AGAR T Cell Therapy for Pediatric Solid Cancers

Overseen By Andras Heczey

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Systemic steroids

Disqualifiers: HIV, Organ transplant, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AGAR T cells, a type of immunotherapy, for children and young adults with certain solid tumors that express the protein GPC3. The trial aims to determine the safest dose, assess how long the treatment remains in the body, and identify any side effects. The study uses special T cells combined with proteins to enhance cancer-fighting effectiveness. Children and young adults with GPC3-positive solid tumors, whose cancer has returned or not responded to standard treatments, might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic steroids (medications that reduce inflammation) at least 24 hours before receiving the CAR T cell infusion. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

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

Research has shown that AGAR T cells, which combine T cells with a special protein called IL15, have been tested in the lab and show promise in fighting cancer. These T cells are designed to find and destroy cancer cells, especially those with a protein called GPC3, found in some solid tumors.

In past studies with similar T cell treatments, patients generally tolerated the therapy well, with no serious side effects reported. AGAR T cells include a safety feature that allows them to be turned off with a specific drug if needed, adding extra safety.

Since this trial is in an early stage, it primarily aims to find the best and safest dose. While early tests suggest these cells could be effective, researchers are still learning about possible side effects. The addition of IL15 is believed to help the T cells last longer in the body and work more effectively against tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AGAR T cell therapy for pediatric solid cancers because it offers a novel approach by utilizing genetically engineered T cells. Unlike traditional treatments like chemotherapy and radiation, which can affect healthy cells and cause significant side effects, AGAR T cells specifically target GPC3-positive tumor cells. This precision targeting is possible due to the GPC3-CAR and IL15 components, which enhance the immune system's ability to recognize and attack cancer cells more effectively. This innovative mechanism holds promise for more effective and potentially less harmful cancer treatment options for children.

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

Research has shown that AGAR T cells, which participants in this trial will receive, might be a promising treatment for certain solid tumors in children. These T cells are specially designed to find and destroy cancer cells using a protein called GPC3. In lab studies, adding another protein, IL15, helped these T cells grow and stay active longer, leading to better destruction of cancer cells. Early tests in humans demonstrated that the IL15 protein improves the effectiveness of these T cells against tumors. This approach uses two powerful tools—antibodies and T cells—to target and kill cancer more effectively. While the treatment is still under study, these findings suggest it has potential for treating tumors that express the GPC3 protein. ^{1 2 3 4 6}

Who Is on the Research Team?

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 like liver cancer, rhabdoid tumor, or Wilms tumor that have not responded to standard treatments. Participants need a minimum level of physical functioning (Lansky/Karnofsky score ≥60%), adequate organ function, and must not be pregnant or breastfeeding. They should also have no history of severe allergic reactions to mouse proteins.

Inclusion Criteria

My tumor is GPC3-positive with more than 25% of cells affected and a high intensity score.

Your Child-Pugh-Turcotte score is less than 7 (for patients with liver cancer only).

You are expected to live for at least 16 weeks.

Exclusion Criteria

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

I have had an organ transplant.

You have HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion Chemotherapy

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

3 days

3 visits (in-person)

T-cell Infusion

AGAR 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

• AGAR T cells

Trial Overview The trial tests AGAR T cells, which are genetically engineered immune cells designed to target GPC3-positive solid tumors in pediatric patients. These T cells include a chimeric antigen receptor (CAR) targeting the GPC3 protein on cancer cells and IL15 for enhanced performance. The study aims to determine the highest safe dose, how long these cells last in the body, their side effects, and effectiveness against the tumors.

How Is the Trial Designed?

Group I: AGAR T cells Experimental Treatment 1 Intervention

GPC3-CAR and the IL15 (AGAR T cells) 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+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Published Research Related to This Trial

IL-15 modification significantly enhances the expansion, survival, and antitumor activity of CLDN18.2-targeting CAR-T cells in murine models, leading to improved tumor suppression compared to standard CAR-T cells.

In vivo studies showed that IL-15-expressing CAR-T cells not only infiltrated tumors more effectively but also provided a survival advantage in certain tumor models, highlighting their potential for clinical evaluation in patients with CLDN18.2-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models. Shi, H., Li, A., Dai, Z., et al.[2023]

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-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]

A new T cell activation assay was developed to test how well patient-derived tumor tissues express antigens, which can help identify patients who are likely to respond to gene-engineered T cell therapies, like CAR T cell therapy targeting CAIX in renal cell carcinoma (RCC).

The study found that T cells with the CAIX CAR specifically responded to CAIX-positive tumors by producing key immune signals, indicating that this approach can effectively measure T cell activation and may improve patient selection for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell activation upon exposure to patient-derived tumor tissue: a functional assay to select patients for adoptive T cell therapy. Schroten, C., Kraaij, R., Veldhoven, JL., et al.[2020]

Chimeric T-cell receptors (TCRs) can be genetically engineered into human T cells to provide them with specific tumor targeting capabilities, overcoming challenges associated with traditional T-cell isolation methods.

Recent advancements in retroviral transfer technology allow for the production of large quantities of these engineered T cells, enhancing their potential for effective cancer immunotherapy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic engineering of T cell specificity for immunotherapy of cancer. Willemsen, RA., Debets, R., Chames, P., et al.[2019]

TCR-T cell therapy shows great promise for treating solid tumors by recognizing a wider range of target antigens compared to CAR-T cells, which are primarily effective against CD19+ B cell-derived cancers.

Currently, there are 56 clinical trials worldwide investigating the efficacy of TCR-T cell therapy, highlighting the growing interest and potential for this approach in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. Chen, L., Qiao, D., Wang, J., et al.[2020]

A new method using a chimeric cytokine receptor (4alphabeta) allows for the selective proliferation of CAR(+) T-cells with the addition of IL-4, leading to significant T-cell expansion and activation similar to IL-2.

Engineered T-cells co-expressing 4alphabeta and a CAR targeting the MUC1 tumor antigen showed strong effectiveness in destroying tumor cells while maintaining their specificity and functionality, indicating a promising approach for enhancing T-cell immunotherapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. Wilkie, S., Burbridge, SE., Chiapero-Stanke, L., et al.[2022]

CAR-T cells targeting glypican-1 (GPC1) demonstrated strong antitumor effects in both xenogeneic and syngeneic mouse models, indicating their potential effectiveness against solid tumors.

The use of murine CAR-T cells not only targeted GPC1 but also enhanced the body's own T cell responses against other tumor antigens, showing a mechanism of antigen-spreading and no adverse effects when combined with anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab. Kato, D., Yaguchi, T., Iwata, T., 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]

Gene modification of T cells using chimeric antigen receptors (CARs) allows for the redirection of immune cells to specifically target cancer cells, combining the specificity of antibodies with the killing power of T cells.

The chapter outlines protocols for large-scale expansion and production of CAR-expressing T cells, specifically using an anti-CD19 receptor to target leukemias and lymphomas, with plans to scale up for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-MHC-dependent redirected T cells against tumor cells. Almåsbak, H., Lundby, M., Rasmussen, AM.[2020]

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]

Combining CAR-modified T cells with an armed oncolytic virus significantly enhances their migration and survival in solid tumors, leading to better treatment outcomes.

The local delivery of the chemokine RANTES and the cytokine IL-15 by the oncolytic virus boosts the effectiveness of CAR-T cells by improving their trafficking and persistence at the tumor site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors. Nishio, N., Dotti, G.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04377932

NCT04377932 | Interleukin-15 Armored Glypican 3-specific ... This study will test T cells genetically engineered with a GPC3-CAR and IL15 (AGAR T cells) in patients with GPC3-positive solid tumors.

2. 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.

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

Interleukin-15-armored GPC3-CAR T cells for patients with ... Glypican-3 (GPC3) is expressed in a group of solid cancers, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T ...

4. trials.braintumor.org trials.braintumor.org/trials/NCT05103631

Interleukin-15 Armored Glypican 3-specific Chimeric Antigen ... This study will test T cells genetically engineered with a GPC3-CAR and IL15 (CATCH T cells) in patients with GPC3-positive solid tumors. The CATCH T cells are ...

5. singlecell.chee.uh.edu singlecell.chee.uh.edu/wp-content/uploads/2024/12/s41586-024-08261-8-1.pdf

Interleukin-15-armoured GPC3 CAR T cells for patients with ... Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients.

6. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/309595

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