CAR T Cell Therapy for Glioblastoma

(IMPACT Trial)

Overseen by Ashley Ghiaseddin, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Florida

Must not be taking: Immunosuppressants

Disqualifiers: HIV, Unstable angina, Autoimmune, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment where a patient's own immune cells are modified to better attack brain cancer cells. It targets adults with a specific type of brain cancer (glioblastoma) that shows a certain marker (CD70). The modified cells are designed to recognize and kill the cancer more effectively. CD70 is a protein that is usually limited in normal tissue but appears in various cancers.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressants or other treatments for autoimmune diseases, you may need to stop them, as these conditions are part of the exclusion criteria.

What data supports the effectiveness of the treatment Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells for glioblastoma?

Research shows that modifying CAR T cells with the IL-8 receptor (CXCR2) enhances their ability to move into tumors and stay there, leading to complete tumor regression and long-lasting immune memory in aggressive tumors like glioblastoma in pre-clinical models. ^{1 2 3 4 5}

Is CAR T Cell Therapy for Glioblastoma safe?

The research on CAR T cell therapy, including modifications like IL-8 receptor (CXCR2) and RVG29, shows promising antitumor activity in preclinical models with no significant adverse effects reported. However, these findings are primarily from early-stage studies, and more research is needed to fully understand the safety profile in humans. ^{1 3 4 6 7}

What makes the 8R-70CAR T cell treatment unique for glioblastoma?

The 8R-70CAR T cell treatment is unique because it uses T cells modified with the IL-8 receptor (CXCR2) to enhance their ability to migrate and persist within the tumor, potentially leading to complete tumor regression and long-lasting immune memory, which is a novel approach compared to other treatments for glioblastoma. ^{1 4 5 8 9}

Research Team

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Eligibility Criteria

Adults over 18 with newly-diagnosed, high-grade glioblastoma without prior brain tumors, who've had a recent surgical resection leaving less than 9 cm2 tumor. They must have CD70 positive and MGMT-unmethylated tumors, good liver and kidney function, stable blood counts, no severe illnesses or immune conditions that could interfere with the treatment. Women of childbearing age must test negative for pregnancy and agree to contraception.

Inclusion Criteria

My tumor is located in the upper part of my brain.

I have been newly diagnosed with a high-grade brain tumor without any previous brain tumor history.

CBC with differential with adequate bone marrow function: ANC ≥ 1500 cells/mm3, Platelet count ≥ 100,000 cells/mm3, Hemoglobin ≥ 10 g/dl

Exclusion Criteria

I have been cancer-free for over 3 years, except for non-melanoma skin cancer.

I do not have HIV or any diseases that weaken my immune system.

My cancer has spread to the lining of my brain and spine, but it's limited.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation

Patients undergo standard of care chemoradiation

6-8 weeks

Treatment

Administration of a single dose of 8R-70CAR T cells after completion of radiation

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells (CAR T-cell Therapy)

Trial Overview The trial is testing a new therapy using the patient's own T cells that are modified to target IL-8 receptor in CD70+ glioblastoma cells. It aims to evaluate if this personalized cellular therapy is safe and can be feasibly produced for each participant.

Participant Groups

Group I: 8R-70CAR T cells Experimental Treatment 1 Intervention

Cohort 1 will receive 1 x 10\^6 cells/kg. Cohort 2 will receive 1 x 10\^7 cells/kg. Cohort 3 will receive 1 x 10\^8 cells/kg. Cohort 4 will receive Cy/Flu + CAR T cells at established maximum tolerated dose.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Dr. Stephen J. Motew

University of Florida

Chief Executive Officer since 2024

MD cum laude from the University of Illinois at Chicago School of Medicine, Master's in Healthcare Administration from the University of North Carolina at Chapel Hill

Dr. Timothy E. Morey

University of Florida

Chief Medical Officer since 2023

MD and Bachelor's from the University of Florida

AM Rosen Foundation

Collaborator

Trials

1

Recruited

40+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

Findings from Research

Modifying CAR T-cells to express IL-8 receptors (CXCR1 or CXCR2) significantly improves their ability to migrate to and persist within solid tumors, which is crucial for effective treatment.

In pre-clinical models of aggressive cancers like glioblastoma, ovarian, and pancreatic cancer, this enhanced CAR T-cell therapy led to complete tumor regression and the development of long-lasting immunologic memory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Jin, L., Tao, H., Karachi, A., et al.[2021]

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 study developed a new cytokine receptor, C7R, that enhances the function of CAR T cells by providing continuous IL7 signaling without the toxic effects associated with external cytokines, improving T-cell proliferation and survival.

C7R-coexpressing CAR T cells showed significant antitumor activity in preclinical models of metastatic neuroblastoma and glioblastoma, indicating that this approach could enhance the effectiveness of T-cell therapies against solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. Shum, T., Omer, B., Tashiro, H., et al.[2022]

CD4+ CAR T cells targeting the IL-13 receptor α2 showed superior long-term antitumor effects against glioblastoma compared to CD8+ CAR T cells, which became exhausted quickly after initial activation.

The study suggests that maintaining a higher proportion of CD4+ CAR T cells in therapy could enhance the effectiveness of CAR T cell treatments for solid tumors like glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. Wang, D., Aguilar, B., Starr, R., et al.[2019]

Engineering CAR T cells to express IL7 and/or Flt3L significantly increased their abundance within glioblastoma tumors, leading to improved overall survival rates of 67% and 50% respectively, compared to only 9% survival with conventional CAR T cells.

This study highlights the potential of using non-lymphodepleting irradiation to enhance CAR T cell therapy effectiveness in heterogeneous tumors, suggesting that combining IL7 or IL7 Flt3L CAR T cells with other immunotherapies could be a promising strategy for treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma. Swan, SL., Mehta, N., Ilich, E., et al.[2023]

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]

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]

A patient with recurrent multifocal glioblastoma treated with IL13Rα2-targeted CAR T cells showed no severe toxic effects (grade 3 or higher) after multiple infusions over 220 days, indicating a favorable safety profile for this therapy.

The treatment resulted in significant tumor regression in both intracranial and spinal tumors, with a sustained clinical response lasting 7.5 months, alongside increased cytokine and immune cell levels in the cerebrospinal fluid, suggesting effective immune activation against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. Brown, CE., Alizadeh, D., Starr, R., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. [2021]

2. 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]

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

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. [2022]

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

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma. [2023]

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

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

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

Rabies virus glycoprotein 29 (RVG29) promotes CAR-T immunotherapy for glioma. [2023]

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

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. [2023]