Armored CAR T-Cell Therapy for Pediatric Solid Cancers

Overseen By David Steffin

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Systemic steroids

Disqualifiers: Pregnancy, HIV, Organ transplant, others

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

Compensation: Varies

Number of Visits: 7

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called CARE T cells to help children with solid tumors that have not responded to standard treatments or have relapsed. CARE T cells are specially designed immune cells that target and attack cancer cells using specific proteins. The trial aims to determine the safest dose of these cells, how long they remain active in the body, and whether they can effectively shrink tumors. Children and young adults with certain solid tumors containing a protein called GPC3, who have tried other treatments without success, may be eligible to participate. 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 innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there is a 'washout period' required, meaning you need to recover from the effects of any previous treatments before starting this study. Also, if you are on systemic steroids, you must adjust or stop them at least 24 hours before the CAR T cell infusion.

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

Research has shown that the experimental drug AP1903, used with CARE T cells, has been tested in people without causing harmful side effects, suggesting this part of the treatment is relatively safe. However, the CARE T cells themselves are a new cancer treatment and have not yet received approval from the Food and Drug Administration (FDA).

CARE T cells are specially designed to better attack cancer cells. Researchers enhance these T cells with substances like IL15 and IL21 to help them last longer in the body and work more effectively. While these features are promising, the study remains in its early stages. The main goals are to determine the safest dose of CARE T cells, understand their function in the body, and identify any side effects.

Because this study is in an early phase, there is limited information on long-term safety and side effects. Participation in this trial will help gather important safety data. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for pediatric solid cancers?

Researchers are excited about CARE T cells for pediatric solid cancers because this treatment harnesses the power of genetically modified immune cells to target and destroy cancer cells. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, CARE T cells specifically recognize and bind to GPC3-positive cancer cells, potentially reducing damage to healthy cells. Additionally, the inclusion of IL15 and IL21 in these cells aims to enhance their persistence and effectiveness, offering hope for improved outcomes in children with these challenging cancers.

What evidence suggests that CARE T cells might be an effective treatment for pediatric solid cancers?

Research has shown that CARE T cells, which participants in this trial will receive, could effectively fight certain solid tumors, such as some types of pediatric liver cancer. In the lab, these T cells are specially modified to find and destroy cancer cells. They possess a receptor that helps them recognize a protein called GPC3 on tumor cells. To enhance their strength, genes for IL15 and IL21 are added, aiding the T cells in growing and remaining active longer. Lab results indicate that these enhanced T cells are more effective at killing tumor cells than those without IL15 and IL21. This suggests that CARE T cells might effectively treat solid tumors in patients. ^{1 2 3 4 5}

Who Is on the Research Team?

Andras Heczey, MD

Principal Investigator

Baylor College of Medicine

David Steffin, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 21 with certain solid tumors that haven't responded to standard treatments or when such treatments aren't an option. Participants need good organ function, no uncontrolled infections, not be on high-dose steroids, and can't be pregnant or have HIV. They must also agree to effective birth control post-treatment.

Inclusion Criteria

My liver is functioning well enough for treatment.

I can care for myself but may need occasional help.

My tumor is GPC3-positive and has relapsed or is not responding to treatment.

Exclusion Criteria

I am not on high doses of steroids or can stop them 24 hours before CAR T cell therapy.

I do not have any infections that aren't responding to treatment.

Pregnancy or lactation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Participants receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine for 3 days before T-cell infusion

1 week

3 visits (in-person)

T-cell Infusion

CARE T cells are thawed and injected into the patient 48 to 72 hours after completing chemotherapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood tests and tumor measurements

15 years

Regular visits every 3 months for 1 year, every 6 months for 4 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• CARE T cells

Trial Overview The study tests CARE T cells (genetically modified T cells) in patients with GPC3-positive tumors. These T cells are engineered to target cancer more effectively by recognizing a specific protein on tumor cells. The trial aims to determine the highest safe dose of these cells, their lifespan in the body, side effects, and effectiveness against the cancer.

How Is the Trial Designed?

Group I: CARE T cells + Fludarabine and Cytoxan Experimental Treatment 3 Interventions

GPC3-CAR and the IL15 plus IL21 (CARE T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Published Research Related to This Trial

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]

The study developed a new technology that uses membrane-tethered IL15 and IL21 to enhance the effectiveness of CAR and TCR T-cell therapies against solid tumors, showing improved resilience and function of engineered T cells.

In preclinical models, T cells expressing both IL15 and IL21 demonstrated the greatest antitumor efficacy, preventing functional exhaustion and limiting the development of dysfunctional NK-like T cells, suggesting a promising approach for improving patient outcomes in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy. Nguyen, R., Doubrovina, E., Mousset, CM., et al.[2023]

CAR-T cells engineered to overexpress IL-15 showed improved viability and anti-tumor effects, but also led to serious liver injuries and lower survival rates in mouse models, indicating potential toxicity issues.

Combining IL-15 with IL-15 receptor alpha (IL-15Ra) in CAR-T cells reduced cytokine release and improved mouse survival while still effectively inhibiting tumor growth, suggesting a way to enhance the safety and efficacy of CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy. Zhang, Y., Zhuang, Q., Wang, F., et al.[2022]

T cells engineered with GPC3-specific CARs demonstrated strong cytotoxic effects against various solid tumors, including hepatocellular carcinoma and malignant rhabdoid tumors, indicating their potential as an effective treatment option.

Among the different CAR constructs tested, the GBBz CAR showed superior T cell expansion and a Th1-biased cytokine profile, suggesting it may be the most promising candidate for further clinical development in treating GPC3-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Li, W., Guo, L., Rathi, P., et al.[2022]

CAR-engineered immune cell therapy has shown promise in treating blood cancers, but solid tumors remain challenging due to issues like immunogenicity and off-tumor toxicity, which can lead to serious side effects.

To improve the effectiveness and safety of CAR therapy for solid tumors, strategies such as regional delivery, repeated dosing, and the development of multi-targeted CAR approaches are being explored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR Based Immunotherapy of Solid Tumours-A Clinically Based Review of Target Antigens. Maher, J., Davies, DM.[2023]

CAR T-cell therapy is a groundbreaking treatment for pediatric cancers, particularly effective against hematological malignancies like acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), by using modified lymphocytes to target tumor cells directly.

While CAR T-cell therapy shows promise for solid tumors, its effectiveness is still under investigation, facing challenges such as antigen escape and poor tumor infiltration, which need to be addressed to improve therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy in Children with Solid Tumors. Kulczycka, M., Derlatka, K., Tasior, J., et al.[2023]

CAR T cells engineered to target the tumor-associated glycoprotein-72 (TAG72) and modified with membrane-bound IL-12 (mbIL12) show enhanced anti-tumor activity and improved T cell proliferation, demonstrating significant efficacy in human ovarian cancer models.

The use of mbIL12 in CAR T cells not only promotes effective tumor cell killing but also positively impacts the immunosuppressive tumor microenvironment, suggesting a promising approach for treating both local and systemic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Lee, EHJ., Murad, JP., Christian, L., et al.[2023]

CAR T-cell therapy has shown great success in treating blood cancers, but it faces significant challenges in effectively targeting solid tumors due to a lack of supportive signals and a hostile tumor environment.

Researchers have developed a new approach by engineering T cells to recognize unique tumor-specific patterns, which may enhance the effectiveness of CAR T cells in solid tumors by delivering a targeted immune response directly in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell Integration of Multiple Input Signals Allows for Precise Targeting of Cancer. Achkova, D., Pule, M.[2019]

A novel method to expand umbilical cord blood (UCB) T cells using interleukin (IL)-12 and IL-15 achieved over 150-fold growth, producing T cells with a beneficial central memory/effector phenotype for treating acute lymphoblastic leukemia (ALL).

Modified UCB T cells expressing a CD19-specific chimeric antigen receptor (CAR) and secreting IL-12 showed enhanced antitumor activity and significantly improved survival in tumor-bearing mice, suggesting potential for better outcomes in UCB transplantation for ALL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Pegram, HJ., Purdon, TJ., van Leeuwen, DG., et al.[2021]

Chimeric-receptor engineered T cells have shown promise in treating refractory B-lineage malignancies, indicating that T cells can be effectively redirected to target cancers that typically lack preexisting T cell responses, such as many childhood cancers.

The review discusses various strategies to enhance the effectiveness of engineered T cells in solid tumors, including identifying target antigens and addressing challenges like tumor microenvironment hostility and the variability of tumor-associated antigen expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T cells to treat solid pediatric cancers. Rauwolf, KK., Rossig, C.[2020]

Incorporating the IL15 cytokine into the CAR construct (GD2.CAR.15) significantly enhances the survival and antitumor activity of T cells against neuroblastoma, showing improved performance compared to the standard GD2.CAR-T cells in both laboratory and animal models.

The engineered GD2.CAR.15-T cells exhibited reduced PD-1 expression and a stem cell-like phenotype, which contributed to their superior effectiveness, while also including a safety switch (iC9) that allows for controlled elimination of these cells if necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15. Chen, Y., Sun, C., Landoni, E., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11030543/

Interleukin-15-armored GPC3-CAR T cells for patients with ... The efficacy of CAR T cells has been limited in patients with solid tumors in part due to the tumor microenvironment (TME), which contains inhibitory signals ...

2. kidneycancer.org kidneycancer.org/trial/interleukin-15-and-21-armored-glypican-3-specific-chimeric-antigen-receptor-expressed-in-t-cells-for-pediatric-solid-tumors/

Interleukin-15 and -21 Armored Glypican-3-specific ... This study will test T cells genetically engineered with a GPC3-CAR and IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors. The CARE T ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04715191

NCT04715191 | Interleukin-15 and -21 Armored Glypican- ... This study will test T cells genetically engineered with a GPC3-CAR and IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31953246/

Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 ... We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-05480

21 Armored Glypican-3-specific Chimeric Antigen Receptor ... This phase I trial tests the safety, side effects and best dose of interleukin-15 and -21 armored glypican-3-specific chimeric antigen receptor expressing ...