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

Trial Summary

What is the purpose of this trial?

This is a single site, open label, Phase 1 study using a 3 + 3 dose escalation design in two cohorts of adults with recurrent, platinum-resistant ovarian tumors.

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.

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

Research shows that CAR T-cell therapy, which involves modifying a patient's own T cells to better recognize and attack cancer cells, has shown promise in treating ovarian cancer. Preclinical studies have demonstrated that CAR T cells can effectively target and destroy ovarian tumor cells, suggesting potential for this treatment in clinical settings. ^{1 2 3 4 5}

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

Research on B7-H3 CAR T cells shows they can control tumor growth without evident toxicity in some models, but other CAR T cell therapies have shown side effects like cytokine-associated and 'on-target, off-tumor' toxicities. This suggests that while B7-H3 CAR T cells appear promising, careful monitoring for potential side effects is important. ^{1 4 5 6 7}

What makes the B7-H3 CAR T Cells treatment unique for ovarian cancer?

B7-H3 CAR T Cells are unique because they target the B7-H3 protein, which is overexpressed in ovarian cancer and linked to poor survival, offering a new approach for patients who do not respond well to existing immunotherapies like PD-1 blockade. This treatment uses engineered T cells to specifically attack cancer cells, potentially reducing tumor growth and improving survival without significant toxicity. ^{1 6 8 9 10}

Research Team

Oliver Dorigo

Principal Investigator

Stanford University

Eligibility Criteria

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

My bone marrow and organs are functioning well.

I have received platinum-based chemotherapy for ovarian cancer.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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-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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer. [2019]

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

Reprogramming T-cells for adoptive immunotherapy of ovarian cancer. [2019]

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

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

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

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

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

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

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

A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. [2022]

9. 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]

10. England 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. [2020]