CAR T Cell Therapy for Brain Cancer

(IMPACT Trial)

Overseen By Marcia Hodik, RN, BSHS, CCRP

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Florida

Must not be taking: Systemic steroids

Disqualifiers: Prior malignancy, Spinal metastasis, Bulky tumors, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I study to assess the safety and feasibility of IL-8 receptor modified patient-derived activated CD70 CAR T cell therapy in CD70+ pediatric high-grade glioma

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

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on systemic steroids or immunosuppressive agents, you may need to discuss this with the study team, as these could affect eligibility.

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

Research shows that modifying CAR T cells with the IL-8 receptor (CXCR2) enhances their ability to move into and persist within tumors, 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 generally safe for humans?

CAR T cell therapy can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are known and are being studied to improve safety. ^{1 3 6 7 8}

What makes the CAR T Cell Therapy for Brain Cancer treatment unique?

This treatment is unique because it uses T cells modified with the IL-8 receptor (CXCR2) to enhance their ability to migrate and persist in the tumor, improving their effectiveness against solid tumors like brain cancer. ^{1 2 3 4 9}

Research Team

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for children with high-grade gliomas, a type of brain cancer that expresses CD70. Participants must have enough T cells to modify and be able to handle the cell collection process. Specific criteria will determine eligibility.

Inclusion Criteria

CBC with differential showing: ANC ≥ 1000 cells/mm3, Platelet count ≥ 100,000 cells/mm3, Hemoglobin ≥ 10 g/dl

Negative serum pregnancy test for females of childbearing potential at enrollment

Willingness to use acceptable contraceptive methods for females of childbearing potential and males with female partners of childbearing potential

Exclusion Criteria

Concurrent illness with specific conditions

Pregnant or lactating women

Treatment on other therapeutic clinical protocols within 30 days prior to enrollment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

PBMCs are collected through peripheral venipuncture and tumor CD70 status is confirmed

2 weeks

Radiation

Standard-of-care chemoradiation is administered

4 weeks

Adjuvant Chemotherapy

Adjuvant chemo with dose-intensified TMZ 75-100 mg/m2/day for up to 3 cycles

9 weeks

CAR T Cell Treatment

8R-70CAR T cells are administered as a single intravenous infusion

1 week

Follow-up

Participants are monitored for safety and effectiveness after CAR T cell infusion

4 weeks

Treatment Details

Interventions

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

Trial Overview The study tests a new therapy where a patient's own T cells are modified with an IL-8 receptor and CD70 CAR to target glioma cells. It's in phase I, focusing on safety and how well it can be done.

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.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Florida Department of Health

Collaborator

Trials

30

Recruited

13,000+

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]

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]

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]

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]

Radiolabeling CAR-T cells with 89Zr-oxine is an effective method that allows for tracking their distribution in the body using PET imaging, while maintaining the cells' viability and functional characteristics for at least 8 days.

The study found that radiolabeled CAR-T cells retain their ability to target and kill IL-13Rα2 positive tumor cells without significant changes in activation or exhaustion markers, indicating that this labeling technique could enhance our understanding of CAR-T cell behavior in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13R&#945;2 after radiolabeling with 89Zirconium oxine for PET imaging. Leland, P., Kumar, D., Nimmagadda, S., et al.[2023]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

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]

References

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

Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. [2023]

2. 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]

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

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

4. 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]

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. England pubmed.ncbi.nlm.nih.gov

Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13R&#945;2 after radiolabeling with 89Zirconium oxine for PET imaging. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Toxicity and management in CAR T-cell therapy. [2023]

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

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