GPC2 CAR T Cells for Neuroblastoma
(GPC2 Trial)
Recruiting in Palo Alto (17 mi)
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Stephan Grupp MD PhD
Must not be taking: Systemic steroids, Immunosuppressants
Disqualifiers: Hepatitis B, Hepatitis C, HIV, others
No Placebo Group
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.
12345What 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.
12456Is 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.
12356Eligibility 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.
+5 more
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.
+7 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Dose Expansion ArmExperimental Treatment1 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 ArmExperimental Treatment1 Intervention
The dose escalation arm will determine the maximum tolerated dose of GPC2 CAR T cells using a standard 3+3 trial design.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of PhiladelphiaPhiladelphia, PA
Loading ...
Who Is Running the Clinical Trial?
Stephan Grupp MD PhDLead Sponsor
Tmunity TherapeuticsIndustry Sponsor
University of PennsylvaniaCollaborator
National Cancer Institute (NCI)Collaborator
Children's Hospital of PhiladelphiaCollaborator
Gilead SciencesIndustry Sponsor
References
Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. [2021]The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.
Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. [2018]In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2.
Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. [2023]We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4(+) cells and central memory cells (CD45RO(+)CD62L(+)) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930.
CAR T Cell Therapy for Neuroblastoma. [2023]Patients with high risk neuroblastoma have a poor prognosis and survivors are often left with debilitating long term sequelae from treatment. Even after integration of anti-GD2 monoclonal antibody therapy into standard, upftont protocols, 5-year overall survival rates are only about 50%. The success of anti-GD2 therapy has proven that immunotherapy can be effective in neuroblastoma. Adoptive transfer of chimeric antigen receptor (CAR) T cells has the potential to build on this success. In early phase clinical trials, CAR T cell therapy for neuroblastoma has proven safe and feasible, but significant barriers to efficacy remain. These include lack of T cell persistence and potency, difficulty in target identification, and an immunosuppressive tumor microenvironment. With recent advances in CAR T cell engineering, many of these issues are being addressed in the laboratory. In this review, we summarize the clinical trials that have been completed or are underway for CAR T cell therapy in neuroblastoma, discuss the conclusions and open questions derived from these trials, and consider potential strategies to improve CAR T cell therapy for patients with neuroblastoma.
Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. [2021]Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB.
Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma. [2022]We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target.