CAR-T Cells for Ovarian Cancer

Overseen By Caroline Babinec

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Disqualifiers: Concurrent malignancy, Non-compliance, others

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

Compensation: Varies

Number of Visits: 4

27 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment iC9-CAR.B7-H3 T cells for ovarian cancer?

Research shows that CAR-T cells targeting B7-H3 can control the growth of ovarian cancer in lab and animal studies, suggesting they might be effective in treating this cancer. Additionally, B7-H3 is a promising target because it is highly expressed in ovarian cancer cells, which may help overcome resistance to other treatments. ^{1 2 3 4 5}

Is CAR-T cell therapy targeting B7-H3 safe for humans?

Initial trials of CAR-T cell therapy targeting B7-H3 have shown it to be safe, with no evident toxicity in preclinical models. However, other CAR-T therapies, like those targeting B7-H4, have shown delayed toxic effects, highlighting the importance of ongoing safety evaluations. ^{1 4 5 6 7}

What makes the iC9-CAR.B7-H3 T cell treatment unique for ovarian cancer?

The iC9-CAR.B7-H3 T cell treatment is unique because it targets the B7-H3 protein, which is highly expressed in ovarian cancer cells but not in normal tissues, making it a promising target for immunotherapy. This approach is particularly beneficial for patients who do not respond to traditional PD-1/PD-L1 therapies, as B7-H3 is a different checkpoint molecule involved in suppressing the immune response. ^{1 3 4 5 8}

What is the purpose of this trial?

The purpose of this study is to test the safety and tolerability of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (iC9-CAR.B7-H3 T cells) in patients with ovarian cancer that came back after receiving standard therapy for this cancer. The iC9.CAR.B7-H3 treatment is experimental and has not been approved by the Food and Drug Administration. The study team wants to know how much (dose) of the iC9-CAR.B7-H3 T cells are safe to use in patients without causing too many side effects and what is the maximum dose could be tolerated. There are two parts to this study. In part 1, approximately blood will be collected from subjects to prepare the iC9.CAR.B7-H3 T cells. The study team will collect disease-fighting T cells from the blood and modify them to prepare the iC9.CAR.B7-H3 T cells. In part 2, the iC9.CAR.B7-H3 T cells will be given to eligible subjects by infusion three days after completion of lymphodepletion chemotherapy.

Research Team

Linda Van Le

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

This trial is for individuals with ovarian cancer that has returned after standard treatment. Participants must have sufficient T cells to modify, and meet specific health criteria not detailed here.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

My cancer came back or got worse within 6 months after platinum chemotherapy.

Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information explained to, understood by and signed by the subject or legally authorized representative

Exclusion Criteria

I do not have another cancer that could affect the trial's safety or results.

I am willing and able to follow the study's procedures.

I am not willing to have biopsies before, during, and after treatment if my doctor thinks it's safe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Subjects receive lymphodepletion chemotherapy prior to CAR-T cell infusion

1 week

1 visit (in-person)

CAR-T Cell Treatment

iC9-CAR.B7-H3 T cells are infused into subjects after lymphodepletion chemotherapy

3 days

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after CAR-T cell treatment

4 weeks

2 visits (in-person)

Long-term Follow-up

Participants are monitored for progression-free survival and overall survival

Up to 2 years

Treatment Details

Interventions

• iC9-CAR.B7-H3 T cells

Trial Overview The study tests a new therapy using modified T cells (iC9-CAR.B7-H3) after chemotherapy with Fludarabine and Cyclophosphamide. It's in two parts: cell collection/modification, then infusion post-chemotherapy.

Participant Groups

Group I: Chimeric Antigen Receptors Experimental Treatment 3 Interventions

blood will be collected to prepare the iC9-CAR.B7-H3 T cells. Disease-fighting T cells will be isolated and modified to prepare the iC9-CAR.B7-H3 T cells. In part 2, the iC9-CAR.B7-H3 T cells are given by infusion after completion of lymphodepletion chemotherapy.

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

Findings from Research

B7-H3.CAR-T cells effectively controlled the growth of various cancers, including pancreatic ductal adenocarcinoma, ovarian cancer, and neuroblastoma, in both laboratory and mouse models, indicating their potential as a powerful immunotherapy.

The use of 4-1BB co-stimulation in B7-H3.CAR-T cells led to lower PD-1 expression and enhanced antitumor activity, suggesting a mechanism that could improve the effectiveness of these CAR-T therapies without causing significant toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. Du, H., Hirabayashi, K., Ahn, S., et al.[2021]

A specific population of tissue-resident memory T cells (TIM-3/CXCL13-positive) was identified in epithelial ovarian cancer (EOC), which is associated with improved survival in patients, based on analysis of around 175 patients with high-grade serous EOC.

The study suggests that combining TIM-3 and PD-1 blockade therapies could enhance anti-cancer immunity in EOC, particularly since CXCL13-positive CD8 T cells are linked to better responses to existing immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival. Vlaming, M., Bilemjian, V., Freile, JÁ., et al.[2022]

Adoptive T-cell therapies, particularly CAR T-cell therapy, are gaining attention for their potential to enhance immune responses against ovarian cancer, leveraging T cells' critical role in immune surveillance.

Recent advancements, such as dual specificity CARs and affinity-tuned single-chain Fv fragments, may improve the effectiveness and safety of CAR T-cell therapies compared to traditional T cell receptor therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of chimeric antigen receptor-engineered T cells in ovarian cancer therapy. Zhang, M., Zhang, DB., Shi, H.[2021]

In ovarian cancer, PD-L1 is not highly expressed, and instead, B7-H3 is a major checkpoint molecule that contributes to T-cell exhaustion and immunosuppression in the tumor microenvironment.

Blocking B7-H3, rather than PD-1, significantly improved survival in mouse models of ovarian cancer, suggesting that targeting B7-H3 could be a promising strategy for patients who do not respond to existing PD-L1/PD-1 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-expressed B7-H3 mediates the inhibition of antitumor T-cell functions in ovarian cancer insensitive to PD-1 blockade therapy. Cai, D., Li, J., Liu, D., et al.[2022]

Chimeric antigen receptor-modified T (CAR-T) cell therapy shows promising clinical efficacy in treating ovarian cancer, as supported by various preclinical experiments and clinical trials.

While CAR-T therapy offers a novel approach to cancer treatment, it is associated with side effects and toxicities, including cytokine release syndrome and 'on-target, off-tumor' effects, which need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cell therapy in ovarian cancer: from the bench to the bedside. Zhu, X., Cai, H., Zhao, L., et al.[2019]

B7-H4 CAR T cell therapy effectively targets and kills ovarian cancer cells expressing the B7-H4 protein, demonstrating antitumor activity in preclinical models with human ovarian tumor xenografts.

However, this therapy also caused delayed and lethal toxicity in mice 6-8 weeks post-treatment, likely due to the widespread expression of B7-H4 in normal tissues, highlighting the need for safety measures in CAR T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy. Smith, JB., Lanitis, E., Dangaj, D., et al.[2022]

B7-H3 is a promising target for immunotherapy in solid tumors due to its overexpression in tumors and limited presence in normal tissues, making it a suitable candidate for chimeric antigen receptor (CAR) therapies.

Initial trials of B7-H3-targeted CAR-T cell therapies have shown safety, but their effectiveness has been limited; strategies such as local delivery, enhancing CAR-T cell persistence, and combining with other treatments may improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3-targeted CAR-T cell therapy for solid tumors. Li, G., Wang, H., Wu, H., et al.[2022]

The study analyzed T-cell receptor (TCR) changes in ovarian carcinoma using samples from 24 malignant and 23 benign masses, revealing that TCRB-B positivity was higher in malignant cases, suggesting a potential role in immune response to cancer.

Higher levels of TCRG-B were associated with earlier-stage tumors and better overall survival, indicating that understanding TCR pathways could lead to new immunotherapy approaches for ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The investigation of T-cell receptor subtypes in ovarian cancer: effects on survival and prognostic factors. Özkan, S., Selvi Gunel, N., Aygünes, D., et al.[2021]

References

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

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival. [2022]

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

Application of chimeric antigen receptor-engineered T cells in ovarian cancer therapy. [2021]

4. China pubmed.ncbi.nlm.nih.gov

Tumor-expressed B7-H3 mediates the inhibition of antitumor T-cell functions in ovarian cancer insensitive to PD-1 blockade therapy. [2022]

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

CAR-T cell therapy in ovarian cancer: from the bench to the bedside. [2019]

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

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy. [2022]

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

B7-H3-targeted CAR-T cell therapy for solid tumors. [2022]

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

The investigation of T-cell receptor subtypes in ovarian cancer: effects on survival and prognostic factors. [2021]