CAR T-Cell Therapy for Ovarian Cancer

Overseen By Caroline Babinec

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Systemic corticosteroids

Disqualifiers: Pregnancy, Brain metastases, Bowel obstruction, others

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

Compensation: Varies

Number of Visits: 9

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CAR.B7-H3 T cells (a type of CAR T-cell therapy) for ovarian cancer to determine the best dose for future studies. It focuses on patients whose ovarian cancer has recurred and does not respond well to standard treatments like platinum-based chemotherapy. Suitable candidates have already tried at least two other treatments and still have the disease. Participants will receive three weekly infusions of CAR.B7-H3 cells, with the goal of assessing the safety and effectiveness of these doses. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are using systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent, you may not be eligible. Please discuss your current medications with the trial investigator for more details.

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 using systemic corticosteroids at doses of 10 mg prednisone daily or more, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the CAR.B7-H3 T cell product holds promise in the lab. In one study, these specially designed cells successfully eliminated tumors in early tests and controlled tumors upon recurrence. Another study found this treatment active against ovarian cancer, suggesting it could help combat the disease.

As this is an early-stage trial, the primary goal is to assess the treatment's safety and tolerability in people. The trial will carefully adjust doses to determine the most effective level without causing major side effects. This approach aims to ensure the treatment remains as safe as possible for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for ovarian cancer?

Most treatments for ovarian cancer, like chemotherapy and surgery, aim to remove or kill cancer cells but can also harm healthy cells. Unlike these standard methods, CAR B7-H3 T-cell therapy is unique because it harnesses the body's own immune system to specifically target and destroy cancer cells. This therapy involves modifying a patient's T-cells to better recognize and attack ovarian cancer cells, potentially offering a more targeted and less harmful approach. Researchers are excited about this innovative treatment because it represents a shift toward precision medicine, aiming for higher effectiveness and fewer side effects.

What evidence suggests that CAR.B7-H3 T cell therapy might be an effective treatment for ovarian cancer?

Studies have shown that CAR-T cells targeting a protein called B7-H3 effectively fight tumors. B7-H3 often appears on cancer cells, and these CAR-T cells are specifically designed to attack it. Research indicates that these cells exhibit strong anti-tumor activity in lab tests and animal studies, particularly against cancers like osteosarcoma. In this trial, participants will receive the CAR.B7-H3 T cell product, designed to enhance the growth and effectiveness of the CAR-T cells, potentially making them powerful against ovarian cancer. Additionally, when combined with another protein called IL2, these CAR-T cells demonstrate long-lasting effects, suggesting a strong and enduring response in both lab and animal models. ^{1 2 3 4 6}

Who Is on the Research Team?

Linda Van Le, MD

Principal Investigator

UNC

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent ovarian cancer that's resistant to platinum-based chemotherapy and PARP inhibitors if they have BRCA mutations. Participants must be in good enough health to undergo procedures, agree to use two forms of contraception, and not be pregnant or breastfeeding. They can't join if they have certain other cancers, brain metastases, active infections like HIV or hepatitis, or recent bowel complications.

Inclusion Criteria

I am older than 18 years.

I am willing to have multiple biopsies as my doctor thinks it's safe.

Written informed consent to undergo cell procurement is explained to, understood by, and signed by the subject; the subject is given a copy of the informed consent form for cell procurement

Exclusion Criteria

I have had a gastrointestinal perforation in the past.

I had an abscess inside my belly in the last 3 months.

I have had signs or symptoms of a blocked intestine recently.

Timeline for a Trial Participant

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 three consecutive days to prepare for CAR.B7-H3 T cell infusion

1 week

3 visits (in-person)

CAR.B7-H3 T Cell Infusion

Participants receive three weekly infusions of CAR.B7-H3 T cells through a catheter in the abdomen

3 weeks

3 visits (in-person)

Initial Follow-up

Post-infusion visits to monitor safety and effectiveness, including blood, fluid, and tumor sample collection

6 weeks

3 visits (in-person)

Long-term Follow-up

Participants are monitored every 3 months for one year, then annually for a total of 5 years to assess progression-free survival and overall survival

5 years

Quarterly visits for the first year, then annual visits

What Are the Treatments Tested in This Trial?

Interventions

• CAR.B7-H3
• Cyclophosphamide
• Fludarabine

Trial Overview

The study tests CAR T-cells targeting B7-H3 antigen in patients with ovarian cancer using a '3+3 design' to find the safest dose for phase 2 trials. Up to 21 people will receive this treatment after being screened for eligibility. The process includes placing an intraperitoneal port and multiple biopsies before and after treatment.

How Is the Trial Designed?

Group I: CAR.B7-H3 T cell product Experimental Treatment 3 Interventions

Up to 12 patients will receive three weekly CAR.B7-H3 T cell product infusions at the same dose. To determine the recommended phase 2 dose (RP2D), a modified 3+3 dose escalation design will be used to evaluate two dose levels: Dose Level 1 (7.5x10\^7 cells/infusion), Dose Level 2 (2x10\^8 cells/infusion). If this dose is not tolerated, then a lower dose of 3.75 × 10\^6 cells/infusion will be explored. Up to 3 dose levels of CAR.B7-H3 cells will be tested with at least 3 patients enrolled at each dose cohort before dose escalation is considered based on the incidence of dose limiting toxicity (DLT). An expansion cohort will enroll up to 9 patients at the recommended phase 2 dose. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and cyclophosphamide.

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

High-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS) are aggressive cancers that are often unresponsive to traditional immune checkpoint inhibitors, making them challenging to treat.

T-cell receptor therapy (TCR-T) is being explored as a promising alternative to CAR-T therapy for these 'cold' tumors, potentially offering a new immunotherapy option for patients with limited treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review. Wu, JWY., Dand, S., Doig, L., et al.[2021]

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-H4 and B7-H3 are overexpressed in ovarian tumors, with B7-H4 serving as a potential biomarker for ovarian cancer, especially when combined with CA125 levels.

Research indicates that blocking B7-H3 could reduce tumor growth and improve survival rates, suggesting it may be a promising therapeutic target, although further studies using antibody-mediated suppression are needed for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. Fauci, JM., Straughn, JM., Ferrone, S., et al.[2022]

B7-H3 is highly expressed in bladder cancer cells, making it a promising target for immunotherapy, particularly using bispecific antibodies (B7-H3Bi-Ab) combined with activated T cells (ATC).

The study demonstrated that B7-H3Bi-Ab significantly enhances the cytotoxicity of ATC against bladder cancer cells, including those resistant to chemotherapy, suggesting a novel and effective strategy for treating bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting immunotherapy for bladder cancer using anti-CD3× B7-H3 bispecific antibody. Ma, W., Ma, J., Ma, P., et al.[2021]

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]

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]

Immunotherapy, particularly immune checkpoint blockers, has not been effective in treating ovarian cancer, highlighting the need for alternative approaches like CAR T-cell therapy.

CAR T-cell therapy shows promise for treating ovarian cancer, but selecting the right tumor antigens is challenging due to their expression on both tumor and normal cells, which complicates effective targeting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The challenge of selecting tumor antigens for chimeric antigen receptor T-cell therapy in ovarian cancer. Ding, H., Zhang, J., Zhang, F., 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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12539249/

B7-H3-mediated reversal of CAR-T cell exhaustion induces ...

Through structure-based screening, we identified HI-TOPK-032 as a potent B7-H3 inhibitor that synergised with CAR-T cell therapy by reversing ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06305299

Autologous CAR-T Cells Targeting B7H3 in Ovarian ...

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 ...

3.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0304383523003063

Highly proliferative and hypodifferentiated CAR-T cells ...

We combined a variety of elements to form a CAR targeting B7–H3. These elements improved the proliferation and stemness of CAR-T cells, and ...

4.

aacrjournals.org

aacrjournals.org/cancerres/article/84/23/4066/750179/B7-H3-Targeted-CAR-V-1T-Cells-Exhibit-Potent-Broad

B7-H3–Targeted CAR-Vδ1T Cells Exhibit Potent Broad ...

Coexpression of IL2 with the B7-H3-CAR led to durable antitumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9628043/

B7-H3 targeted CAR-T cells show highly efficient anti- ...

Our study showed that B7-H3 targeted CAR-T cells had high anti-tumor efficacy against osteosarcoma both in vitro and in vivo.

6.

jitc.bmj.com

jitc.bmj.com/content/13/1/e010083

Novel B7-H3 CAR T cells show potent antitumor effects in ...

Our preclinical study demonstrates that these B7-H3-targeted CAR T cells effectively eliminated primary tumors and controlled rechallenge tumor ...