Immunotherapy for Ependymoma

Overseen By Sharon Dibridge

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: James Felker

Must not be taking: Interferon, Growth factors

Disqualifiers: Immune disorders, Pregnancy, Outside North America, 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: Unknown

Duration: 2 years

24 Participants Needed

Trial Summary

Do I need to stop taking my current medications to join the trial?

The trial requires that you stop certain medications at least one week before joining, including interferon, allergy shots, growth factors, interleukins, and any investigational drugs. You must also not use immunosuppressive agents within four weeks prior to the study, except for low-dose dexamethasone.

What data supports the effectiveness of the treatment HLA-A2 restricted synthetic tumor antigen, Imiquimod, for ependymoma?

Research on similar treatments shows that targeting specific proteins in brain tumors can trigger immune responses, which may help in fighting the tumor. For example, a study on a different type of brain tumor found that certain antigens (proteins that trigger immune responses) were over-expressed, and patients showed strong immune responses to these antigens, suggesting potential for similar approaches in ependymoma. ^{1 2 3 4 5}

Is immunotherapy for ependymoma safe for humans?

The safety data for similar immunotherapy treatments, like ipilimumab, show that while they can improve survival in some cancers, they may cause side effects such as skin rash, diarrhea, and inflammation of the pituitary gland (hypophysitis). Serious reactions can occur, so close monitoring is important. ^{6 7 8 9 10}

How is the treatment with HLA-A2 restricted synthetic tumor antigen and Imiquimod different from other treatments for ependymoma?

This treatment is unique because it uses a synthetic tumor antigen combined with Imiquimod, which is known for its immune-boosting properties, to specifically target tumor cells in ependymoma. Unlike traditional treatments like surgery and radiotherapy, this approach aims to harness the body's immune system to fight the tumor, potentially offering a novel therapeutic option for a condition with limited effective treatments. ^{1 3 4 11 12}

What is the purpose of this trial?

The purpose of this study is to see if vaccination with HLA-A2 restricted peptides, combined with the immunoadjuvant imiquimod is safe and can induce immune responses in children with recurrent ependymomas. Eligible patients are stratified by primary tumor location.

Research Team

James Felker, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for children with recurrent ependymoma, a type of brain tumor. Participants must be between 1 and 21 years old, HLA-A2 positive, have had prior standard therapy including surgery and radiation if appropriate, and be off high-dose steroids. They should not have immune deficiencies or be on immunosuppressive drugs.

Inclusion Criteria

I have been stable and on low-dose or no corticosteroids for at least a week.

I am mostly active and can care for myself.

My diagnosis is ependymoma, regardless of its grade.

Exclusion Criteria

I have received a tetanus vaccine recently or will receive it during my treatment.

I haven't taken any medications or treatments for at least a week.

I have previously received immunotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive HLA-A2 restricted tumor antigen peptide vaccine in conjunction with imiquimod

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• HLA-A2 restricted synthetic tumor antigen
• Imiquimod

Trial Overview The study tests whether a vaccine made from specific tumor proteins combined with an immune-boosting cream (Imiquimod) can provoke an immune response safely in these patients. The treatment involves regular visits to Pittsburgh for vaccination over several months.

Participant Groups

Group I: HLA-A2 restricted tumor antigen vaccine Experimental Treatment 6 Interventions

This is a single-arm study of a HLA-A2 restricted tumor antigen peptide vaccine, administered in conjunction with imiquimod

Who Is Running the Clinical Trial?

James Felker

Lead Sponsor

Trials

3

Recruited

110+

Ian F. Pollack, M.D.

Lead Sponsor

Trials

5

Recruited

130+

Solving Kids' Cancer

Collaborator

Trials

11

Recruited

200+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 178 ependymoma cases, higher levels of CD3+ and CD8+ immune cells were linked to longer progression-free survival (PFS), while higher levels of FOXP3+ and CD68+ cells were associated with shorter PFS, indicating that the immune microenvironment plays a crucial role in patient outcomes.

The presence of PD-L1 was noted in a small subset of supratentorial ependymomas, suggesting potential for immunotherapy, although PD-L1 expression did not show significant prognostic value in this study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma. Nam, SJ., Kim, YH., Park, JE., et al.[2019]

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]

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]

In pediatric ependymoma (EPN), particularly the supratentorial RELA fusion (ST-RELA) subtype, there is a significant expression of PD-L1, which is associated with immune evasion and T-cell exhaustion, indicating a potential target for immunotherapy.

The study suggests that clinical trials using checkpoint inhibitors targeting PD-L1/PD-1 should focus on ST-RELA tumors, as they show high levels of PD-L1 and exhausted T cells, which could benefit from these novel therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy. Witt, DA., Donson, AM., Amani, V., et al.[2019]

Complete surgical resection of ependymomas is the only consistent factor that improves survival rates in pediatric patients, highlighting the importance of effective surgical intervention.

Recent genomic studies have identified unique molecular characteristics of ependymomas, suggesting that targeted therapies and personalized treatment approaches could enhance outcomes for patients with these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Management of Pediatric Ependymomas. Lin, FY., Chintagumpala, M.[2018]

Ipilimumab, a monoclonal antibody used to treat melanoma, enhances T-cell activation and has been linked to improved overall survival, but it can also cause immune-related adverse events like skin rash, diarrhea, and colitis.

This report highlights a rare case of a patient developing both uveitis and hypophysitis after ipilimumab treatment, demonstrating that these immune-related side effects can occur weeks after the last dose and may present diagnostic challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash. Nallapaneni, NN., Mourya, R., Bhatt, VR., et al.[2022]

In a Phase II study involving 18 patients with leptomeningeal disease, the combination of ipilimumab and nivolumab showed promising efficacy, with 44% of patients alive at three months, surpassing the expected 18%.

The treatment had an acceptable safety profile, although one-third of patients experienced significant adverse events, including two cases leading to treatment discontinuation due to hepatitis and colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Brastianos, PK., Strickland, MR., Lee, EQ., et al.[2021]

In a study of 51 patients with metastatic melanoma treated with immune checkpoint inhibitors, 11.7% developed hypophysitis, highlighting a notable incidence of this immune-mediated adverse event.

Patients who experienced immune-mediated adverse events (IMAEs) showed significantly improved overall survival and progression-free survival compared to those who did not, suggesting a potential link between IMAEs and better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypophysitis induced by immune checkpoint inhibitors in a Scottish melanoma population. Wei, KZ., Baxter, M., Casasola, R.[2022]

Ipilimumab significantly improves survival rates in patients with malignant melanoma by stimulating the immune system.

While ipilimumab is generally safe, it can cause serious side effects like hypophysitis and severe diarrhea, which require prompt diagnosis and treatment to prevent fatal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lymphocytic hypophysitis due to ipilimumap therapy]. Thomsen, HH.[2017]

Immunotherapy-induced hypophysitis (IIH) occurs more frequently in males and leads to more severe pituitary dysfunction compared to primary hypophysitis (PH), with central hypocortisolism being a common feature in IIH.

Patients with IIH often present with similar symptoms to those with PH, but diabetes insipidus is very rare in IIH, and 20% of IIH patients report no symptoms at all, indicating a need for careful monitoring in patients receiving immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences between immunotherapy-induced and primary hypophysitis-a multicenter retrospective study. Amereller, F., Deutschbein, T., Joshi, M., et al.[2022]

In a study of 19 pediatric and 13 adult ependymomas, a high percentage of pediatric cases (95% for EphA2 and Survivin, 84% for IL-13Rα2) showed overexpression of tumor-associated antigens, indicating potential targets for immunotherapy.

The consistent expression of these antigens in both pediatric and adult ependymomas supports the feasibility of using a peptide-based vaccine targeting these antigens in clinical trials to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy. Yeung, JT., Hamilton, RL., Okada, H., et al.[2021]

Patients with supratentorial extraventricular ependymoma (SEE) who underwent gross total resection (GTR) had significantly better progression-free survival compared to those who had subtotal resection (STR), with STR patients facing much higher recurrence risks over time.

The expression of PD-L1 was identified as an independent predictor of worse outcomes in SEE patients, suggesting that PD-L1 positivity correlates with increased recurrence rates and could serve as a reliable biological marker for prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study. Wang, L., Han, S., Yan, C., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma. [2019]

2. 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]

3. 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]

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

Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy. [2019]

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

Advances in Management of Pediatric Ependymomas. [2018]

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

Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash. [2022]

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

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Hypophysitis induced by immune checkpoint inhibitors in a Scottish melanoma population. [2022]

9. Denmark pubmed.ncbi.nlm.nih.gov

[Lymphocytic hypophysitis due to ipilimumap therapy]. [2017]

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

Differences between immunotherapy-induced and primary hypophysitis-a multicenter retrospective study. [2022]

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

Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy. [2021]

12. Germany pubmed.ncbi.nlm.nih.gov

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study. [2021]