CAR T-Cell Therapy for Lung Cancer

Overseen By Caroline Babinec

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Disqualifiers: Less than 12 weeks expectancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1, single-center, open-label study that enrolls adult subjects with extensive stage lung cancer or stage IV non-small cell lung cancer that is platinum-refractory and received PD-1 and/or PD-L1 therapy. The purpose of this study is to test the safety of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the GD2 antigen (iC9-GD2.CAR.IL-15 T cells) in subjects with lung cancer. How much (dose) of the iC9-GD2.CAR.IL-15 T cells are safe to use without causing too many side effects and what is the maximum dose that could be tolerated will be studied. Modified immune cells as an experimental treatment that combines antibodies and T cells will be used. Antibodies are proteins that protect the body from foreign invaders like bacteria. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill viruses and other cells, including tumor cells. Although antibodies and T cells have been used to treat cancer and they both have shown promise, neither alone has been able to cure most patients. This study will combine T cells and antibodies to create a more effective treatment. The treatment that is being researched in this study is called autologous T lymphocyte chimeric antigen receptor cells targeted against the disialoganglioside (GD2) antigen that expresses Interleukin (IL)-15, and the inducible caspase 9 safety switch (iC9). The short name for this treatment is iC9.GD2.CAR.IL-15 T cells therapy is an experimental therapy and has not been approved by the Food and Drug Administration. There are two steps. In the first step, blood will be collected from the subjects to prepare the iC9-GD2.CAR.IL-15 T cells. T cells will be isolated from the blood and modified to make iC9-GD2.CAR.IL-15. In the second step, the iC9-GD2.CAR.IL-15 T cells produced from the subject's own blood will be administered to the subject.

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, if you are taking systemic corticosteroids at doses less than 10 mg of prednisone daily, you may still be eligible to participate.

What data supports the effectiveness of the treatment iC9.GD2.CAR.IL-15 T cells for lung cancer?

Research shows that adding IL-15 to CAR-T cells can improve their ability to fight tumors by helping them expand and survive longer. In a study with a similar treatment targeting a different cancer, IL-15-enhanced CAR-T cells showed significant tumor-suppressive effects in mice, suggesting potential benefits for lung cancer treatment. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Lung Cancer safe for humans?

CAR T-Cell Therapy, including versions with IL-15, has been tested in humans for other conditions like neuroblastoma and glioblastoma. Some studies report no severe toxicities, while others mention potential risks like cytokine release syndrome (a severe immune reaction) and neurotoxicity. Overall, safety varies, and monitoring is essential. ^{2 4 5 6 7}

What makes the CAR T-cell therapy iC9.GD2.CAR.IL-15 T cells unique for lung cancer treatment?

This treatment is unique because it uses genetically modified T cells to target the GD2 antigen on cancer cells, and includes interleukin-15 (IL-15) to enhance the persistence of these cells, potentially improving their effectiveness against solid tumors like lung cancer. Unlike traditional treatments, it aims to overcome the immunosuppressive environment of solid tumors, which is a significant challenge in current cancer therapies. ^{2 8 9 10 11}

Research Team

Jared Weiss

Principal Investigator

[e-mail]

Eligibility Criteria

This trial is for adults with advanced lung cancer that's resistant to platinum chemotherapy and has been treated with PD-1/PD-L1 inhibitors. Participants must be in good enough health, have a life expectancy of at least 12 weeks, and women able to have children need a negative pregnancy test before cell collection.

Inclusion Criteria

My organs are functioning well.

I am taking less than 10 mg of prednisone daily or its equivalent.

I am resistant to platinum-based cancer treatment and have been treated with a PD1/PDL1 inhibitor. I am currently on low-dose steroids or none at all.

Exclusion Criteria

You are expected to live for less than 12 weeks.

My organs are not functioning properly.

I have not had platinum-based chemotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

T Cell Preparation

Blood is collected from subjects to prepare the iC9-GD2.CAR.IL-15 T cells. T cells are isolated and modified.

2-4 weeks

Treatment

Administration of iC9-GD2.CAR.IL-15 T cells to subjects.

Up to 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events, cytokine release syndrome, and neurotoxicity.

4 weeks

Long-term Follow-up

Monitoring of progression-free survival, overall survival, and duration of response.

Up to 2 years

Treatment Details

Interventions

• iC9.GD2.CAR.IL-15 T cells

Trial Overview The study tests autologous T lymphocyte chimeric antigen receptor cells targeting GD2 (iC9.GD2.CAR.IL-15 T cells). It aims to find the safe dosage levels of these modified immune cells designed to fight lung cancer more effectively than antibodies or T cells alone.

Participant Groups

Group I: iC9.GD2.CAR.IL-15 T Therapy Experimental Treatment 1 Intervention

Experimental: Single Arm Subjects with extensive stage lung cancer or stage IV non-small cell lung cancer that is platinum-refractory and received PD-1 and/or PD-L1 therapy will receive iC9.GD2.CAR.IL-15 T cells were manufactured from their collected blood sample.

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

Findings from Research

Interleukin 15 (IL-15) enhances the effectiveness of cell-based cancer immunotherapies, such as CAR T and NK cell therapies, by boosting T and NK cell immune responses and supporting the persistence of CD8+ memory T cells.

IL-15 not only improves long-term anti-tumor immunity by preventing T cell death but also presents both advantages and challenges in its integration into current immunotherapy strategies, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 15 in Cell-Based Cancer Immunotherapy. Zhou, Y., Husman, T., Cen, X., 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]

Interleukin-15 (IL-15) is a promising cytokine in cancer immunotherapy that enhances the immune response by activating natural killer (NK) cells, natural killer T (NKT) cells, and memory CD8+ T cells, potentially leading to the destruction of cancer cells in the tumor microenvironment.

IL-15-based therapies, including CAR T and CAR NK cell treatments, show encouraging results in preclinical and early clinical trials, suggesting that they could be effectively combined with other therapies like checkpoint inhibitors for improved cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological effects of IL-15 on immune cells and its potential for the treatment of cancer. Zhang, S., Zhao, J., Bai, X., et al.[2021]

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]

In a phase 1 trial involving 12 children with neuroblastoma, GD2-CAR.15 NKTs were found to be safe, with no dose-limiting toxicities and only one case of mild cytokine release syndrome that was manageable with treatment.

The treatment showed an objective response rate of 25%, including one complete response, suggesting that GD2-CAR.15 NKTs can effectively target neuroblastoma, and their anti-tumor activity may be further improved by targeting the BTG1 protein.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Heczey, A., Xu, X., Courtney, AN., et al.[2023]

Murine GD2 CAR-T cells can cause severe neurotoxicity, which is influenced by the costimulatory domain used, highlighting the need for careful evaluation of CAR designs in preclinical models.

The newly developed SynNotch gated CAR-T, GD2-B7H3, shows improved efficacy and specificity against neuroblastoma in mouse models, benefiting from enhanced metabolic fitness and reduced exhaustion compared to traditional CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. Moghimi, B., Muthugounder, S., Jambon, S., et al.[2021]

Infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells in eight patients with GD2-positive glioblastoma (GBM) was found to be safe and well tolerated, with no severe adverse events reported.

Of the eight patients, four experienced a partial response lasting between 3 to 24 months, indicating that 4SCAR-T cells can exert anti-GBM activity, with a median overall survival of 10 months post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Liu, Z., Zhou, J., Yang, X., et al.[2023]

CAR-T cell therapy has shown remarkable success in treating blood cancers, but its effectiveness against solid tumors is limited due to the immunosuppressive environment of these tumors.

There is a pressing need for the development of next-generation personalized CAR-T cells targeting solid tumors, focusing on improving their efficacy, survival, persistence, and safety, particularly in lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cells for the Treatment of Lung Cancer. Chocarro, L., Arasanz, H., Fernández-Rubio, L., et al.[2022]

The second-generation GD3-specific chimeric antigen receptor (CAR) T cells, which include a CD28 costimulation domain, demonstrated improved antitumor activity, including better cytokine secretion and cytotoxicity, compared to first-generation CAR T cells.

In a mouse model of established GD3+ melanoma, the combination of these second-generation CAR T cells with systemic interleukin-2 (IL2) led to a 50% complete remission rate, highlighting the importance of IL2 for enhancing the efficacy of designer T-cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Lo, AS., Ma, Q., Liu, DL., et al.[2017]

CAR-T cell therapy is a promising new immunotherapy that has shown success against both blood cancers and solid tumors, despite facing challenges in treating thoracic malignancies.

Key issues affecting CAR-T cell effectiveness include the lack of specific tumor antigens and an immunosuppressive environment, but ongoing research aims to address these challenges and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy Against Thoracic Malignancies: Challenges and Opportunities. Chen, L., Chen, F., Niu, H., et al.[2022]

CAR T-cell therapy, which involves engineering a patient's T cells to target cancer cells, has shown impressive success in treating leukemia and lymphoma, particularly with the CD19 target.

Research is ongoing to adapt CAR T-cell therapy for solid tumors like lung cancer and esophageal cancer, but there are significant challenges that need to be addressed to improve its effectiveness in these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. Kiesgen, S., Chicaybam, L., Chintala, NK., et al.[2022]

References

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

Interleukin 15 in Cell-Based Cancer Immunotherapy. [2022]

2. 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]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Biological effects of IL-15 on immune cells and its potential for the treatment of cancer. [2021]

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

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. [2023]

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

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-T Cells for the Treatment of Lung Cancer. [2022]

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

Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. [2017]

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

Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy Against Thoracic Malignancies: Challenges and Opportunities. [2022]

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

Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. [2022]