B7-H3 CAR T Cells for Ovarian Cancer

Overseen By Bela Shah

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Crystal Mackall, MD

Must not be taking: Corticosteroids, others

Disqualifiers: Active infection, Heart conditions, Autoimmune diseases, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called B7-H3 CAR T cells for ovarian cancer that has returned and does not respond to standard treatments. Researchers aim to determine if this treatment can effectively target and destroy cancer cells in patients with specific types of ovarian cancer. Participants will receive the treatment either through a vein (IV) or directly into the abdomen (IP), depending on the cancer's location. The trial seeks adults with platinum-resistant ovarian cancer who have already tried standard 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 new 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 must be at least 3 weeks post-chemotherapy or 5 half-lives since any prior systemic therapy, except for certain immune therapies that require 3 months. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that B7-H3 CAR T Cells are likely to be safe for humans?

Research has shown that B7-H3 CAR T cells have generally been well-tolerated in earlier studies. These studies tested both intravenous (IV) and intraperitoneal (IP) methods of administering the treatment. The main goal was to determine a safe dose and monitor any side effects.

For the IV method, studies found that targeting B7-H3 in cancer cells did not harm normal tissues, suggesting the treatment might be safe for humans. For the IP method, earlier research demonstrated that these treatments can effectively control tumor growth without causing serious side effects.

However, it is important to remember that these findings come from early-stage research. While the results are promising, researchers are still collecting safety data. The trial under consideration is part of this ongoing research to ensure the treatment is safe and effective. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for ovarian cancer?

Researchers are excited about B7-H3 CAR T cells for ovarian cancer because these cells represent a cutting-edge approach that differs from traditional treatments like chemotherapy and surgery. Unlike standard therapies that target the cancer broadly, B7-H3 CAR T cells are engineered to specifically seek out and destroy cancer cells by recognizing the B7-H3 protein, which is often overexpressed in ovarian cancer cells. This targeted mechanism not only promises to be more effective but also potentially reduces damage to healthy tissues. Additionally, the treatment can be administered either intravenously or directly into the peritoneal cavity, offering flexibility based on the cancer's location and patient needs.

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

Research has shown that B7-H3 CAR T cell therapy holds promise for treating ovarian cancer, particularly for patients unresponsive to standard treatments. In this trial, participants will receive B7-H3 CAR T cells through either intravenous (IV) or intraperitoneal (IP) administration, based on their specific condition. Studies have found that these specially modified immune cells can locate and destroy cancer cells with the B7-H3 protein. In early animal tests, B7-H3-targeted CAR T cells successfully slowed tumor growth. Initial research also suggests that this method might address common issues with CAR T cell therapies, such as immune cell exhaustion. While further research is necessary, these early results offer hope for improved outcomes in ovarian cancer treatment. ^{1 3 6 7 8}

Who Is on the Research Team?

Oliver Dorigo

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults with ovarian tumors that have come back and don't respond to platinum-based chemotherapy. Participants must meet certain health standards, but specific inclusion criteria are not listed.

Inclusion Criteria

Have measurable disease with specific size criteria for lesions

I have received platinum-based chemotherapy for ovarian cancer.

My bone marrow and organs are functioning well.

Exclusion Criteria

Active or uncontrolled autoimmune diseases

I have a specific heart condition.

Any other issues that would make the patient ineligible for the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Lymphodepletion

Participants undergo conditioning lymphodepletion at least 7 days before the start of CAR T cell infusion

1 week

Treatment

Participants receive B7-H3 CAR T cell infusion and are monitored for dose limiting toxicity

4 weeks

Multiple visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• B7-H3 CAR T Cells

Trial Overview The study tests a new therapy called B7-H3CART, which involves modifying a patient's own immune cells to fight cancer. It uses a '3 + 3 dose escalation' method in two groups to find the safest dose.

How Is the Trial Designed?

Group I: Intravenous (IV) Administration Experimental Treatment 1 Intervention

At the time of enrollment, based on imaging studies, clinical history and physical exams, the principal investigator will make a preliminary decision regarding Arm Assignment. Arm B will consist of participants with disease outside the peritoneum and with participants who either cannot undergo IP catheter insertion or who, in the judgement of the principal investigator do not have an intraperitoneal environment that would allow for adequate product distribution. Participants in Arm B will have a Tenckhoff catheter inserted in Interventional Radiology at least 7 days before the start of conditioning lymphodepletion.

Group II: Intraperitoneal (IP) Administration Experimental Treatment 1 Intervention

At the time of enrollment, based on imaging studies, clinical history and physical exams, the principal investigator will make a preliminary decision regarding Arm Assignment. Participants with ovarian cancer confined to the peritoneum will undergo laparoscopic placement of an intraperitoneal catheter (PowerPort™ device and catheter) for cell infusion. When feasible, a Tenckhoff catheter for research sample collection of ascites, will also be placed. If laparoscopic placement is not possible, the PowerPort catheter may be inserted in interventional radiology. If adhesions within the peritoneum would preclude effective distribution of CAR cells throughout the peritoneum, the participant may be placed in Arm B.

Who Is Running the Clinical Trial?

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

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]

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]

B7-H3 is expressed by both tumor and stromal cells in ovarian cancer, while B7-H4 is restricted to tumor cells, indicating their potential as immunotherapeutic targets in the tumor microenvironment.

A higher tumor-to-stroma ratio correlates with specific immune cell characteristics, such as increased PD-1 expression on CD8+ T cells and higher PD-L1 expression on antigen-presenting cells, which could inform the development of targeted immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation. MacGregor, HL., Sayad, A., Elia, A., et al.[2020]

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]

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]

In a study involving 12 ovarian cancer patients, T cells were successfully modified to express chimeric antigen receptors (CARs) targeting the 5T4 tumor-associated antigen, which is present on most solid tumors.

The engineered CAR T cells showed a strong immune response by secreting IFN-gamma when exposed to the patients' own tumor cells, and they demonstrated therapeutic benefits in a mouse model, indicating that targeting 5T4 could be a promising strategy for treating ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer. Owens, GL., Sheard, VE., Kalaitsidou, M., et al.[2019]

IL-12-producing CAR T cells, or armored CAR T cells, have been developed to enhance the effectiveness of CAR T cell therapy against solid tumors like ovarian cancer by targeting both the tumor cells and their surrounding environment.

The commentary emphasizes the need for careful selection of experimental animal models in preclinical studies to ensure the reliability and relevance of findings related to CAR T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary: IL-12-secreting tumor-targeted chimeric antigen receptor T cells: An unaddressed concern on Koneru et al. (2015). Mirzaei, HR., Hadjati, J.[2021]

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]

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]

Chimeric Antigen Receptor (CAR) T cells show potential for treating epithelial ovarian cancer (EOC) due to the high presence of tumor-associated antigens (TAAs) and the unique tumor microenvironment, although robust clinical data is still lacking.

Preclinical studies suggest that CAR T cells could be effective in EOC, but further research is necessary to optimize administration methods and identify the most effective CAR types for patient treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprogramming T-cells for adoptive immunotherapy of ovarian cancer. Genta, S., Ghisoni, E., Giannone, G., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06305299

Autologous CAR-T Cells Targeting B7H3 in Ovarian ... This phase 1, single-center, open-label study to determine the safety of escalating dosing of chimeric antigen receptor T (CAR-T) cells targeting the B7-H3 ...

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

B7-H3-mediated reversal of CAR-T cell exhaustion induces ... In this study, we aimed to investigate the role and mechanism of lipid metabolites in anti-MSLN CAR-T cell exhaustion in ovarian cancer cells.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-02577

Chimeric Antigen Receptor (CAR) T-cell Therapy with iC9- ... This phase I trial studies the safety, side effects, and best dose of using autologous T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen.

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 ... Despite extensive research, CAR-T cell therapy's clinical outcomes in solid tumors have not matched the success seen in hematologic malignancies ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2372770520300449

B7-H3-Targeted CAR-T Cells Exhibit Potent Antitumor ... In conclusion, although B7-H3 represents a promising pan-cancer target, and B7-H3-redirected CAR-T cells can effectively control tumor growth, the expression ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11960814/

Tumor Immunotherapy Targeting B7-H3: From Mechanisms to ... Therapeutically, tumor-expressed B7-H3 has been observed to inhibit the function of CD8+ T cells in ovarian cancer that is insensitive to PD-1 ...

7. thelancet.com thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00393-7/fulltext

B7-H3-mediated reversal of CAR-T cell exhaustion induces ... In this study, we aimed to investigate the role and mechanism of lipid metabolites in anti-MSLN CAR-T cell exhaustion in ovarian cancer cells. Methods. We ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1535610819300029

Antitumor Responses in the Absence of Toxicity in Solid ... We developed CAR-Ts for targeting B7-H3 in solid tumors, which effectively controlled tumor cell growth in vitro and in orthotopic, metastatic, and patient- ...