IL13Ralpha2 CAR T Cells for Advanced Skin Cancer

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Antoni Ribas

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Immunotherapy, Corticosteroids

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

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests the safety and best dose of modified immune cells for patients with advanced melanoma or other cancers that have spread. The treatment uses the patient's own T cells, which are changed in a lab to better attack cancer cells. The goal is to see if these modified cells can safely and effectively fight the cancer.

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.

What data supports the effectiveness of the IL13Ralpha2 CAR T Cells treatment for advanced skin cancer?

Research on similar CAR T cell therapies shows promise in targeting specific cancer markers like IL13Ralpha2, which is effective in glioblastoma models by reducing tumor recurrence and improving survival. Additionally, the use of 4-1BB in CAR T cells has been shown to enhance their effectiveness against solid tumors by boosting immune responses and reducing suppressive cells in the tumor environment. ^{1 2 3 4 5}

Is IL13Ralpha2 CAR T cell therapy safe for humans?

CAR T cell therapies, including those targeting IL13Ralpha2, have shown potential in treating various cancers, but they can also cause side effects like cytokine release syndrome (CRS), which is an overactive immune response. Some studies have reported severe side effects such as graft-versus-host disease (GVHD) in certain CAR T cell therapies, highlighting the need for careful monitoring and management of these treatments. ^{2 3 6 7 8}

How is the IL13Ralpha2 CAR T cell treatment different from other skin cancer treatments?

The IL13Ralpha2 CAR T cell treatment is unique because it uses specially engineered T cells to target a specific protein (IL13Ralpha2) found on cancer cells, which is not commonly targeted by other treatments. This approach is designed to enhance the immune system's ability to fight cancer, particularly in solid tumors, by providing strong costimulatory signals and reducing immunosuppressive cells at the tumor site. ^{1 2 4 5 9}

Research Team

Antoni Ribas

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

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%.

Trial Timeline

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

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Fludarabine Phosphate (Chemotherapy)
• IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells (CAR T-cell Therapy)
• Recombinant Interleukin-2 (Immunotherapy)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Dr. Aparna Bhaduri

Jonsson Comprehensive Cancer Center

Chief Medical Officer since 2024

MD

Dr. Michael A. Teitell

Jonsson Comprehensive Cancer Center

Chief Executive Officer since 2024

MD, PhD

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+

Jonathan Thomas

California Institute for Regenerative Medicine (CIRM)

Chief Executive Officer

BA in Biology and History from Yale University, JD from Yale Law School, PhD in Commonwealth History from Oxford University

Rosa Canet-Avilés

California Institute for Regenerative Medicine (CIRM)

Chief Medical Officer since 2024

PhD in Neuroscience from Leeds University, BS in Organic Chemistry from Central University of Barcelona

City of Hope National Medical Center

Collaborator

Trials

17

Recruited

8,900+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

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

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. [2022]

3. England pubmed.ncbi.nlm.nih.gov

IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells. [2022]

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

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. [2018]

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

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning. [2017]

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

Evidence of clinical efficacy of a first generation CD19 CAR T cell in B cell malignancies. [2023]

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

Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain. [2023]

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

Interleukin-23 engineering improves CAR T cell function in solid tumors. [2021]