GPC2 CAR T Cells for Neuroblastoma

(GPC2 Trial)

Overseen By Yael Mosse, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Stephan Grupp MD PhD

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first in human dose escalation trial to determine the safety of administering GPC2 CAR T cells in patients with advanced neuroblastoma.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use systemic steroids or immunosuppressants at the time of cell infusion or collection, unless they are for disease treatment at other times, or are physiologic replacement hydrocortisone or inhaled steroids.

What data supports the idea that GPC2 CAR T Cells for Neuroblastoma is an effective treatment?

The available research shows that GPC2 is a promising target for neuroblastoma treatment, as it is specifically found on neuroblastoma cells. While the studies primarily focus on GD2 CAR T cells, they highlight the potential of CAR T cell therapy in treating neuroblastoma. For instance, in one study, three out of eleven patients with active neuroblastoma achieved complete remission with GD2 CAR T cells, and the persistence of these cells was linked to better outcomes. Although GPC2 CAR T cells are not directly discussed, the success of GD2 CAR T cells suggests that targeting specific markers like GPC2 could be effective. However, more research is needed to confirm the effectiveness of GPC2 CAR T cells specifically. ^{1 2 3 4 5}

What safety data exists for GPC2 CAR T-cell therapy in neuroblastoma?

The provided research does not directly mention safety data for GPC2 CAR T-cell therapy in neuroblastoma. However, it highlights the potential of GPC2 as a therapeutic target due to its selective expression in neuroblastoma and absence in normal tissues, suggesting a favorable safety profile. The research on GD2 CAR T cells, a different target, indicates that CAR T-cell therapy for neuroblastoma is generally safe, with some patients experiencing cytokine release syndrome but no on-target off-tumor toxicity. This suggests that GPC2 CAR T-cell therapy might also be safe, but specific safety data for GPC2 is not provided in the research. ^{1 2 4 5 6}

Is GPC2 CAR T-cell treatment a promising treatment for neuroblastoma?

Yes, GPC2 CAR T-cell treatment is promising for neuroblastoma because it targets a specific protein, GPC2, which is found on neuroblastoma cells but not on normal cells. This makes it a strong candidate for treating this type of cancer effectively. ^{1 2 3 5 6}

Research Team

Lisa Wray, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for patients over 1 year old with high-risk neuroblastoma that has come back or didn't respond to treatment. They must have a confirmed diagnosis, disease that can be measured, good organ function and performance status, and agree to use birth control if they can have children. People with active hepatitis B/C, HIV, uncontrolled infections or immune disorders, recent heart issues or vaccines cannot join.

Inclusion Criteria

Patients must have evaluable or measurable disease at enrollment

My neuroblastoma has come back or hasn't gone away after treatment.

My organs are working well.

Exclusion Criteria

I have active hepatitis B or C.

Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable Cytokine Release Syndrome and/or neurotoxicity

I have not received any live vaccines in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

The dose escalation arm will determine the maximum tolerated dose of GPC2 CAR T cells using a standard 3+3 trial design

Varies

Dose Expansion

If at least one dose from the dose expansion arm is determined to be safe, additional patients will be enrolled to preliminarily evaluate the rate of response to GPC2 CAR T cells and further characterize the safety profile

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• GPC2 CAR T cells

Trial Overview The trial is testing GPC2 CAR T cells in patients with advanced neuroblastoma. It's the first time this treatment is being used on humans and aims to find out how safe it is by gradually increasing the dose given to participants.

Participant Groups

Group I: Dose Expansion Arm Experimental Treatment 1 Intervention

If at least one dose from the dose expansion arm is determined to be safe, additional patients will be enrolled to the dose expansion arm to preliminarily evaluate the rate of response to GPC2 CAR T cells and further characterize the safety profile of GPC2 CAR T cells.

Group II: Dose Escalation Arm Experimental Treatment 1 Intervention

The dose escalation arm will determine the maximum tolerated dose of GPC2 CAR T cells using a standard 3+3 trial design.

Who Is Running the Clinical Trial?

Stephan Grupp MD PhD

Lead Sponsor

Trials

5

Recruited

370+

Tmunity Therapeutics

Industry Sponsor

Trials

7

Recruited

140+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Findings from Research

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]

GPC2 is identified as a specific therapeutic target for neuroblastoma, as it is selectively expressed on the surface of neuroblastoma cells and is essential for the survival of these cancer cells.

The study highlights the potential of using an antibody-drug conjugate that targets GPC2, suggesting a promising new treatment strategy for patients with neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. Malone, CF., Stegmaier, K.[2018]

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]

Despite the integration of anti-GD2 monoclonal antibody therapy, the 5-year overall survival rate for high-risk neuroblastoma patients remains around 50%, highlighting the need for improved treatment options.

CAR T cell therapy has shown promise in early clinical trials for neuroblastoma, demonstrating safety and feasibility, but challenges such as T cell persistence and an immunosuppressive tumor environment need to be addressed to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. Richards, RM., Sotillo, E., Majzner, RG.[2023]

A 3rd generation CAR T-cell construct targeting GD2 showed improved anti-tumor efficacy in neuroblastoma compared to other constructs, highlighting the importance of the 4-1BB costimulatory domain in enhancing T-cell characteristics like persistence and tumor control.

The inclusion of an inducible safety switch (iC9) in the CAR construct allows for the controlled elimination of CAR T cells if necessary, without compromising their anti-tumor activity, making it a safer option for treating pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. Quintarelli, C., Orlando, D., Boffa, I., et al.[2021]

GPC2 is identified as a promising immunotherapeutic target for neuroblastoma, showing high expression in cancer cells due to MYCN activation, while being minimally present in normal childhood tissues.

A GPC2-directed antibody-drug conjugate was developed, demonstrating potent cytotoxic effects on neuroblastoma cells that express GPC2, indicating its potential for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma. Bosse, KR., Raman, P., Zhu, Z., et al.[2022]

References

1. 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]

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

Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. [2018]

3. 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]

4. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. [2023]

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

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. [2021]

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

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma. [2022]