Adoptive Cellular Therapy for Pediatric Brain Tumors

(IMPACT Trial)

Overseen By Fahmida Hoq, MBBS

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's National Research Institute

Must not be taking: ATG, Campath, others

Disqualifiers: Uncontrolled infections, HIV, bulky tumors, others

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

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received certain immunotherapy treatments within 28 days before the trial, and you must be on a stable or decreasing dose of steroids before receiving the TSA-T cells.

What data supports the effectiveness of the treatment Multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) for pediatric brain tumors?

Research shows that adoptive T-cell therapy, which involves using immune cells to fight cancer, has been effective in treating various solid tumors and brain tumors in experimental models. Although challenges exist, such as the tumor environment and T-cell migration, strategies are being developed to improve outcomes for brain tumors. ^{1 2 3 4 5}

Is adoptive cellular therapy safe for humans?

Adoptive cellular therapy, including treatments like multi-antigen-targeted T cells, has been studied for safety in humans with various types of cancer, such as solid tumors and breast cancer. These studies suggest that the therapy is potentially effective and nontoxic, although some challenges like severe toxicities (e.g., cytokine release syndrome or neurotoxicity) have been noted, particularly with CAR-T cell therapies. ^{1 2 6 7 8}

How is the treatment for pediatric brain tumors using TSA-T different from other treatments?

The TSA-T treatment is unique because it uses the patient's own immune cells, specifically T cells, that are engineered to target multiple tumor antigens, making it a more precise and potentially effective approach for eliminating cancer cells compared to traditional therapies. ^{1 2 3 9 10}

Research Team

Eugene Hwang, MD

Principal Investigator

Children's National Research Institute

Brian Rood, MD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for children under 5 with certain brain tumors (like medulloblastoma, pineoblastoma) who can have a device called an Ommaya reservoir placed in their brain. They should be able to handle the procedure to collect blood cells and have enough tumor tissue available. Their body must be functioning well overall, with acceptable blood counts and organ function.

Inclusion Criteria

My parent or guardian can give consent for me.

My neurological condition has been stable for 2 weeks, and I agree to a short steroid treatment.

My doctor thinks I can have surgery to place a Rickham reservoir.

Exclusion Criteria

Prior immunotherapy with an investigational agent within the last 28 days prior to procurement

I do not have any infections that aren't responding to treatment.

Patients with known HIV infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Standard of Care Treatment

Patients receive up to 3 induction chemotherapy cycles and up to 3 consolidation cycles with autologous stem cell rescue

12-18 weeks

TSA-T Infusion and Monitoring

Patients receive TSA-T infusions with safety monitoring for dose-limiting toxicities

42 days

Multiple visits for infusions and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Long-term Follow-up

Overall survival and progression-free survival are monitored

5 years

Treatment Details

Interventions

• Multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T)

Trial Overview The IMPACT study tests personalized immune cells (TSA-T) designed to target specific proteins on a child's own brain tumor. It's after standard treatments like chemo. The goal is to see if these custom-made cells are safe and how they affect the tumor and the child's immune system.

Participant Groups

Group I: Embryonal brain tumors Experimental Treatment 1 Intervention

These patients are young children (\<5 years of age) with newly diagnosed high-risk embryonal CNS malignancies and are expected to have a modest male predominance reflecting the sex-based incidence of pediatric brain tumors. Patients will have a Lansky performance status of ≥60.

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Findings from Research

In a first-in-human trial involving 15 patients with relapsed or refractory solid tumors, tumor-associated antigen cytotoxic T cells (TAA-Ts) were administered safely without any dose-limiting toxicities, demonstrating a promising new therapeutic approach.

Of the evaluable patients, 73% showed stable disease or better at day 45 post-infusion, with 6 patients remaining progression-free for a median of 13.9 months, indicating that TAA-Ts can effectively stabilize disease and prolong time to progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. Hont, AB., Cruz, CR., Ulrey, R., et al.[2020]

Adoptive cell therapy using CAR T cells has shown great success in treating B-cell malignancies, leading to FDA approval, but has faced challenges in effectively targeting pediatric solid tumors and brain tumors due to factors like varied antigen expression and a hostile tumor environment.

The review discusses ongoing strategies to improve the effectiveness of CAR T-cell therapy for solid tumors, highlighting the need to enhance T cell migration to tumor sites and overcome the immunosuppressive conditions present in these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors. DeRenzo, C., Krenciute, G., Gottschalk, S.[2022]

Adoptive T-cell therapy involves using tumor-fighting T-cells that are either taken from the patient or donors, modified in the lab, and then reintroduced into the patient to target and eliminate cancer cells.

Over the past 30 years, various strategies have evolved in adoptive T-cell therapy, leading to more precise targeting of tumors and improved effectiveness in treating cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in application of adoptive T-cell therapy for cancer patients]. Jixia, Z., Chengyan, Z., Pingli, W.[2023]

Adoptive transfer of ex vivo activated T lymphocytes from tumor-draining lymph nodes has shown effectiveness in treating experimental brain tumors, requiring both CD4 and CD8 T cells for optimal tumor regression.

A phase I clinical trial is underway to evaluate this T cell therapy for malignant astrocytomas, highlighting its potential as a targeted immunotherapy for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of intracranial tumors by systemic transfer of tumor-draining lymph node cells (Review). Plautz, G., Shu, S.[2019]

In a study involving 10 patients with progressive malignant glioma, systemic adoptive immunotherapy was found to be feasible and safe, with no severe toxicities reported, indicating a promising safety profile for this treatment approach.

Two patients experienced significant tumor regression lasting at least 6 months, and one patient maintained stable disease for over 17 months, suggesting potential therapeutic benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic T cell adoptive immunotherapy of malignant gliomas. Plautz, GE., Barnett, GH., Miller, DW., et al.[2007]

In a first-in-human trial involving 10 heavily pre-treated patients with relapsed or metastatic breast cancer, multi-antigen-targeted T cells (multiTAA-T) were well tolerated with no treatment-related toxicities, indicating a promising safety profile for this therapy.

One patient experienced prolonged disease stabilization for 5 months, which was linked to the in vivo expansion and persistence of T cells targeting specific tumor antigens, along with evidence of broader immune activation against non-targeted tumor antigens in 7 out of 10 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. Hoyos, V., Vasileiou, S., Kuvalekar, M., et al.[2022]

Adoptive T cell transfer (ACT) using CAR-T cells shows great promise in treating hematological cancers, as these engineered T cells can specifically target cancer cells, but they also pose risks of severe side effects like cytokine release syndrome and neurotoxicity.

Challenges remain in applying CAR-T therapy to solid tumors due to their complex antigens and microenvironments, leading to ongoing clinical trials aimed at enhancing the safety and effectiveness of CAR-T cells in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cell and Personalized Medicine. Cruz-Ramos, M., García-Foncillas, J.[2020]

Cytotoxic T lymphocytes (CTLs) play a crucial role in fighting cancer by recognizing tumor-specific antigens, which are presented by cells in the body.

The review discusses the development of peptide-based vaccines that target these tumor-associated antigens, highlighting their potential to enhance the immune response against cancer and improve CTL therapy in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tumor antigen-specific cytotoxic T lymphocytes and cancer immunotherapy - review]. Liu, Y.[2016]

CAR-T cell therapy, while currently approved only for B cell malignancies, shows promising potential for treating pediatric brain tumors, with early clinical trials indicating some positive responses.

Recent preclinical studies have identified new tumor antigens and combination strategies that enhance the effectiveness of CAR-T cells, particularly when administered directly to the tumor site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. Leruste, A., Beccaria, K., Doz, F.[2021]

Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T-cell therapies, are showing promise in treating aggressive primary brain tumors like glioblastoma and diffuse midline glioma, H3 K27M-mutant, which have been challenging to treat with traditional immunotherapy.

Despite the potential of CAR T-cell therapies, significant challenges remain in their development and implementation for brain tumor patients, indicating that while progress is being made, more work is needed to achieve transformative benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors. Mount, CW., Gonzalez Castro, LN.[2022]

References

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

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. [2020]

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

The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Advances in application of adoptive T-cell therapy for cancer patients]. [2023]

4. Greece pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of intracranial tumors by systemic transfer of tumor-draining lymph node cells (Review). [2019]

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

Systemic T cell adoptive immunotherapy of malignant gliomas. [2007]

6. England pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. [2022]

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

CAR-T cell and Personalized Medicine. [2020]

8. China pubmed.ncbi.nlm.nih.gov

[Tumor antigen-specific cytotoxic T lymphocytes and cancer immunotherapy - review]. [2016]

9. France pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors. [2022]