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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called AGAR T cells, a new experimental treatment. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. Investigators have found from previous research that they can put a new gene (a tiny part of what makes-up DNA and carries your traits) into T cells that will make them recognize cancer cells and kill them. In the lab, investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GPC3. The antibody GPC3 recognizes a protein found solid tumors including pediatric liver cancers. This CAR is called GPC3-CAR. To make this CAR more effective, investigators also added a gene that includes IL15. IL15 is a protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15 .This study will test T cells that investigators made (called genetic engineering) with GPC3-CAR and the IL15 (AGAR T cells) in patients with GPC3-positive solid tumors such as yours. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called Rimiducid. The investigators will insert the iCasp9 and IL15 together into the T cells using a virus that has been made for this study. The drug (Rimiducid) is an experimental drug that has been tested in humans with no bad side-effects. The investigators will use this drug to kill the T cells if necessary due to side effects. This study will test T cells genetically engineered with a GPC3-CAR and IL15 (AGAR T cells) in patients with GPC3-positive solid tumors. The AGAR T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the biggest dose of AGAR T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the AGAR T cells will help people with GPC3-positive solid tumors.

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.

What data supports the effectiveness of the AGAR T Cell Therapy for Pediatric Solid Cancers treatment?

Research shows that T cells engineered with chimeric antigen receptors (CARs) can effectively target and destroy cancer cells, even in solid tumors. Additionally, the use of interleukin-15 (IL-15) has been shown to enhance the survival and function of these engineered T cells, improving their ability to fight cancer. ^{1 2 3 4 5}

Is AGAR T Cell Therapy safe for humans?

Research on similar T cell therapies, like those targeting glypican-1 (GPC1) and using interleukin-15 (IL-15), shows they can be effective against tumors without causing adverse effects in animal models. However, high levels of IL-15 can lead to severe side effects like cytokine release syndrome (CRS) and neurotoxicity, so careful monitoring is needed. ^{4 6 7 8 9}

What makes AGAR T Cell Therapy unique for treating pediatric solid cancers?

AGAR T Cell Therapy is unique because it uses genetically engineered T cells that are specifically designed to target and attack cancer cells in children with solid tumors. These T cells are modified to express a chimeric antigen receptor (CAR) that recognizes a specific protein on cancer cells, and they are 'armored' with interleukin-15 to enhance their survival and effectiveness in the challenging environment of solid tumors. ^{3 5 10 11 12}

Research Team

Andras Heczey, MD

Principal Investigator

Baylor College of Medicine

David Steffin, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. [2023]

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

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

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

Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. [2022]

4. Switzerland 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. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Redirecting T cells to treat solid pediatric cancers. [2020]

6. United States 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. [2022]

7. Netherlands 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. [2020]

8. England 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. [2020]

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

Genetic engineering of T cell specificity for immunotherapy of cancer. [2019]

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

Non-MHC-dependent redirected T cells against tumor cells. [2020]