Genetically Modified T-cell Therapy for Brain Cancer

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Disqualifiers: Active infections, Other malignancies, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 11 months

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific waiting periods after certain chemotherapy treatments before you can start the trial, such as 6 weeks for nitrosourea-containing regimens and 4 weeks for bevacizumab.

What safety data exists for IL13Ralpha2-specific CAR T cell therapy in humans?

IL13Ralpha2-specific CAR T cell therapy has been studied for its safety, particularly focusing on its ability to target cancer cells without affecting normal tissues. Research indicates that certain designs of these CAR T cells can selectively target tumor cells with minimal off-target effects, which is important for safety. However, like other CAR T cell therapies, there is a potential risk of severe side effects such as cytokine release syndrome and neurotoxicity, which are influenced by the specific structural components of the CAR T cells. ^{1 2 3 4 5}

What makes the IL13Ralpha2-specific CAR T cell treatment unique for brain cancer?

This treatment is unique because it uses genetically modified T cells that specifically target the IL13Ralpha2 protein, which is commonly found in glioblastoma (a type of brain cancer) but not in normal brain tissue. The inclusion of the 4-1BB costimulatory domain enhances the selectivity and effectiveness of these T cells, making them more potent against tumors while reducing the risk of attacking healthy cells. ^{1 3 4 6 7}

What data supports the effectiveness of the treatment Genetically Modified T-cell Therapy for Brain Cancer?

Research shows that IL13Rα2-specific CAR T cells, which are part of this treatment, have demonstrated significant anti-tumor activity and improved survival in animal models of glioblastoma (a type of brain cancer). These T cells specifically target the IL13Rα2 protein found on tumor cells, leading to effective tumor cell killing without affecting normal brain tissue. ^{1 2 3 4 8}

Who Is on the Research Team?

Behnam Badie

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with malignant glioma that has returned or hasn't responded to treatment. They must have had progression after initial radiation, be able to consent, not need excessive steroids during therapy, and meet specific blood and organ function criteria. Pregnant women can't participate, nor those needing dialysis, with other active cancers, severe infections or major surgery recovery.

Inclusion Criteria

Platelets >= 100,000/dl

International normalized ratio (INR) < 1.3

White blood cell (WBC) > 2,000/dl or Absolute neutrophil count (ANC) > 1,000

Exclusion Criteria

You need help to support your blood pressure or have heart rhythm problems that cause symptoms.

Research participants with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it unwise to enter the research participant on protocol shall be ineligible

You need to undergo dialysis treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive genetically modified T-cell immunotherapy in a dose-escalation study with initial low dose followed by higher doses in subsequent cycles.

11 months

Multiple infusions over cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits at 4 weeks, 3, 6, 8, 10, and 12 months, and then yearly for 15 years.

15 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
• IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells

Trial Overview The trial tests genetically modified T-cells designed to target and kill glioma cells in the brain. Patients' own T-cells are engineered in a lab to recognize tumor cells better. The study also includes MRI scans and quality-of-life assessments to monitor effects.

How Is the Trial Designed?

Group I: Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV) Experimental Treatment 5 Interventions

Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)

Group II: Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV) Experimental Treatment 5 Interventions

Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)

Group III: Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV]) Experimental Treatment 5 Interventions

Arm 3 (Tcm-derived CAR T cells, Intraventricular \[ICV\])

Group IV: Arm 2 (Tcm-derived CAR T cells, ICTb/r) Experimental Treatment 5 Interventions

Arm 2 (Tcm-derived CAR T cells, Intratumoral a/f biopsy \[ICTb\] or Intracavitary a/f resection \[ICTr\])

Group V: Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb]) Experimental Treatment 5 Interventions

Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy \[ICTb\]

IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes is already approved in United States for the following indications:

Approved in United States as IL13Rα2-specific CAR T cells for:

• Recurrent or refractory IL13Rα2-positive brain tumors in children

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Published Research Related to This Trial

IL13Rα2-specific CAR T cells, designed to target glioblastoma without affecting normal brain tissue, demonstrated effective recognition and destruction of IL13Rα2-positive cancer cells without cross-reactivity to IL13Rα1.

In vivo studies showed that CAR T cells with short spacer regions and specific endodomains significantly improved survival in mice with glioma, indicating their potential as a promising treatment for glioblastoma and similar cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. Krenciute, G., Krebs, S., Torres, D., et al.[2018]

Integrating co-stimulatory signaling domains into a tumor-targeting CAR (IL13-CD28-41BBzeta) significantly enhances the activation and sustained function of CD4+ T cells against tumors, compared to using CD3zeta activation alone.

In vivo studies showed that CD4+ T cells with the co-stimulatory CAR effectively controlled established CNS glioma xenografts in mice, highlighting the potential for improved anti-tumor responses in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning. Chang, L., Chang, WC., McNamara, G., et al.[2017]

The study demonstrates that second-generation IL13-BBζ CAR T cells show superior proliferation and antitumor potency against glioblastoma compared to first-generation and third-generation CAR designs, indicating enhanced efficacy in targeting the cancer antigen IL13Rα2.

IL13-BBζ CARs also exhibit improved selectivity for the intended tumor target over the unintended target IL13Rα1, which is crucial for minimizing off-tumor effects and enhancing safety in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells. Starr, R., Aguilar, B., Gumber, D., et al.[2023]

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 YYB-103 CAR T cells demonstrated selective targeting and toxicity against malignant glioma cells expressing IL13Rα2, while sparing cells that express IL13Rα1, indicating a promising therapeutic approach for treating glioblastoma.

Both intravenous and intracerebroventricular administration of YYB-103 CAR T cells significantly reduced tumor volume and improved survival in mouse models, suggesting effective delivery across the blood-brain barrier and potential for clinical application in patients with recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study. Kim, K., Gwak, HS., Han, N., et al.[2021]

Transgenic expression of IL15 in CAR T cells targeting the IL13Rα2 antigen significantly enhances their ability to proliferate, survive, and produce cytokines, leading to improved antiglioma activity in a glioblastoma model.

Despite the improved persistence and effectiveness of IL13Rα2-CAR.IL15 T cells, gliomas that recurred after treatment showed reduced IL13Rα2 expression, indicating the need for strategies that target multiple tumor antigens to prevent antigen loss and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. Krenciute, G., Prinzing, BL., Yi, Z., et al.[2018]

A novel chimeric antigen receptor (CAR) T cell therapy targeting the IL13 receptor α-2 (IL13Rα2) shows promise in treating glioblastoma multiforme (GBM), demonstrating effective tumor cell killing and increased survival in animal models.

While the IL13 dTc therapy effectively targets GBM cells, it also retains some activity against normal cells expressing IL13Rα1, indicating a potential safety concern for systemic administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. Kong, S., Sengupta, S., Tyler, B., et al.[2021]

Citations

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

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning. [2017]

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

Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells. [2023]

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

Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study. [2021]

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

The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. [2021]

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

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. [2018]

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

Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. [2021]