GPC2 CAR T Cells for Neuroblastoma

(GPC2 Trial)

Overseen By Melissa Varghese, M.S.

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

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new treatment called GPC2 CAR T cells, a type of immunotherapy, for patients with advanced neuroblastoma or retinoblastoma. Researchers seek to determine the safest dose and evaluate the treatment's effectiveness. The trial consists of two parts: one to identify the right dose and another to assess the effects of that dose on more patients. Those with high-risk neuroblastoma that is difficult to treat or recurs, or those with metastatic retinoblastoma, might be suitable candidates for this study. As a Phase 1 trial, this 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 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.

Is there any evidence suggesting that GPC2 CAR T cells are likely to be safe for humans?

Research has shown that GPC2 CAR T cells are safe and effective in early lab studies for treating neuroblastoma, a type of cancer. These studies found no major safety problems, indicating that the treatment is generally well-tolerated. This treatment is now in a Phase 1 trial, marking its first test in humans. Phase 1 trials primarily focus on safety, so researchers will closely monitor any serious side effects. The trial's progression suggests that earlier research indicated it might be safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about GPC2 CAR T cells for neuroblastoma because this treatment represents a novel approach to fighting cancer. Unlike traditional treatments like chemotherapy and radiation, which target rapidly dividing cells indiscriminately, GPC2 CAR T cells are engineered to specifically recognize and attack cancer cells by targeting a protein called GPC2 found on neuroblastoma cells. This precise targeting aims to reduce damage to healthy cells, potentially leading to fewer side effects and better outcomes. Additionally, CAR T cell therapy is a form of immunotherapy, which harnesses the body's own immune system to combat cancer, offering a promising new avenue for patients with this challenging condition.

What evidence suggests that GPC2 CAR T cells might be an effective treatment for neuroblastoma?

Research shows that GPC2 CAR T cells could help treat neuroblastoma, a type of cancer. Studies have found that these specially designed cells can more effectively attack cancer cells in lab tests and animal studies. GPC2 serves as a strong target for this therapy, potentially aiding in the fight against this cancer. Early results suggest that GPC2 CAR T cells can shrink tumors and enhance treatment effectiveness. The trial includes a Dose Escalation Arm to determine the maximum tolerated dose and a Dose Expansion Arm to evaluate the response rate and further characterize the safety profile of GPC2 CAR T cells. This approach could offer a promising new option for people with advanced neuroblastoma. ^{1 2 3 6 7}

Who Is on the Research Team?

Lisa Wray, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

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

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

Patients must have evaluable or measurable disease at enrollment

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

Pregnant or nursing (lactating) women

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Kite, A Gilead Company

Industry Sponsor

Trials

45

Recruited

4,300+

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41026583/

D3-GPC2-directed CAR T cells are safe and efficacious in ... These data validate GPC2 as a bona fide CAR T cell target in neuroblastoma and other cancers. The safety and preliminary efficacy of GPC2 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40569285/

GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible ... All three versions of GPC2-CAR T cells significantly enhanced killing against a high neuroblastoma burden, both in vitro and in vivo, relative ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05650749

NCT05650749 | GPC2 CAR T Cells for Relapsed or ... This is a first in human dose escalation trial to determine the safety of administering GPC2 CAR T cells in patients with advanced neuroblastoma or ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-25-0089/766013/D3-GPC2-directed-CAR-T-cells-are-safe-and

D3-GPC2-directed CAR T cells are safe and efficacious in ... Conclusions: These data validate GPC2 as a bona fide CAR T cell target in neuroblastoma and other cancers. The safety and preliminary efficacy ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1535610821006589

GPC2-CAR T cells tuned for low antigen density mediate ... GPC2-CAR T cells exhibited markedly increased anti-tumor activity, CAR expansion, and persistence (Figures 6E–6G) and also significantly ...

6. chop.edu chop.edu/news/preclinical-car-t-studies-offer-foundation-safer-more-effective-solid-pediatric-tumor

Preclinical CAR-T Studies Offer Foundation for Safer, More ... Immune profiling revealed that GPC2 CAR-T cells had poor intratumoral persistence, meaning that the CAR-T cells did not remain within the tumor ...

7. clinicaltrials.stanford.edu clinicaltrials.stanford.edu/trials/g/NCT07087002.html

GPC2-CAR T Cell Therapy for Relapsed or Refractory ... This is a single-site, open-label Phase 1 clinical trial evaluating the feasibility, safety, and preliminary activity of autologous GPC2-targeted chimeric ...