E-SYNC T Cells for Glioblastoma

Overseen By Stephanie Lewis, MSN, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Hideho Okada, MD, PhD

Must not be taking: EGFR-targeting therapy

Disqualifiers: HIV, Hepatitis B/C, Alcohol addiction, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

20 Participants Needed

Trial Summary

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications, but you must be off systemic steroids for at least 3 days before certain procedures. It's best to discuss your specific medications with the trial team.

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

Research shows that using synNotch-CAR T cells, which are part of the E-SYNC T Cells treatment, can effectively target glioblastoma by recognizing multiple tumor-specific markers, leading to better tumor cell killing and T cell persistence. Additionally, CAR T cells targeting EphA2, another component of the treatment, have shown promising results in improving survival in glioblastoma models. ^{1 2 3 4 5}

What safety data exists for E-SYNC T Cells or similar treatments for glioblastoma?

Research on similar CAR T cell therapies targeting glioblastoma suggests that safety considerations are important, as seen in the selection of CD28.ζ CAR T cells for further development based on safety. Additionally, synNotch-CAR T cells have been designed to improve specificity and reduce off-target effects, which may enhance safety. ^{1 4 5 6 7}

What makes the E-SYNC T Cells treatment unique for glioblastoma?

The E-SYNC T Cells treatment is unique because it uses a synNotch receptor system that requires dual activation by targeting both EGFRvIII and either IL-13Rα2 or EphA2, making it highly specific for glioblastoma cells and potentially reducing side effects by sparing normal brain tissue. ^{1 2 6 7 8}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of E-SYNC chimeric antigen receptor (CAR) T cells after lymphodepleting chemotherapy in treating patients with EGFRvIII positive (+) glioblastoma. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so the CAR T cells will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Lymphodepleting chemotherapy with cyclophosphamide and fludarabine before treatment with CAR T cells may make the CAR T cells more effective.

Research Team

Jennifer Clarke, MD, MPH

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with a specific mutation in their epidermal growth factor receptor (EGFRvIII) who have been diagnosed with glioblastoma, a type of brain cancer. Participants must meet certain health standards and not be receiving other treatments that could interfere.

Inclusion Criteria

I can breathe normally without feeling short of breath and my oxygen level is above 92%.

My cancer has a low or no MGMT gene methylation.

My latest surgery confirmed I have EGFRvIII+ GBM.

Exclusion Criteria

I have been treated with drugs targeting EGFR.

I have a condition like HIV or an autoimmune disease that affects my immune system.

I can attend all required follow-up visits and tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants complete non-interventional, standard of care radiation therapy

2 weeks

Leukapheresis and Manufacturing

Participants undergo leukapheresis for the creation of E-SYNC T cells

2 weeks

Lymphodepleting Chemotherapy

Participants receive cyclophosphamide and fludarabine IV on days -5, -4, and -3

1 week

Treatment

Participants receive a single infusion of E-SYNC T cells

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 96 weeks

Days 1, 3, 7, 10, 14, 21, 28, then every 4 weeks in weeks 8-24, every 8 weeks in weeks 32-48, every 12 weeks in weeks 60-96

Treatment Details

Interventions

• E-SYNC T Cells

Trial Overview The trial is testing E-SYNC T Cells, which are engineered immune cells designed to target cancer cells in the brain. It's an early-stage study to see if this treatment is safe and how well it works.

Participant Groups

Group I: Cohort 2: Tissue analysis cohort Experimental Treatment 5 Interventions

Participants with EGFRvIII+ glioblastoma recurrence after initial non-investigational, chemoradiation who need surgery will have the EGFRvIII H-scored based on digital image analysis of EGFRvIII immunohistochemistry (IHC) slides, with the score denoting both extent of and intensity of positive staining. Participants with an H-score of \>=250 will undergo leukapheresis for manufacturing of E-SYNC T cells at the maximum tolerated dose, or recommended dose based on results from cohort 1 more than 2 weeks after completion of their non-investigational, standard of care radiation therapy. Participants will receive a single infusion of drug product (DP) on day 0 and will be admitted to the hospital for surgical resection (non-investigational) between days 14 and 28, and monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood, and anti-tumor response of E-SYNC T cells.

Group II: Cohort 1: Starting Dose Level 1 (5 x 10^7 CAR+ cells) (DL1) Experimental Treatment 4 Interventions

Participants with newly diagnosed EGFRvIII+ GBM with unmethylated MGMT promotor status will undergo leukapheresis for manufacturing of E-SYNC T cells at least 2 weeks after completion of non-interventional, standard of care radiation therapy. Participants receive cyclophosphamide IV and fludarabine IV on days -5, -4, and -3 and then receive E-SYNC T cells IV on day 0. Participants will receive a single infusion of drug product (DP) (5 x 10\^7 CAR+ T cells) and be monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood.

Group III: Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2) Experimental Treatment 4 Interventions

If there are no dose-limiting toxicities in the starting dose cohort, participants with newly diagnosed EGFRvIII+ GBM with unmethylated MGMT promotor status will undergo leukapheresis for manufacturing of E-SYNC T cells at least 2 weeks after completion of tnon-interventional, standard of care radiation therapy. Participants receive cyclophosphamide IV and fludarabine IV on days -5, -4, and -3 and then receive E-SYNC T cells IV on day 0. Participants will receive a single infusion of drug product (DP) (1.5 x 10\^8 CAR+ T cells) and be monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood.

Who Is Running the Clinical Trial?

Hideho Okada, MD, PhD

Lead Sponsor

Trials

1

Recruited

20+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

CAR T cell therapy targeting the glioblastoma antigen EphA2 shows promise for treating this aggressive brain tumor, as EphA2 is highly expressed in glioblastoma but minimally in normal brain tissue.

Among the evaluated CAR designs, CD28.ζ CAR T cells were chosen for clinical development due to their effective antitumor activity and better safety profile, despite no significant functional differences found between various CAR configurations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing EphA2-CAR T Cells for the Adoptive Immunotherapy of Glioma. Yi, Z., Prinzing, BL., Cao, F., et al.[2020]

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]

The study found that different designs of B7-H3-specific CAR T-cells showed strong functionality in lab tests, but their effectiveness against gliomas varied significantly in a living model, highlighting the importance of CAR structure.

Successful anti-tumor responses were linked to the presence and activity of macrophages and endogenous T-cells in the tumor immune microenvironment, indicating that both CAR design and the immune context are crucial for effective therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity. Haydar, D., Ibañez-Vega, J., Crawford, JC., et al.[2023]

The study introduces a novel approach using multi-antigen prime-and-kill recognition circuits to enhance the effectiveness of CAR T cell therapy for glioblastoma, allowing for targeted killing of tumor cells while minimizing damage to healthy tissue.

In experiments with immunodeficient mice, T cells engineered with a synNotch-CAR targeting the glioblastoma-specific antigen EGFRvIII showed improved antitumor efficacy and durability compared to traditional CAR T cells, demonstrating the potential for this method to be applied to other solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Choe, JH., Watchmaker, PB., Simic, MS., et al.[2022]

Two types of CAR-T cells targeting the EphA2 receptor showed significant anti-glioblastoma (GBM) efficacy in vitro and improved survival in tumor-bearing mice, eliminating 20%-50% of tumors in xenograft models.

The effectiveness of these CAR-T cells is linked to the balance of interferon-γ (IFN-γ) production and CXCR-1/2 expression, with excessive IFN-γ leading to reduced anti-tumor activity due to PD-L1 upregulation in GBM cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of the third generation EphA2 CAR-T cells against glioblastoma is associated with interferon gamma induced PD-L1. An, Z., Hu, Y., Bai, Y., et al.[2022]

The proposed CAR T cell therapy utilizes a novel synNotch receptor pathway to enhance specificity and reduce toxicity in targeting glioblastoma multiforme, potentially addressing high recurrence rates seen in traditional CAR T therapies.

This innovative approach combines a tandem CAR targeting two glioblastoma stem cell antigens (IL-13Rα2 and CD133) with a synNotch receptor that requires dual activation, which may lead to more effective tumor elimination while minimizing damage to healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proposing a tandem AND-gate CAR T cell targeting glioblastoma multiforme. Sabahi, M., Jabbari, P., Alizadeh Haghighi, M., et al.[2022]

EphA2 has been identified as a promising target for immunotherapy in glioblastoma (GBM) due to its overexpression in glioma cells, and T cells engineered to target EphA2 showed effective tumor recognition and killing in laboratory tests.

In experiments with severe combined immunodeficiency (SCID) mice, the transfer of EphA2-specific T cells led to significant tumor regression and improved survival compared to untreated mice, suggesting that this approach could be a viable treatment for patients with EphA2-positive GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells redirected to EphA2 for the immunotherapy of glioblastoma. Chow, KK., Naik, S., Kakarla, S., 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]

References

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

Optimizing EphA2-CAR T Cells for the Adoptive Immunotherapy of Glioma. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity. [2023]

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

SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. [2022]

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

Antitumor activity of the third generation EphA2 CAR-T cells against glioblastoma is associated with interferon gamma induced PD-L1. [2022]

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

Proposing a tandem AND-gate CAR T cell targeting glioblastoma multiforme. [2022]

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

T cells redirected to EphA2 for the immunotherapy of glioblastoma. [2022]

8. 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]