Genetically Modified T-Cells for Brain Cancer

(PNOC018 Trial)

Overseen By PNOC Operations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: Anticancer agents, Immunosuppressive therapy

Disqualifiers: Uncontrolled infection, HIV, Hepatitis B, others

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

Compensation: Varies

Number of Visits: 6

12 Participants Needed

Trial Summary

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.

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. ^{1 2 3 4 5}

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). ^{3 4 6 7 8}

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. ^{1 3 7 9 10}

Research Team

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Hideho Okada, MD, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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.

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.

Timeline

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

Treatment Details

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.

Participant Groups

Group I: Treatment (KIND T cells, cyclophosphamide, fludarabine) Experimental Treatment 3 Interventions

Patients receive fludarabine IV on days -4, -3, and -2 and cyclophosphamide IV on day -2 in the absence of disease progression or unacceptable toxicity for the conditioning regimen. Patients also receive KIND T cells IV at dose level 1 (2 x 106 dextramer®+ CD8+ cells/kg) on day 0. If no DLTs are reported, newly enrolling participants may receive dose level 2 of KIND T cells on day 0.

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+

Findings from Research

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

This study successfully used CRISPR-Cas9 technology to create personalized T cells that can target specific cancer mutations by knocking out the patients' own T cell receptors and inserting new, neoantigen-specific T cell receptors (neoTCRs).

In a phase I clinical trial involving 16 patients with refractory solid cancers, the engineered T cells showed the ability to persist in the body and traffic to tumors, although most patients experienced disease progression, highlighting the need for further research on efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-viral precision T cell receptor replacement for personalized cell therapy. Foy, SP., Jacoby, K., Bota, DA., et al.[2023]

A new method was developed to create a library of T-cell receptors (TCRs) from frozen tumor biopsies, allowing for the rapid identification of TCR genes that target various tumor antigens, which is crucial for personalized cancer therapies.

When tested, T cells engineered with these tumor-specific TCRs showed strong antitumor effects in a tumor xenograft model, demonstrating the potential of this approach for effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Construction of Antitumor T-cell Receptor Vectors from Frozen Tumors for Engineered T-cell Therapy. Tsuji, T., Yoneda, A., Matsuzaki, J., et al.[2019]

The study demonstrated that using CRISPR/Cas9 to knock out the TCR gene in ARI-0001 CAR-T cells can effectively disrupt the TCR without significantly altering the T cell phenotype, achieving over 80% efficiency.

While this method shows promise for creating allogeneic CAR-T cells with maintained anti-tumor activity, there are potential safety risks due to possible large deletions in the genome that require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. Maldonado-Pérez, N., Tristán-Manzano, M., Justicia-Lirio, P., et al.[2022]

The novel TCR 'single editing' (SE) approach allows for the disruption of only the endogenous TCR α chain, enabling the introduction of tumor-specific TCRs, which is safer and more efficient than traditional methods that require extensive cell manipulation.

In preclinical models, SE T cells demonstrated effective tumor rejection with a favorable safety profile, significantly improving survival rates compared to TCR transferred (TR) cells, which showed high alloreactivity and risk of graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. Mastaglio, S., Genovese, P., Magnani, Z., et al.[2021]

A new cell line was developed that lacks endogenous T cell receptors, allowing for the rapid generation of homogeneous cells to evaluate T cell receptor (TCR) activity more efficiently.

The engineered Natural Killer (NK) cells expressing human CD3 and interleukin-2 demonstrated similar cytotoxic effects and cytokine production as primary TCR-transduced T cells, making them a promising tool for assessing TCR functions in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene modified NK cell line as a powerful tool for evaluation of cloned TCRs for TCR-T cell therapy. Kobayashi, E., Ozawa, T., Hamana, H., et al.[2023]

T cells play a crucial role in fighting cancer, and recent advances in immunotherapy are focusing on enhancing their effectiveness through genetic engineering.

The introduction of tumor-specific receptors, such as Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), shows promise in ongoing clinical trials, indicating a potential for strong anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Kalos, M.[2012]

This study demonstrates that allogeneic T cells engineered with a novel siTCR vector can effectively target tumors while minimizing the risk of graft-versus-host disease (GVHD), making them a safer option for adoptive immunotherapy.

The engineered T cells showed significant anti-tumor efficacy in mouse models without triggering GVHD, suggesting that this 'off-the-shelf' therapy could be a viable treatment for cancer patients, expanding the application of genetically engineered T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor gene-modified allogeneic T cells with siRNA for endogenous T cell receptor induce efficient tumor regression without graft-versus-host disease. Okada, S., Muraoka, D., Yasui, K., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma. [2023]

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

Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. [2022]

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

TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. [2021]

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

Non-viral precision T cell receptor replacement for personalized cell therapy. [2023]

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

Rapid Construction of Antitumor T-cell Receptor Vectors from Frozen Tumors for Engineered T-cell Therapy. [2019]

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

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]

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

NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Gene modified NK cell line as a powerful tool for evaluation of cloned TCRs for TCR-T cell therapy. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012]

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

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]