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

36 Participants Needed

Trial Summary

What is the purpose of this trial?

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 patients with MPP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells.

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.

What data supports the effectiveness of this treatment for brain cancer?

Research shows that CLTX-CAR T cells, which use a component from scorpion venom to target brain cancer cells, have been effective in mice, causing tumor regression without harming normal cells. This suggests potential for treating glioblastoma in humans. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy, including versions targeting brain cancer, has shown significant promise in treating certain cancers, but it can cause serious side effects. Common risks include cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), which can be life-threatening. While management of these side effects has improved, they remain a concern, especially as the therapy is used for more types of cancer. ^{6 7 8 9 10}

How is the CAR T-Cell Therapy for Brain Cancer different from other treatments?

This treatment uses a unique approach by engineering T cells with a chlorotoxin (a component of scorpion venom) to specifically target and destroy glioblastoma cells, which is different from other treatments that may not effectively target the diverse tumor cells in brain cancer. ^{1 2 9 11 12}

Research Team

Behnam Badie

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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-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]

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]

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]

References

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

Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. [2022]

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

Looking to Scorpion Venom for GBM Treatment. [2021]

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

Immunotoxins and recombinant toxins in the treatment of solid carcinomas. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Neuropilin-1 drives tumor-specific uptake of chlorotoxin. [2020]

5. England pubmed.ncbi.nlm.nih.gov

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

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

Neurologic Toxicities of Cancer Immunotherapies: a Review. [2020]

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

Building safety into CAR-T therapy. [2023]

8. United States 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. [2021]

9. France pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Evaluation and management of chimeric antigen receptor (CAR) T-cell-associated neurotoxicity. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. [2022]