12 Participants Needed

Genetically Modified T-Cells for Brain Cancer

(PNOC018 Trial)

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Overseen ByPNOC Operations
Age: < 65
Sex: Any
Trial Phase: Phase 1
Sponsor: University of California, San Francisco
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of KIND T cells, which are modified immune cells, in patients with a specific type of brain tumor. The treatment involves chemotherapy to prepare for the new T cells, which are designed to better attack the cancer.

Will I have to stop taking my current medications?

The trial requires participants to stop taking all anti-cancer agents and radiotherapy before enrolling. Chemotherapy or biologic therapy must be stopped at least 7 days prior, and immunotherapy must be stopped for at least 30 days or 3 half-lives, whichever is shorter.

Is the genetically modified T-cell treatment generally safe for humans?

Research on genetically modified T-cells, including those using TCR gene editing, shows that while there are potential risks like genotoxicity (damage to the genetic information within a cell), the treatments have been generally safe in clinical trials. Some patients experienced expected side effects from chemotherapy, and a few had mild to moderate reactions like cytokine release syndrome (a condition where the immune system is overly activated) and encephalitis (inflammation of the brain).12345

What makes the treatment with Autologous Anti-H3.3K27M TCR-expressing T-cells unique for brain cancer?

This treatment is unique because it involves genetically modifying a patient's own T-cells to specifically target a mutation found in some brain cancers, aiming to enhance the body's immune response against the tumor. Unlike traditional treatments, this approach uses the patient's immune system to fight the cancer, although research suggests that the specific mutation targeted may not be suitable for effective immunotherapy.24678

What data supports the effectiveness of the treatment Autologous Anti-H3.3K27M TCR-expressing T-cells for brain cancer?

Research shows that T cells engineered with specific T cell receptors (TCRs) can effectively target and kill glioma cells with the H3.3K27M mutation in a lab setting, and these TCR-transduced T cells significantly slowed tumor growth in mice, suggesting potential for this treatment in targeting brain cancer.238910

Who Is on the Research Team?

Dr. Sabine Mueller | UCSF Benioff ...

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

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Hideho Okada, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for HLA-A*0201-positive patients aged 3-21 with a specific brain tumor (H3.3K27M-mutated diffuse midline glioma) who've finished standard radiation therapy. They must not be pregnant, agree to use contraception, and have no immune disorders like HIV or hepatitis B/C. No prior treatments for the tumor are allowed.

Inclusion Criteria

I am a man who can father children and agree to use birth control and not donate sperm for 6 months after the study ends.
My bilirubin levels are within the normal range for my age.
I can sign the consent form and follow the study rules.
See 26 more

Exclusion Criteria

I do not have any infections that are currently uncontrolled.
I have had a solid organ or bone marrow transplant.
I am not pregnant or breastfeeding.
See 8 more

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Patients receive fludarabine IV on days -4, -3, and -2 and cyclophosphamide IV on day -2

1 week
4 visits (in-person)

T Cell Therapy

Patients receive KIND T cells IV over 10 minutes on day 0

1 day
1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years
Multiple visits at day 1, 3, 7, 10, 14, 21, 28, weeks 8-24, 28-92, months 24-36, and yearly until year 15

What Are the Treatments Tested in This Trial?

Interventions

  • Autologous Anti-H3.3K27M TCR-expressing T-cells
  • Cyclophosphamide
  • Fludarabine
Trial Overview The trial tests genetically modified KIND T cells after chemotherapy drugs cyclophosphamide and fludarabine in young patients with a certain type of brain cancer. It aims to find the safest dose and see how well these engineered T cells can target and fight the tumor.
How Is the Trial Designed?
1Treatment groups
Experimental Treatment
Group I: Treatment (KIND T cells, cyclophosphamide, fludarabine)Experimental Treatment3 Interventions

Find a Clinic Near You

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials
2,636
Recruited
19,080,000+

Alliance for Cancer Gene Therapy

Collaborator

Trials
3
Recruited
70+

The V Foundation

Collaborator

Trials
10
Recruited
320+

Parker Institute for Cancer Immunotherapy

Collaborator

Trials
12
Recruited
460+

Published Research Related to This Trial

The study found that T cells specifically targeting the H3.3K27M mutation in diffuse midline glioma, a deadly childhood cancer, were unable to recognize tumor cells expressing this mutation, despite high functional avidity.
This suggests that the H3.3K27M mutation may not be a viable target for cancer immunotherapy due to issues with how the epitope is processed or presented by the immune system, limiting the effectiveness of T cell responses.
H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma.Immisch, L., Papafotiou, G., Popp, O., et al.[2023]
Children with diffuse intrinsic pontine glioma (DIPG) have a very short median overall survival of less than one year, highlighting the urgent need for effective treatments.
A novel T cell therapy targeting the H3.3K27M mutation in glioma cells showed promising results in preclinical models, effectively killing tumor cells and significantly suppressing tumor growth in mice, suggesting potential for safe application in human patients.
Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy.Chheda, ZS., Kohanbash, G., Okada, K., et al.[2022]
In a prostate cancer model, combining vaccination with the adoptive transfer of genetically modified T cells that express a tumor-specific TCR significantly suppressed tumor growth, even though each treatment alone had no effect.
The study highlights the potential of TCR gene transfer to effectively target nonimmunogenic tumor-associated antigens, provided that the modified T cells can expand in the body after transfer.
TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation.de Witte, MA., Bendle, GM., van den Boom, MD., et al.[2021]

Citations

H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma. [2023]
Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. [2022]
TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. [2021]
Non-viral precision T cell receptor replacement for personalized cell therapy. [2023]
Rapid Construction of Antitumor T-cell Receptor Vectors from Frozen Tumors for Engineered T-cell Therapy. [2019]
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]
NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. [2021]
Gene modified NK cell line as a powerful tool for evaluation of cloned TCRs for TCR-T cell therapy. [2023]
Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012]
T cell receptor gene-modified allogeneic T cells with siRNA for endogenous T cell receptor induce efficient tumor regression without graft-versus-host disease. [2023]
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