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

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 CARE 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 a person's 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 two genes that includes IL15 and IL21, which are 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 plus IL21 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15 plus IL21 .This study will test T cells that investigators made (called genetic engineering) with GPC3-CAR and the IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The investigators will insert the iCasp9 and IL15 plus IL21 together into the T cells using a virus that has been made for this study. The drug (AP1903) 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 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors. The CARE 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 CARE 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 CARE T cells will help people with GPC3-positive solid tumors.

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.

What data supports the effectiveness of the treatment CARE T cells, IL15 and IL21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for pediatric solid cancers?

Research shows that combining IL-15 and IL-21 can enhance the effectiveness of T-cell therapies in solid tumors. Additionally, CAR T-cell therapy has been successful in treating blood cancers and is being actively researched for solid tumors, with promising strategies to improve its effectiveness. ^{1 2 3 4 5}

Is Armored CAR T-Cell Therapy safe for humans?

Research shows that certain CAR T-cell therapies, including those using IL-15, can be effective against solid tumors without causing toxicity. However, high levels of IL-15 can lead to severe side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). ^{3 5 6 7 8}

What makes the Armored CAR T-Cell Therapy for Pediatric Solid Cancers unique?

This treatment is unique because it uses CARE T cells, which are engineered to include IL15 and IL21, enhancing their ability to survive and function in the challenging environment of solid tumors. This approach aims to improve the effectiveness of CAR T-cell therapy in pediatric solid cancers, which are typically difficult to treat with standard CAR T-cell therapies. ^{2 3 9 10 11}

Research Team

David Steffin, MD

Principal Investigator

Baylor College of Medicine

Andras Heczey, 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 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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy in Children with Solid Tumors. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. [2021]

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

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

6. 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]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]

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

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

CAR Based Immunotherapy of Solid Tumours-A Clinically Based Review of Target Antigens. [2023]

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

CAR T-cell Integration of Multiple Input Signals Allows for Precise Targeting of Cancer. [2019]