CD200AR-L + Vaccine for Brain Tumors

Overseen By Anne Bendel, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: OX2 Therapeutics

Must not be taking: Immunosuppressants

Disqualifiers: Malignancy, Infection, Heart failure, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: 4

Duration: 24 months

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 28 days since the last dose of any targeted therapy, immunotherapy, or investigational agents, and at least 10 days since any anti-cancer intervention. If you are on these types of treatments, you will need to stop them before joining the trial.

What data supports the effectiveness of the treatment CD200AR-L + Vaccine for brain tumors?

Research suggests that blocking CD200, which usually suppresses the immune system's response to vaccines, can improve cancer immunotherapy. A peptide inhibitor like CD200AR-L can activate immune cells, increasing their ability to fight tumors, and has shown promise in increasing survival in brain tumor models. ^{1 2 3 4 5}

Is CD200AR-L + Vaccine for Brain Tumors safe for humans?

There is no specific safety data available for CD200AR-L in humans, but early phase clinical trials of similar vaccine strategies for brain tumors have shown they can be safe and feasible, with no major safety concerns reported. ^{1 2 6 7 8}

How does the treatment CD200AR-L + Vaccine for brain tumors differ from other treatments?

The CD200AR-L + Vaccine treatment is unique because it combines a vaccine with a CD200 inhibitor, which helps activate the immune system to better fight brain tumors by overcoming immune tolerance that usually suppresses the body's response to vaccines. ^{1 2 4 9 10}

What is the purpose of this trial?

This is a single center Phase I study of a new adjuvant CD200 activation receptor ligand, CD200AR-L, in combination with imiquimod and GBM6-AD vaccine to treat malignant glioma in children and young adults. The primary objective of this study is to determine the maximum tolerated dose (MTD) of CD200AR-L when given with a fixed dose of GBM6-AD vaccine, imiquimod, and a single dose of radiation for patients with recurrent High Grade Glioma (HGG) or following standard of care therapy radiation therapy for newly diagnosed Newly Diagnosed Diffuse Midline Glioma/Diffuse Intrinsic Pontine Glioma (DIPG/DMG).

Eligibility Criteria

This trial is for children and young adults with malignant glioma, specifically those with recurrent High Grade Glioma (HGG) or newly diagnosed Diffuse Midline Glioma/Diffuse Intrinsic Pontine Glioma (DIPG/DMG). Participants must have completed standard radiation therapy if they are newly diagnosed.

Inclusion Criteria

I finished my last radiation dose between 14 and 30 days ago.

Prior therapy wash-out required

Able to comply with follow-up visit schedule

Exclusion Criteria

I have had cancer within the last 5 years.

Known pregnancy or anticipated conception during study period

I am allergic to certain cancer vaccines or medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CD200AR-L, GBM6-AD vaccine, and imiquimod, with a single dose of radiation on day 15. Treatment includes weekly injections for the first 3 weeks, then every 4 weeks starting at week 7 for 8 weeks, and every 8 weeks starting at week 19 for 2 years.

24 months

Weekly visits for the first 3 weeks, then every 4 weeks, then every 8 weeks

Radiation

A single dose of 300 cGy radiation is administered on day 15 to sensitize the tumor to immune attack.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRIs, blood work, and performance assessments.

24 months

Open-label extension (optional)

Participants may opt into continuation of treatment beyond 2 years if they are tolerating the treatment and their tumor is controlled.

Long-term

Treatment Details

Interventions

• CD200AR-L

Trial Overview The study tests a new treatment called CD200AR-L combined with imiquimod and GBM6-AD vaccine. It aims to find the highest dose of CD200AR-L that's safe when given alongside these treatments and a single dose of radiation in patients with certain brain tumors.

Participant Groups

Group I: CD200AR-L Experimental Treatment 1 Intervention

Up to 3 dose levels (2.0, 3.75, and 5.0 micrograms/kg/dose) of CD200AR-L will be tested with a Dose Level -1 (1.0 microgram/kg/dose) in the event of toxicity at the 2.0 micrograms/kg/dose level. This will be given with fixed doses of 1mg GBM6-AD vaccine and topical imiquimod. A single dose of 300cGy re-irradiation will be given on Day 15. Patients with DMG/DIPG must have completed standard-of-care radiation before enrolling. The MTD will be identified using the standard 3+3 design. Upon determination of the MTD, additional patients will be enrolled as part of an expansion cohort. This study will first enroll patients ≥ 12 years of age into Dose Level 1 in order to acquire safety data prior to subsequent enrollment of study subjects aged 2-11 years.

Who Is Running the Clinical Trial?

OX2 Therapeutics

Lead Sponsor

Trials

2

Recruited

50+

Findings from Research

CD200, a molecule found in glioma tumors, suppresses the immune response to tumor-derived vaccines, contributing to the variable effectiveness of these treatments in brain tumors like glioblastoma.

Using a CD200 peptide inhibitor can enhance the immune response by activating antigen-presenting cells, leading to increased immune cell activity and potentially improving the effectiveness of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy. Xiong, Z., Ampudia-Mesias, E., Shaver, R., et al.[2018]

Genetically engineered tumor vaccines expressing GM-CSF significantly improved survival rates in rats with intracerebral gliomas, with 60% survival for irradiated and 100% for live vaccines, compared to control groups.

In contrast, vaccines expressing B7.1 or a combination of GM-CSF and B7.1 showed little to no therapeutic effect, likely due to reduced T-cell infiltration and increased T-cell apoptosis at the vaccine sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of T-cell apoptosis in rats by genetically engineered glioma cells expressing granulocyte-macrophage colony-stimulating factor and B7.1. Tseng, SH., Chen, Y., Chang, CJ., et al.[2017]

The study introduces a new peptide ligand, CD200AR-L, which targets the CD200 immune-checkpoint receptor, showing potential to enhance anti-glioma responses by activating the DAP10 signaling pathway, crucial for tumor control.

Combining CD200AR-L with immune-stimulatory gene therapy in an intracranial glioblastoma model significantly increased median survival and resulted in long-term survivors, indicating a promising new approach for glioblastoma treatment currently under investigation in a phase I trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway. Ampudia-Mesias, E., Puerta-Martinez, F., Bridges, M., et al.[2023]

A study of 159 patients with grade II/III gliomas revealed significant over-expression of specific tumor-associated antigens (BCAN, CSPG4, IGF2BP3, PTPRZ1, and TNC) at both mRNA and protein levels, indicating their potential as targets for immunotherapy.

In a smaller group of 27 patients, spontaneous T cell responses to the IMA950 antigens were detected in all grade II patients and 71% of grade III patients, suggesting that these antigens are relevant for effective tumor targeting and could enhance the efficacy of immunotherapy when combined with other peptides.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma. Dutoit, V., Migliorini, D., Ranzanici, G., et al.[2021]

Malignant brain tumors remain difficult to treat, with long-term survival only improving from 6 to 15 months over the last 80 years, despite advancements in surgery, chemotherapy, and radiotherapy.

Immunotherapy, particularly using immune modulators like CTLA-4 and PD-1/PD-L1, is being actively researched in ongoing phase I and III trials, showing promise in targeting glioma antigens, but challenges remain in achieving complete responses and understanding the lack of adverse brain inflammation in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of EGFRvIII as the target for glioma vaccines. Lowenstein, PR., Castro, MG.[2021]

Chimeric antigen receptor T cells targeting EPHA2, HER2, and interleukin 13 receptor α2 have been validated as effective treatments for recurrent medulloblastoma and ependymoma in mouse models, showing promise for bypassing the blood-brain barrier through intrathecal delivery.

The combination of these targeted T cells with azacytidine demonstrated high efficacy against multiple metastatic models of group 3 medulloblastoma and PFA ependymoma, suggesting a strong rationale for future clinical trials in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Donovan, LK., Delaidelli, A., Joseph, SK., et al.[2022]

Vaccination strategies targeting cancer-associated antigens have shown promise in preclinical brain tumor models, demonstrating the immune system's ability to safely eliminate established tumors in the central nervous system.

Early phase clinical trials, particularly in glioblastoma patients, have confirmed the safety and immunogenicity of these vaccines, with initial results suggesting potential clinical benefits, although further studies are needed to establish definitive outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccination strategies for neuro-oncology. Sampson, JH., Mitchell, DA.[2018]

Engineering CAR T cells with a medium-length spacer significantly improves their effectiveness against HER2-positive pediatric CNS tumors, as demonstrated in a medulloblastoma model.

The ongoing BrainChild-01 trial shows that repeated locoregional delivery of HER2-specific CAR T cells in children and young adults is feasible and well tolerated, with initial patients showing no dose-limiting toxicity and signs of local immune activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Vitanza, NA., Johnson, AJ., Wilson, AL., et al.[2021]

A vaccine using bone marrow-derived dendritic cells loaded with RNA from GL261 glioma cells successfully induced a specific T cell response and provided protection against brain tumors in mice.

The effectiveness of this vaccine was enhanced by adding recombinant interleukin-12, which suggests that combining immunotherapy with cytokines could improve treatment outcomes for intracranial malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A dendritic cell vaccine induces protective immunity to intracranial growth of glioma. Insug, O., Ku, G., Ertl, HC., et al.[2021]

The study identified two specific peptides from the ARF4L protein that can activate T-cells in patients with brain tumors, suggesting they could be potential targets for immunotherapy in HLA-A2 positive patients.

Despite the widespread expression of ARF4L in normal tissues, the T-cells reactive to these peptides did not show cytotoxicity against normal lymphoid cells, indicating a potential safety profile for targeting these antigens in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recognition of ADP-ribosylation factor 4-like by HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes from patients with brain tumors. Nonaka, Y., Tsuda, N., Shichijo, S., et al.[2019]

References

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

Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy. [2018]

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

Induction of T-cell apoptosis in rats by genetically engineered glioma cells expressing granulocyte-macrophage colony-stimulating factor and B7.1. [2017]

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

CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway. [2023]

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

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma. [2021]

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

The value of EGFRvIII as the target for glioma vaccines. [2021]

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

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Vaccination strategies for neuro-oncology. [2018]

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

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. [2021]

9. Greece pubmed.ncbi.nlm.nih.gov

A dendritic cell vaccine induces protective immunity to intracranial growth of glioma. [2021]

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

Recognition of ADP-ribosylation factor 4-like by HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes from patients with brain tumors. [2019]