CAR T-Cell Therapy for Brain Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Bevacizumab

Disqualifiers: Uncontrolled seizures, Active infection, HIV, others

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

Compensation: Varies

Number of Visits: 33

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for brain cancer patients with recurrent or worsening glioblastoma. It uses CAR T-Cell therapy, which modifies a patient's immune cells to better attack cancer cells. Specifically, the trial involves Chimeric Antigen Receptor (CAR) T Cells with a Chlorotoxin Tumor-Targeting Domain, also known as Chlorotoxin-directed CAR T cells or CLTX-CAR T cells. The study examines the safety and optimal dosage of these specially-designed immune cells. People with glioblastoma that has returned or worsened, and who have not responded to standard treatments, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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, it does mention that participants should not have uncontrolled illnesses or active infections requiring antibiotics, which might imply some restrictions. It's best to discuss your current medications with the trial team to get a clear answer.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that a new treatment called CAR T-cell therapy, which uses a chlorotoxin to target tumors, is under study for safety and effectiveness. This treatment is being tested for glioblastoma, an aggressive and complex brain cancer.

In studies, CAR T-cell therapy has shown promise in locating and attacking glioblastoma tumor cells. The chlorotoxin helps the T-cells specifically target the cancer cells. Although promising, this approach remains in the early stages of research.

Early studies aim to understand possible side effects and determine the right dose for safety. As a Phase 1 trial, the treatment is just beginning to be tested in humans, with researchers primarily focused on safety and identifying any side effects.

Participants in early trials have reported some side effects, but these studies are crucial to assess how well the treatment is tolerated. As with any new treatment, risks may exist, and participants should discuss these with the research team.

Overall, while promising signs exist, more research is needed to fully understand the safety of this CAR T-cell therapy. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for brain cancer, which typically involve surgery, radiation, and chemotherapy, CAR T-cell therapy harnesses the body's own immune system to fight the cancer. This therapy is unique because it uses specially engineered T cells that are designed to recognize and attack tumor cells. Researchers are excited about this approach because it includes a chlorotoxin tumor-targeting domain, which helps the CAR T cells home in on the cancer more precisely. Additionally, the therapy is delivered directly into the brain via innovative delivery methods that could enhance its effectiveness and potentially offer a more targeted attack on brain cancer cells.

What evidence suggests that CAR T-cell therapy might be an effective treatment for brain cancer?

Studies have shown that CAR T-cell therapy with chlorotoxin offers a promising approach to treating brain cancer, particularly glioblastoma. This trial will test two delivery methods for this therapy. One group of participants will receive a single delivery of chlorotoxin-directed CAR T cells, while another group will receive dual delivery. This therapy uses specially altered immune cells to locate and attack cancer cells. Early results suggest that chlorotoxin, a substance from scorpion venom, enhances these immune cells' ability to recognize and attach to cancer cells. Research indicates that these modified cells can specifically target glioblastoma cells, potentially improving treatment outcomes. Although the therapy remains under investigation, initial findings show it may enhance the immune system's ability to combat this aggressive cancer. ^{1 2 3 4 5}

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 adults with a specific brain cancer called MMP2+ recurrent or progressive glioblastoma. They must have a certain level of physical function, normal liver and kidney tests, not be pregnant, and agree to use birth control. People can't join if they have uncontrolled seizures, HIV/hepatitis infections, are pregnant/breastfeeding, recently had certain therapies like bevacizumab, or any condition that makes it unsafe to participate.

Inclusion Criteria

Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (to be performed within 14 days prior to leukapheresis unless otherwise stated)

I have no allergies or adverse reactions to leukapheresis, steroids, or tocilizumab.

I was diagnosed with a high-grade brain tumor.

Exclusion Criteria

I have another active cancer besides the one being studied.

I have not received bevacizumab therapy in the last 3 months.

I have a serious illness that is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes via dual or single delivery for 3 weekly cycles over 28 days

4 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Visits at 30 days, 3, 6, 9, and 12 months

Long-term follow-up

Participants are monitored yearly for up to 15 years to assess long-term outcomes and safety

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Chimeric Antigen Receptor (CAR) T Cells with a Chlorotoxin Tumor-Targeting Domain

Trial Overview The study is testing CAR T cells modified with chlorotoxin to target tumor cells in patients with aggressive brain tumors. It aims to find the safest dose and see how well these engineered immune cells work against glioblastoma when delivered either directly into the tumor site or into cerebrospinal fluid.

How Is the Trial Designed?

Group I: Treatment (CAR T cell therapy) II Experimental Treatment 1 Intervention

Arm 2 participants will undergo resection/biopsy of their tumor and placement of a Rickham catheter at the site of the resection/biopsy and the lateral ventricle. Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via dual delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with two CAR T cell infusions (intracranial intratumoral or intracavitary \[ICT\]) and also into the lateral ventricle (intracranial intraventricular \[ICV\]) and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.

Group II: Treatment (CAR T cell therapy) I Experimental Treatment 1 Intervention

Arm 1 participants will undergo resection/biopsy of their tumor and placement of a Rickham catheter at the site of the resection/biopsy. Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via single delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with one CAR T cell infusion delivered intracranial intratumoral or intracavitary \[ICT\] and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T cell treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.

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+

Published Research Related to This Trial

Checkpoint inhibitor therapy and CAR T cell therapy can lead to significant neurotoxicities, affecting both the peripheral and central nervous systems, which are important to recognize for patient management.

Understanding the biological mechanisms behind these immune-related adverse events is crucial for identifying at-risk patients and developing strategies to prevent and treat these toxicities effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurologic Toxicities of Cancer Immunotherapies: a Review. Harrison, RA., Tummala, S., de Groot, J.[2020]

Immunotoxins, which combine potent toxins with targeting agents to kill cancer cells, have shown promising results in recent clinical trials after initial disappointing outcomes, indicating a potential new avenue for cancer treatment.

Newer immunotoxins, including those developed through genetic engineering, are being designed to target specific cancer cell antigens and may help overcome challenges like immunogenicity that limit their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotoxins and recombinant toxins in the treatment of solid carcinomas. Theuer, CP., Pastan, I.[2023]

CAR T cell therapy shows promise for treating aggressive brain tumors like glioblastoma, but its effectiveness has been limited due to challenges such as tumor antigen heterogeneity and an immunosuppressive environment.

Innovative techniques like focused ultrasound are being explored to enhance the activation of CAR T cells, potentially leading to safer and more effective treatments for brain cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Lin, YJ., Mashouf, LA., Lim, M.[2022]

Recombinant immunotoxins are engineered to selectively target and kill cancer cells while sparing normal cells, utilizing a combination of cancer-specific antibodies and modified bacterial or plant toxins.

These immunotoxins have demonstrated significant cytotoxic activity against cancer cells in laboratory settings and have shown potential to reduce tumor growth in mouse models, with ongoing clinical trials aimed at confirming their effectiveness in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant immunotoxins: protein engineering for cancer therapy. Brinkmann, U.[2023]

CAR T-cell therapies are highly effective cancer treatments that involve infusing engineered immune cells to target specific tumor antigens, with several products already approved for leukemia and lymphoma.

Despite their effectiveness, CAR T-cell therapies can cause significant systemic and neurological toxicities, necessitating the development of specific management protocols, especially for neurotoxic effects which are more complex to diagnose and treat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and management of chimeric antigen receptor (CAR) T-cell-associated neurotoxicity. Gonzalez Castro, LN., Dietrich, J.[2021]

CLTX-CAR T cells, which use a peptide from chlorotoxin to target glioblastoma (GBM), show strong anti-tumor activity and can effectively target tumors that do not express other common GBM antigens, addressing the challenge of tumor heterogeneity.

These CAR T cells demonstrated tumor regression in mouse models without causing damage to normal cells, indicating a high level of safety and specificity, and their effectiveness relies on the presence of matrix metalloproteinase-2 on the tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Wang, D., Starr, R., Chang, WC., et al.[2022]

CAR T cell therapy, particularly with CD19-targeting CARs like KYMRIAH™ and YESCARTA™, has shown high remission rates in patients with difficult-to-treat lymphomas, marking a significant advancement in cancer immunotherapy.

Despite their effectiveness, CAR T therapies can cause serious side effects such as cytokine release syndrome and neurotoxicity, prompting the need for improved safety measures and next-generation developments in the technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Next generation engineered T cells for cell therapy: from lymphoma to solid tumors]. Catros, V.[2019]

CAR-T therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T-cell therapies, are showing promise in treating aggressive primary brain tumors like glioblastoma and diffuse midline glioma, H3 K27M-mutant, which have been challenging to treat with traditional immunotherapy.

Despite the potential of CAR T-cell therapies, significant challenges remain in their development and implementation for brain tumor patients, indicating that while progress is being made, more work is needed to achieve transformative benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors. Mount, CW., Gonzalez Castro, LN.[2022]

Chlorotoxin, derived from scorpion venom, can be engineered into T-cell therapies to specifically target and destroy glioblastoma cells, showing promise in preclinical studies with mice.

The therapy demonstrated efficacy without causing off-target toxicity in mice, and it is set to be tested in human patients, indicating a potential advancement in glioblastoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Looking to Scorpion Venom for GBM Treatment. [2021]

Chlorotoxin (Cltx) has been identified to target Neuropilin-1 (NRP1), a receptor on tumor and endothelial cells, which enhances the uptake of drugs into tumors, improving therapeutic efficacy.

The study demonstrated that the antitumor activity of the Cltx-drug conjugate (ER-472) is significantly dependent on NRP1 expression in tumors, suggesting that targeting NRP1 could optimize the use of Cltx-based therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropilin-1 drives tumor-specific uptake of chlorotoxin. McGonigle, S., Majumder, U., Kolber-Simonds, D., et al.[2020]

A 53-year-old patient with high-grade B-cell lymphoma experienced severe neurotoxicity after CAR-T therapy, which was successfully treated with extracorporeal blood purification using CytoSorb, leading to complete recovery.

This case highlights the potential of CytoSorb as a rescue strategy for managing severe neurotoxicity and cytokine release syndrome associated with CAR-T therapy, demonstrating significant reductions in inflammatory markers without side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Use of Extracorporeal Blood Purification for Treatment of Severe, Refractory Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy-A Case Report. Singbartl, K., Rosenthal, A., Leis, J., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7500824/

Chlorotoxin-directed CAR T cells for specific and effective ... Therapeutic outcomes for GBM-targeting CAR T cell designs would thus be expected to benefit from immunotherapies with broader tumor recognition, but progress ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666379125003751

Chlorotoxin-directed CAR T cell therapy for recurrent ... Chimeric antigen receptor (CAR) T cell immunotherapy is being explored as a strategy to improve GBM outcomes and has demonstrated early ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04214392

NCT04214392 | Chimeric Antigen Receptor (CAR) T Cells ... This phase I trial studies the side effects and best dose of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain in treating ...

4. nature.com nature.com/articles/s41698-024-00753-0

CAR-T cell therapy for the treatment of adult high-grade ... CAR-T cell therapy for brain tumors represents a promising and rapidly growing area of research; however, successful translation remains a ...

5. jitc.bmj.com jitc.bmj.com/content/11/Suppl_2/A1750

1525 Initial clinical experience with chlorotoxin-redirected ... We developed chimeric antigen receptor (CAR) T cells incorporating the CLTX peptide as a tumor-recognizing ligand, thereby redirecting T cells to target GBM ...