rHSC-DIPGVax + Checkpoint Inhibitors for Brain Tumor

Recruiting at 2 trial locations

Overseen By Monica Newmark, BS, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

Must not be taking: Temozolomide

Disqualifiers: Disseminated disease, Autoimmune, Respiratory, others

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

Compensation: Varies

Number of Visits: Unknown

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB. rHSC-DIPGVax is an off-the-shelf neo-antigen heat shock protein containing 16 peptides reflecting neo-epitopes found in the majority of DIPG and DMG tumors. Newly diagnosed patients with DIPG and DMG who have completed radiation six to ten weeks prior to enrollment are eligible.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot receive temozolomide during radiation. Corticosteroids should be reduced to 0.5mg/kg/day or less for at least 7 days before joining the trial.

What data supports the effectiveness of the treatment rHSC-DIPGVax + Checkpoint Inhibitors for Brain Tumor?

Research shows that combining immune checkpoint inhibitors, like anti-CTLA4 and anti-PD1 agents, can be effective in treating brain tumors, including primary and metastatic types. Additionally, immunotherapy approaches, such as vaccines targeting specific mutations in brain tumors, have shown promise in extending survival in patients with diffuse midline gliomas, a group that includes DIPG. ^{1 2 3 4 5}

What safety information is available for rHSC-DIPGVax and checkpoint inhibitors like Balstilimab and Zalifrelimab?

Checkpoint inhibitors, such as those used in treatments like Balstilimab and Zalifrelimab, can cause side effects like diarrhea and colitis (inflammation of the colon). These side effects are more common with CTLA-4 inhibitors like Zalifrelimab, with diarrhea occurring in about 35% of patients and colitis in about 9%. ^{6 7 8 9 10}

What makes the rHSC-DIPGVax + Checkpoint Inhibitors treatment unique for brain tumors?

This treatment is unique because it combines a neoantigen vaccine (rHSC-DIPGVax) with checkpoint inhibitors (Balstilimab and Zalifrelimab) to enhance the immune system's ability to recognize and attack tumor cells, which is different from traditional therapies that have not improved survival in DIPG. ^{1 11 12 13 14}

Research Team

Ashley Plant-Fox, MD

Principal Investigator

Ann and Robert H. Lurie Children's Hospital

Eligibility Criteria

This trial is for children and teens (12 months to 18 years old) with newly diagnosed brain tumors called DIPG or DMG, who've finished radiation therapy recently. They need a confirmed histone mutation and measurable disease. Kids should be able to perform daily activities at least halfway normally, even if in a wheelchair, and not have received any cancer treatment other than radiation.

Inclusion Criteria

Biopsy is not required for subjects with radiographically typical DIPG meeting imaging criteria

I am between 1 and 18 years old.

I have reduced my steroid use to less than or equal to 0.5mg/kg/day for at least 7 days.

Exclusion Criteria

I currently have a lung infection or breathing problem.

Autoimmune or immune disorders

I am not taking temozolomide with my radiation therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead In

Initial study to assess the tolerability of rHSC-DIPGVax monotherapy in older children

8 doses

Part A

Evaluation of rHSC-DIPGVax in combination with BALSTILIMAB for safety and tolerability

1 year or 27 cycles, whichever comes first

Part B

Dose escalation of ZALIFRELIMAB in combination with rHSC-DIPGVax and BALSTILIMAB

1 year or 9 cycles, whichever comes first

Part C

Expansion arm to assess futility versus efficacy at RP2D of ZALIFRELIMAB

1 year or 9 cycles, whichever comes first

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• Balstilimab
• rHSC-DIPGVax
• Zalifrelimab

Trial Overview The trial tests rHSC-DIPGVax combined with two immune checkpoint inhibitors, Balstilimab and Zalifrelimab. It's an early-phase study focusing on safety and how well patients tolerate the treatment. The vaccine targets specific tumor markers while the drugs aim to boost the immune system against the tumor.

Participant Groups

Group I: Part C: Dose Expansion Experimental Treatment 3 Interventions

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (at RP2D from Part B) (1 year of therapy or 9 cycles, whichever comes first) Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. Up to 12 patients will be enrolled on Part C. All subjects in Part C will be monitored for DLT's for the duration of their participation in the study to monitor for excess toxicity.

Group II: Part B: Dose Escalation of ZALIFRELIMAB (Anti-CTLA4) Experimental Treatment 3 Interventions

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (1 year of therapy or 9 cycles, whichever comes first) Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to 12 patients will be enrolled on Part B. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB) plus anti-CTLA4 (ZALIFRELIMAB), the study will proceed to Part C.

Group III: Part A: rHSC-DIPGVax in Combination with BALSTILIMAB (Anti-PD1) Experimental Treatment 2 Interventions

rHSC-DIPGVax (8 total doses) + BALSTILIMAB (1 year of therapy or 27 cycles, whichever comes first) Patients will enroll 6-10 weeks post standard of care (SOC) radiation completion. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to six patients will be enrolled on Part A. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB), the study will proceed to Part B.

Group IV: "Lead In": rHSC-DIPGVax Monotherapy Experimental Treatment 1 Intervention

rHSC-DIPGVax for 8 total doses

Who Is Running the Clinical Trial?

Ann & Robert H Lurie Children's Hospital of Chicago

Lead Sponsor

Trials

275

Recruited

5,182,000+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Children's Hospital of Orange County

Collaborator

Trials

38

Recruited

5,700+

University of Calgary

Collaborator

Trials

827

Recruited

902,000+

Findings from Research

The first three patients with diffuse intrinsic pontine glioma (DIPG) treated with B7-H3-specific CAR T cells showed no dose-limiting toxicities after receiving 40 infusions, indicating the treatment's safety and tolerability.

One patient experienced sustained clinical and radiographic improvement for 12 months, suggesting potential efficacy, while the presence of CAR T cells in cerebrospinal fluid (CSF) and local immune activation were observed, supporting the treatment's mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety. Vitanza, NA., Wilson, AL., Huang, W., et al.[2023]

The H3.3K27M-targeted peptide vaccine was well tolerated in patients with diffuse midline gliomas, with no severe treatment-related adverse events reported, indicating a favorable safety profile.

Patients who developed H3.3K27M-reactive CD8+ T cell responses had a significantly longer overall survival (median OS of 16.1 months) compared to those who did not respond, highlighting the potential efficacy of the vaccine in improving outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. Mueller, S., Taitt, JM., Villanueva-Meyer, JE., et al.[2022]

Immunomodulatory agents targeting CTLA4 and PD1/PDL1 have shown significant effectiveness in treating both primary and metastatic brain tumors, suggesting a promising avenue for cancer therapy.

Combining anti-CTLA4 and anti-PD1 therapies enhances clinical benefits compared to using them individually, although this combination may lead to increased toxicity, highlighting the need to understand the brain tumor microenvironment for better treatment predictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. Passiglia, F., Caglevic, C., Giovannetti, E., et al.[2018]

Diffuse midline gliomas (DMGs) are highly aggressive pediatric tumors with a median overall survival of less than 12 months, highlighting the urgent need for new treatment options.

Immunotherapy, particularly anti-GD2 CAR-T therapy, shows promise in treating DMGs, especially in diffuse intrinsic pontine glioma (DIPG) patients, although challenges remain in translating early successes into standardized treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy approaches for the treatment of diffuse midline gliomas. Bernstock, JD., Hoffman, SE., Kappel, AD., et al.[2022]

The study involved 9 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and demonstrated that autologous dendritic cell vaccines (ADCV) can be safely prepared and administered after radiation therapy, with no adverse effects reported.

Immunological responses to the ADCV were observed in nearly all patients, indicating a specific immune response against DIPG, which suggests that this approach could be a promising foundation for future immunotherapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma. Benitez-Ribas, D., Cabezón, R., Flórez-Grau, G., et al.[2022]

In a study of 104 advanced melanoma patients in Korea, ipilimumab demonstrated similar efficacy and safety profiles as seen in Western populations, with a median progression-free survival of 2.73 months.

The most common adverse event was skin rash, affecting 22.1% of patients, and factors like poor performance status and liver metastasis were identified as independent poor prognostic indicators.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort. Jung, M., Lee, J., Kim, TM., et al.[2022]

In a review of 18 studies involving 4,653 patients, anti-CTLA-4 inhibitors were associated with a significantly higher incidence of diarrhea (35.4%) and colitis (8.8%) compared to anti-PD-1 inhibitors, which had incidences of 13.7% and 1.6%, respectively.

The study found that patients receiving anti-PD-1 therapy had a lower relative risk of developing diarrhea (0.58) and colitis (0.16) compared to those on anti-CTLA-4 therapy, indicating that PD-1 inhibitors may be a safer option regarding these gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. Tandon, P., Bourassa-Blanchette, S., Bishay, K., et al.[2019]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

In a study of 30 patients with advanced pancreatic ductal adenocarcinoma, combining ipilimumab (10 mg/kg) with the GVAX vaccine led to prolonged disease stabilization in 3 patients and a decline in CA19-9 levels, indicating a potential therapeutic benefit.

The combination treatment also showed a trend towards improved overall survival (5.7 months) compared to ipilimumab alone (3.6 months), suggesting that this approach may enhance the effectiveness of cancer immunotherapy, although further studies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. Le, DT., Lutz, E., Uram, JN., et al.[2022]

Ipilimumab is a monoclonal antibody that blocks CTLA-4, enhancing T-cell activation and leading to significant antitumor immune responses, which has been shown to improve survival in patients with advanced melanoma in two global phase 3 clinical studies involving over 13,000 patients.

Approved in over 40 countries, including the U.S. and EU, ipilimumab is the first treatment to demonstrate an overall survival benefit for advanced melanoma, with ongoing trials exploring its efficacy in other cancers like lung and gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ipilimumab]. Tokudome, T.[2017]

The oncolytic virus Delta-24-RGD has been shown to be safe and significantly increase survival in mouse models of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs), indicating its potential as a treatment option.

The therapeutic effect of Delta-24-RGD is attributed to both its ability to directly kill tumor cells and to stimulate an immune response against the tumors, leading to the initiation of a phase I/II clinical trial for newly diagnosed DIPG patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Martínez-Vélez, N., Garcia-Moure, M., Marigil, M., et al.[2021]

Palbociclib, when combined with temsirolimus, effectively inhibits the growth of diffuse intrinsic pontine glioma (DIPG) cells in vitro by targeting CDK4/6 and mTOR signaling pathways, showing synergistic effects across three patient-derived cell lines.

Direct infusion of palbociclib into the brain did not cause neurotoxicity, suggesting a potentially safe method for delivering this treatment in combination with temsirolimus for DIPG, a type of pediatric brain tumor resistant to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity. Asby, DJ., Killick-Cole, CL., Boulter, LJ., et al.[2022]

Recent studies suggest that targeting specific vulnerabilities in DIPG cells, such as using epigenetic modifying agents like histone deacetylase inhibitors and CDK7 inhibitors, may offer new therapeutic options.

Emerging immunotherapies and strategies to disrupt the tumor's supportive microenvironment are being explored, indicating that a combination of approaches will likely be necessary to effectively treat this aggressive childhood brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets. Aziz-Bose, R., Monje, M.[2020]

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brainstem tumor in children with no effective treatments beyond radiation therapy, which only provides temporary relief.

Recent insights suggest that DIPG is biologically distinct from other high-grade gliomas, indicating that existing chemotherapy and targeted therapies should not be adapted for DIPG, and that new approaches, including better drug delivery methods and tumor models, are needed for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DIPG in Children - What Can We Learn from the Past? Vanan, MI., Eisenstat, DD.[2022]

References

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

Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety. [2023]

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

Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. [2018]

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

Immunotherapy approaches for the treatment of diffuse midline gliomas. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma. [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort. [2022]

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

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. [2019]

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

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

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

Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[Ipilimumab]. [2017]

11. England pubmed.ncbi.nlm.nih.gov

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. [2021]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity. [2022]

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

Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets. [2020]

14. Switzerland pubmed.ncbi.nlm.nih.gov

DIPG in Children - What Can We Learn from the Past? [2022]