Immune Cell Therapy for Childhood Cancer

Not currently recruiting at 7 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Uncontrolled illness, CNS metastasis, Infections, others

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

Compensation: Varies

Number of Visits: 16

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new immune cell therapy called GD2CART for children and young adults with certain cancers, such as osteosarcoma or neuroblastoma, that have returned or do not respond to treatment. Researchers aim to determine the optimal dose and assess the therapy's effectiveness by using special T cells from the patient's own body, modified to attack cancer cells. This study suits those diagnosed with relapsed or hard-to-treat osteosarcoma or neuroblastoma. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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

The trial protocol does not specify if you must stop all current medications. However, there are specific 'washout' periods for certain treatments before joining the trial. For example, you must stop myelosuppressive chemotherapy 3 weeks before leukapheresis, and systemic corticosteroids 1 week before. It's best to discuss your current medications with the trial team to see if they fit within these guidelines.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that GD2-CAR T-cell therapy, tested in this trial, generally appears safe. In earlier studies, these specially modified T cells performed well and safely in lab tests and with animals. Some patients who received similar treatments experienced temporary symptom relief and increased immune activity in their blood.

This therapy targets GD2, a protein on certain cancer cells, and helps the immune system find and destroy these cells. Although this trial is in its early stages, testing GD2-CAR T-cell therapy suggests some confidence in its safety. However, as this is an early-phase trial, the main goal is to learn more about possible side effects and the best dose to use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike traditional chemotherapy or radiation treatments for childhood cancer, GD2-CAR-expressing Autologous T-lymphocytes (GD2 CAR T) represent a cutting-edge approach that harnesses the body's own immune system to fight cancer. This treatment involves reprogramming a patient’s T-cells to specifically target and destroy cancer cells by recognizing the GD2 protein, which is often overexpressed in certain types of childhood cancers. Researchers are excited because this method offers a highly targeted attack on cancer cells, potentially leading to fewer side effects and improved outcomes compared to conventional therapies. Additionally, GD2 CAR T therapy provides a personalized treatment option, as it uses the patient's own cells, making it a promising alternative for those who do not respond well to standard treatments.

What evidence suggests that GD2CART might be an effective treatment for osteosarcoma or neuroblastoma?

Research has shown that GD2 is an important target for treating neuroblastoma, a type of cancer in children. In this trial, participants will receive GD2-specific CAR T cells, specially modified immune cells designed to find and attack cancer cells. Early studies suggest these cells might work well for hard-to-treat cancers like neuroblastoma and osteosarcoma, especially when regular treatments fail. These modified T cells enhance the immune system's ability to identify and destroy GD2-positive cancer cells. While more research is needed, these early results offer hope for a new way to combat these challenging cancers. ^{2 3 4 6 7}

Who Is on the Research Team?

Rosandra N Kaplan

Principal Investigator

Cancer Immunotherapy Trials Network

Are You a Good Fit for This Trial?

This trial is for children, adolescents, and young adults with relapsed or treatment-resistant osteosarcoma or neuroblastoma. Participants must have a certain level of physical functioning, adequate blood counts and organ function, confirmed diagnosis with specific disease criteria, and no limit on prior treatments but must meet certain timeframes since last therapy. Pregnant individuals are excluded.

Inclusion Criteria

Patients > 16 years of age must have Karnofsky >= 50%. Patients =< 16 years of age must have Lansky scale >= 50%; or Eastern Cooperative Oncology Group (ECOG) performance status =< 2

Leukocytes >= 750/mcL

Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) (For the purpose of this study, the upper limit of normal [ULN] for SGOT is 50 U/L and the ULN for SGPT is 45 U/L) =< 5 x ULN

Exclusion Criteria

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Ongoing infection with human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface antigen [HBsAg] positive), or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will pose unacceptable risk. A history of HIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing

Pregnant females are excluded from this study because the effects of autologous GD2CART on the developing human fetus are unknown and because the chemotherapy agents used in this trial (cyclophosphamide and fludarabine) are category D agents with the potential for teratogenic or abortifacient effects. Additionally, because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with cyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother is treated with cyclophosphamide/fludarabine. These potential risks may also apply to other agents used in this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion Chemotherapy

Patients receive fludarabine phosphate IV daily on days -5 to -2 and cyclophosphamide IV daily on days -4 to -2

1 week

Daily visits for chemotherapy administration

GD2CART Treatment

Patients receive GD2CART cells IV on day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Three times weekly until day 14, twice weekly until day 28, then at months 2, 3, 6, 9, and 12, every 3 months until the end of the second year, then annually

What Are the Treatments Tested in This Trial?

Interventions

• GD2-CAR-expressing Autologous T-lymphocytes

Trial Overview The trial tests GD2CART immune cell therapy to see its side effects and optimal dose in treating patients whose cancer has returned or isn't responding to treatment. Patients' T cells are modified to target GD2 protein on tumor cells potentially helping the immune system kill these cancer cells.

How Is the Trial Designed?

Group I: Treatment (GD2 CAR T) Experimental Treatment 12 Interventions

LYMPHODEPLETION CHEMOTHERAPY: Patients receive fludarabine phosphate IV daily on days -5 to -2 and cyclophosphamide IV daily on days -4 to -2. GD2CART: Patients receive GD2CART cells IV on day 0. Patients also undergo ECHO, MUGA or cardiac MRI scan during screening, blood sample collection throughout the trial, and tumor biopsies and bone marrow aspiration and biopsy as clinically indicated. In addition, patients undergo standard imaging scans throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study assessing GD2-CAR T cell therapy for pediatric sarcomas, it was found that while 100% of osteosarcomas expressed GD2, the therapy was ineffective against GD2+ sarcomas in xenograft models, highlighting a challenge in treating these tumors.

Combining GD2-CAR T cells with all-trans retinoic acid (ATRA) significantly improved treatment outcomes by reducing myeloid-derived suppressor cells (MDSCs) that inhibit T cell responses, suggesting that retinoids can enhance the efficacy of CAR therapies for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas. Long, AH., Highfill, SL., Cui, Y., et al.[2021]

In a study involving patients treated with GD2-targeting CAR T cells, 75% experienced both radiographic and clinical improvements, indicating a strong efficacy of this treatment approach.

The results suggest that GD2-targeting CAR T cell therapy could be a promising option for patients, potentially leading to significant positive outcomes in their cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas. [2022]

GD2 CAR modified T cells were found to be highly effective in killing osteosarcoma (OS) tumor cells, indicating their potential as a targeted immunotherapy for high-risk OS in children.

The study also revealed that combining GD2 CAR T cells with suboptimal doses of doxorubicin chemotherapy can enhance the cytotoxic effects against OS, suggesting a synergistic approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GD2 chimeric antigen receptor modified T cells in synergy with sub-toxic level of doxorubicin targeting osteosarcomas. Chulanetra, M., Morchang, A., Sayour, E., et al.[2020]

In a study involving 19 patients with high-risk neuroblastoma, GD2 chimeric antigen receptor (CAR) T cells were able to induce complete remission in 3 out of 11 patients with active disease, demonstrating their efficacy in treating this aggressive cancer.

The persistence of CAR T cells in the patients was linked to better clinical outcomes, with some CAR-ATCs lasting up to 192 weeks, suggesting that longer-lasting CAR T cells may contribute to improved survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Louis, CU., Savoldo, B., Dotti, G., et al.[2023]

T cells engineered with chimeric antigen receptors (CARs) targeting glypican-2 (GPC2) can effectively eradicate neuroblastoma tumors that express clinically relevant levels of GPC2, demonstrating strong efficacy in a preclinical setting.

The study shows that optimizing CAR design, including modifications to transmembrane and co-stimulatory domains, can lower the antigen density threshold required for effective tumor targeting, while maintaining safety and minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Heitzeneder, S., Bosse, KR., Zhu, Z., et al.[2023]

Using Vγ9Vδ2 T cells with a CAR targeting the GD2 antigen can reduce off-tumor toxicity while still effectively attacking cancer cells, as these T cells can recognize transformed cells without needing MHC presentation.

The study demonstrated that the combination of CAR and TCR activation enhances the immune response, allowing for efficient destruction of GD2-expressing neuroblastoma cells while sparing normal cells that do not engage the TCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor. Fisher, J., Abramowski, P., Wisidagamage Don, ND., et al.[2021]

In a phase 1 study involving 12 children with relapsed/refractory neuroblastoma, treatment with GD2-directed CAR-T cells showed some clinical activity, with three patients experiencing regression of their disease despite no objective clinical responses at the 28-day evaluation point.

The study reported that while two patients experienced significant cytokine release syndrome, there was no on-target off-tumor toxicity, indicating that targeting neuroblastoma with CAR-T cells is a safe approach, although further modifications are needed to enhance the effectiveness and longevity of the CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Straathof, K., Flutter, B., Wallace, R., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04539366

NCT04539366 | Testing a New Immune Cell Therapy, GD2 ... This phase I trial investigates the side effects and determines the best dose of an immune cell therapy called GD2CART, as well as how well it works in ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2772610X24000382

GD2 targeting CAR T cells for neuroblastoma GD2 is a well-recognised and validated target antigen for neuroblastoma. CAR-T cells targeting GD2 are a tractable novel therapeutic approach for refractory ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/gd2-car-expressing-autologous-t-lymphocytes?pn=1

Clinical Trials Using GD2-CAR-expressing autologous T- ... Review the clinical trials studying gd2-car-expressing autologous t-lymphocytes on this list and use the filters to refine the results by age and location.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9516307/

GD2-targeting CAR-T cells enhanced by transgenic IL-15 ... GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02019

Phase I Trial of GD2.CART Cells Augmented With ... To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11145172/

GD2-Targeting CAR T-cell Therapy for Patients with GD2+ ... CAR.GD2 T cells have shown remarkable efficacy and safety profiles in both in vitro and in vivo models of MB. The dimerizing drug AP1903 was able to cross the ...

7. nature.com nature.com/articles/s41586-024-08171-9

Intravenous and intracranial GD2-CAR T cells for H3K27M ... Whether GD2-CAR T cell therapy favourably impacts overall survival is difficult to discern, given that the eligibility criteria excluded ...