specific antigen EGFRvIII shows promise in effectively eliminating malignant gliomas, particularly when combined with standard chemotherapy and radiotherapy.

The study outlines a method for generating these CAR T cells and demonstrates their efficacy in a murine model of glioblastoma, suggesting that preconditioning with temozolomide and whole brain irradiation enhances the therapeutic potential of the CAR T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care. Riccione, K., Suryadevara, CM., Snyder, D., et al.[2021]

In a first-in-human trial of EGFRvIII-directed CAR T cell therapy for recurrent glioblastoma, the presence of PD1 expression in CD4+ CAR T cells was found to positively correlate with both engraftment in the bloodstream and progression-free survival (PFS).

The study suggests that PD1+ CAR T cells may serve as a predictive marker for therapeutic success in solid tumors, as higher frequencies of PD1+GZMB+ and PD1+HLA-DR+ CAR T cells were associated with better clinical outcomes, while other immune checkpoint markers did not show significant associations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response. Tang, OY., Tian, L., Yoder, T., et al.[2022]

A new preclinical mouse model using D-270 MG xenografts effectively mimics the invasive growth patterns of human glioblastoma (GBM), allowing for better study of potential treatments.

T cells engineered with chimeric antigen receptors targeting the EGFRvIII mutation in GBM were able to migrate to invasive tumor areas, suppress tumor growth, and improve survival in mice, indicating a promising approach for immunotherapy in treating GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. Miao, H., Choi, BD., Suryadevara, CM., et al.[2023]

Clinical trials of CAR-T cell therapy for glioblastoma (GBM) have identified significant challenges, such as incomplete antigen coverage and the immunosuppressive tumor microenvironment, which limit the effectiveness of the treatment.

Novel modifications to CAR-T cells aim to enhance their function and resilience against immunosuppression, potentially transforming GBM from a 'cold tumor' into a more responsive one, thereby improving tumor clearance and reducing CAR-T cell exhaustion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement. Pant, A., Lim, M.[2023]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma. [2021]

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

IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. [2022]

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

CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. [2019]

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

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose. [2022]

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

Chimeric Antigen Receptor T Cells for Glioblastoma: Current Concepts, Challenges, and Future Perspectives. [2021]

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

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis. [2023]

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

CAR T Cells Infiltrate Brain, Target Tumors. [2018]

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

Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response. [2022]

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

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. [2023]

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

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement. [2023]