Immune Cell Therapy for Childhood Cancer

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

67 Participants Needed

Trial Summary

What is the purpose of this trial?

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 treating patients with osteosarcoma or neuroblastoma that has come back (relapsed) or does not respond to treatment (refractory). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this trial will come from the patient and will have a new gene put in them that makes them able to recognize GD2, a protein on the surface of tumor cells. These GD2-specific T cells may help the body's immune system identify and kill GD2 positive tumor cells.

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.

What data supports the idea that Immune Cell Therapy for Childhood Cancer is an effective treatment?

The available research shows that Immune Cell Therapy, specifically GD2-CAR T cells, has shown promise in treating certain childhood cancers. For example, in a study on neuroblastoma, three out of eleven patients with active disease achieved complete remission after treatment with GD2-CAR T cells. Additionally, in another study, GD2-CAR T cells showed clinical improvement in three out of four patients with a type of brain tumor. However, the therapy's effectiveness can vary depending on the type of cancer. For instance, while GD2-CAR T cells were effective against neuroblastoma, they did not show the same success in treating sarcomas without additional treatment. This suggests that while GD2-CAR T cells can be effective, their success may depend on the specific cancer type and potentially combining with other treatments. ^{1 2 3 4 5}

What safety data exists for GD2-CAR T cell therapy in childhood cancer?

GD2-CAR T cell therapy has been evaluated in several studies for safety and efficacy in childhood cancers. In a study on neuroblastoma, GD2-CAR T cells showed antitumor activity without on-target off-tumor toxicity, although some patients experienced grade 2 to 3 cytokine release syndrome. Another study reported that GD2-CAR T cells can induce complete tumor responses in neuroblastoma patients, with extended persistence associated with longer survival. Additionally, a study on osteosarcoma demonstrated that GD2-CAR T cells were effective in inducing tumor cell death, with potential synergy when combined with doxorubicin. Overall, GD2-CAR T cell therapy appears to be a promising and relatively safe strategy, but further modifications are needed to enhance CAR-T cell longevity and efficacy. ^{1 2 3 4 6}

Is GD2-CAR T cell treatment a promising treatment for childhood cancer?

Yes, GD2-CAR T cell treatment shows promise for childhood cancer. It has been effective in killing cancer cells in osteosarcoma and neuroblastoma, leading to complete remission in some cases. It also shows potential in treating certain brain tumors, with patients experiencing clinical improvement. ^{1 2 3 4 7}

Research Team

Rosandra N Kaplan

Principal Investigator

Cancer Immunotherapy Trials Network

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

References

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

GD2 chimeric antigen receptor modified T cells in synergy with sub-toxic level of doxorubicin targeting osteosarcomas. [2020]

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

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

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

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. [2021]

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

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. [2023]

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

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas. [2021]

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

Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor. [2021]

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

GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. [2023]