IL13Ralpha2 CAR T Cells for Advanced Skin Cancer

Recruiting at 2 trial locations

Overseen By Lucie M Cutler

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Anusha Kalbasi

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: HIV, Hepatitis B/C, Dementia, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 1 day

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the safest dose and understand the effects of a new cancer treatment using modified immune cells called IL13Ralpha2 CAR T cells. Researchers take these cells from a patient's blood, alter them in a lab, and design them to target and destroy cancer cells. The trial focuses on treating advanced skin cancer (melanoma) or other solid tumors that have spread and no longer respond to standard treatments. It is suitable for individuals with advanced melanoma or metastatic tumors that show specific markers (IL13Ralpha2) and who have tried other treatments without success. As a Phase 1 trial, the 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 need to stop taking your current medications. However, you cannot have received systemic cancer treatment, including immunotherapy, within 14 days before starting the trial's chemotherapy.

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

Research has shown that IL13Ralpha2 CAR T cells have been studied for their ability to find and destroy cancer cells. This treatment involves modifying a person's own immune cells in a lab to enhance their ability to fight cancer.

In studies of similar CAR T cell treatments, many patients have tolerated them well. However, some have experienced side effects, such as fever, low blood pressure, or difficulty breathing. These side effects often result from the immune system's response to the treatment.

Since this trial is in its early stages, it primarily aims to determine a safe dose and identify any side effects. Early trials like this begin with small groups and closely monitor for safety.

Considering participation in a trial means the treatment is still under safety testing. Understanding side effects from similar treatments can help in deciding if it is suitable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for advanced skin cancer, like chemotherapy and immunotherapy, work by broadly targeting cancer cells or boosting the immune system. But IL13Ralpha2 CAR T cells work differently. They are engineered to specifically target and attack cancer cells expressing the IL13Ralpha2 protein. This precision means potentially fewer side effects and more effective tumor destruction. Researchers are excited because this targeted approach could offer new hope for patients whose cancer doesn't respond well to conventional therapies.

What evidence suggests that IL13Ralpha2 CAR T cells might be an effective treatment for advanced skin cancer?

Research has shown that IL13Ralpha2 CAR T cells, which participants in this trial will receive, could be promising for treating advanced skin cancer, such as melanoma. These specially modified immune cells are designed to find and destroy cancer cells by attaching to a specific protein on the tumor. Early results suggest that these CAR T cells can effectively attack cancer cells and remain in the body long enough to potentially shrink the tumor. Although limited data from human studies exist, the mechanism of these cells provides strong reason to believe they could be effective against metastatic tumors. Early research on similar treatments has shown positive results in reducing tumor size and controlling the disease. ^{1 2 4 6 7}

Who Is on the Research Team?

Allison Betof Warner, MD, PhD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma (Stage IIIC or IV) who have tried at least one other treatment and can't be cured by surgery. They must have a certain protein on their cancer cells, be in good physical shape, and able to undergo a procedure to collect immune cells. Pregnant women, those with heart issues, severe allergies to study drugs, active infections like HIV or hepatitis B/C, or using immunosuppressive drugs can't join.

Inclusion Criteria

My kidney function is within the required range for the study.

You have advanced melanoma that cannot be cured with surgery, and your tumor shows a certain protein when tested. Also, your overall physical condition is good.

Your absolute neutrophil count is at least 1 x 10^9 cells/L, as checked within 30-60 days before starting the trial, and re-checked within 14 days of starting chemotherapy.

Exclusion Criteria

My lung function is below 70% of what is expected.

I may need or have recently taken systemic steroids, but not inhaled or topical ones.

I have heart issues with a heart pump function less than 45%.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning Regimen

Patients receive cyclophosphamide and fludarabine phosphate intravenously as a conditioning regimen

3 days

Daily visits (in-person)

Treatment

Patients receive IL13Ralpha2 CAR T cells intravenously and undergo various imaging and blood sample collections

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 2-3 months

Long-term Follow-up

Participants are followed every 6 months for 3 years, then annually for at least 15 years

At least 15 years

Every 6 months to annually

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine Phosphate
• IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
• Recombinant Interleukin-2

Trial Overview The trial tests genetically modified immune cells called IL13Ralpha2 CAR T Cells after chemotherapy (cyclophosphamide and fludarabine phosphate) plus interleukin-2. It aims to find the safest dose of these modified cells that stay in the body and effectively target melanoma.

How Is the Trial Designed?

Group I: Treatment (chemotherapy, IL13Ralpha2) Experimental Treatment 9 Interventions

Patients may receive cyclophosphamide IV over 60 minutes on days -5 to -3 and fludarabine phosphate IV over 15-30 minutes on days -5 to -2. Patients then receive IL13Ralpha2 CAR T cells IV on day 0. Patients also undergo biopsy at baseline and on study, CT, or PET and CT scan at screening and on study, magnetic resonance imaging (MRI) throughout the trial, and collection of blood samples throughout the trial. Patients with disease progression may receive a second cycle with an infusion of IL13Ralpha2 CAR T cells.

IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells is already approved in United States for the following indications:

Approved in United States as IL13Ralpha2 CAR T cells for:

• Stage IIIC or IV melanoma
• Metastatic solid tumors

Who Is Running the Clinical Trial?

Anusha Kalbasi

Lead Sponsor

Melanoma Research Alliance

Collaborator

Trials

10

Recruited

580+

Parker Institute for Cancer Immunotherapy

Collaborator

Trials

12

Recruited

460+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

City of Hope National Medical Center

Collaborator

Trials

17

Recruited

8,900+

Jonsson Comprehensive Cancer Center

Collaborator

Trials

373

Recruited

35,200+

Published Research Related to This Trial

CAR T cells engineered to express hyper IL-6 (HIL-6) showed enhanced growth and effectiveness against tumors in laboratory models, but also caused severe graft-versus-host disease (GVHD).

By creating CAR T cells with a constitutively-active form of GP130, researchers achieved improved antitumor activity without the harmful effects of GVHD, indicating that targeting the GP130/STAT3 pathway could optimize CAR T cell therapies for better safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells. Jiang, Z., Liao, R., Lv, J., et al.[2022]

This study presents the first evidence that anti-CD19 CAR-T cell therapy using a single activation domain can achieve durable responses in patients with heavily pretreated B cell malignancies, with two patients showing responses lasting up to 28 months.

The therapy demonstrated a favorable safety profile compared to traditional CAR-T therapies that use multiple co-stimulatory domains, which often lead to increased toxicities due to strong cytokine release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence of clinical efficacy of a first generation CD19 CAR T cell in B cell malignancies. Shohdy, KS., Pillai, M., Guest, R., et al.[2023]

Combining α-4-1BB antibody with CAR T-cell therapy significantly enhances the effectiveness of CAR T cells against solid tumors, as demonstrated in a human-Her2 mouse model.

The combination therapy not only boosts CAR T-cell proliferation and IFNγ expression but also reduces immunosuppressive cells in the tumor environment, suggesting a promising approach for improving cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells. Mardiana, S., John, LB., Henderson, MA., et al.[2018]

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]

Engineering T cells to express the IL-23 p40 subunit enhances their proliferation and antitumor activity, showing improved effectiveness compared to traditional CAR T cells in laboratory tests.

In mouse models of solid tumors, p40-Td CAR T cells demonstrated superior tumor-fighting ability and reduced side effects compared to CAR T cells that used other cytokines like IL-15 or IL-18.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-23 engineering improves CAR T cell function in solid tumors. Ma, X., Shou, P., Smith, C., et al.[2021]

IL13Rα2-specific CAR T cells, designed to target glioblastoma without affecting normal brain tissue, demonstrated effective recognition and destruction of IL13Rα2-positive cancer cells without cross-reactivity to IL13Rα1.

In vivo studies showed that CAR T cells with short spacer regions and specific endodomains significantly improved survival in mice with glioma, indicating their potential as a promising treatment for glioblastoma and similar cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. Krenciute, G., Krebs, S., Torres, D., et al.[2018]

The development of a bispecific CAR T cell (TanCAR) targeting both HER2 and IL13Rα2 in glioblastoma showed enhanced antitumor activity and improved survival in a murine model, suggesting a promising approach to overcome antigen escape.

TanCAR T cells demonstrated sustained activation and the ability to engage both antigens simultaneously, leading to improved T cell functionality compared to traditional single-target CAR T cells, which may help in controlling glioblastoma more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. Hegde, M., Mukherjee, M., Grada, Z., et al.[2022]

Incorporating the dectin-1 costimulatory signaling domain into CAR-T cells enhances their cytokine secretion and may improve their effectiveness against solid tumors, which have been challenging to treat with CAR-T therapy.

The performance of dectin-1 engineered CAR-T cells in vitro and in vivo is comparable to that of traditional CAR-T cells using the 4-1BB domain, suggesting that dectin-1 could be a promising new approach for enhancing CAR-T cell therapy in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain. Liang, X., Huang, Y., Li, D., et al.[2023]

Integrating co-stimulatory signaling domains into a tumor-targeting CAR (IL13-CD28-41BBzeta) significantly enhances the activation and sustained function of CD4+ T cells against tumors, compared to using CD3zeta activation alone.

In vivo studies showed that CD4+ T cells with the co-stimulatory CAR effectively controlled established CNS glioma xenografts in mice, highlighting the potential for improved anti-tumor responses in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning. Chang, L., Chang, WC., McNamara, G., et al.[2017]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04119024

NCT04119024 | Gene Modified Immune Cells After ... This phase I trial studies the side effects and best dose of modified immune cells (IL13Ralpha2 CAR T cells) after a chemotherapy conditioning regimen.

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04119024/

Clinical Trial: NCT04119024 This phase I trial studies the side effects and best dose of modified immune cells (IL13Ralpha2 CAR T cells) after a chemotherapy ...

3. clinicaltrials.stanford.edu clinicaltrials.stanford.edu/trials/g/NCT04119024.html

Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After ... This phase I trial studies the side effects and best dose of modified immune cells (IL13Ralpha2 CAR T cells) after a chemotherapy conditioning regimen.

4. withpower.com withpower.com/trial/phase-1-melanoma-10-2019-012f8

IL13Ralpha2 CAR T Cells for Advanced Skin Cancer This trial tests the safety and best dose of modified immune cells for patients with advanced melanoma or other cancers that have spread.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8230324/

Chimeric Antigen Receptor (CAR) T Cell Therapy for ... The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma.

6. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/763113

IL13Ralpha2-specific hinge-optimized 41BB-co-stimulatory ... Hinge optimization prevents the recognition and clearance of the CAR by endogenous Fc receptors (FcRs). CD19t is used as a surface marker to both quantify and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10035515/

Inclusion of 4-1BB Costimulation Enhances Selectivity and ... Inclusion of 4-1BB costimulation enhances selectivity and functionality of IL13Rα2-targeted chimeric antigen receptor T cells.