CAR T-Cell Therapy for Ovarian Cancer

Overseen By Lorna Rodriguez

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Anticoagulants

Disqualifiers: Autoimmune disease, Active infection, HIV, others

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

Compensation: Varies

Number of Visits: 5

Duration: 1 day

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for epithelial ovarian cancer that has not responded to platinum-based therapy. It uses a patient's own T cells, which fight infections, and modifies them to target a specific protein called TAG72 on cancer cells. Known as TAG72-CAR T Cells therapy, this approach aims to determine its safety and optimal dosage. Ideal participants are those whose ovarian cancer has not improved with platinum therapy and have the TAG72 protein on their tumor cells. As a Phase 1 trial, participants will be among the first to receive this innovative treatment, aiding researchers in understanding its effects in people.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor to get a clear answer based on your specific situation.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that CAR T-cell therapies targeting TAG72 have been safe in early studies. For instance, a trial with colorectal cancer patients found these modified immune cells to be safe, although they weren't very effective in that specific case. TAG72 is mostly found on cancer cells and not on normal cells, suggesting that treatments targeting it might have fewer side effects.

As this is an early-phase trial, the main goal is to ensure safety and determine the right dose. Although detailed safety data for this treatment in ovarian cancer is not yet available, early trials like this one are designed to carefully monitor and manage any side effects. Participants will be closely observed to ensure their well-being during the study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for ovarian cancer, which often rely on surgery, chemotherapy, and radiation, TAG72-CAR T cell therapy introduces a completely new approach. This treatment uses the patient's own immune cells, which are engineered to specifically target and destroy cancer cells expressing the TAG72 protein. Researchers are excited because this method not only offers a personalized treatment option but also has the potential to be more precise, reducing damage to healthy cells and possibly leading to better outcomes for patients.

What evidence suggests that TAG72-CAR T cells might be an effective treatment for ovarian cancer?

Research has shown that TAG72-CAR T cells, which participants in this trial will receive, could effectively fight ovarian cancer. In lab studies, these specially designed T cells excelled at killing cancer cells with the TAG72 protein on their surface, a protein often found in ovarian cancer cells. The modified T cells can specifically locate and attack these cancer cells. Early results suggest these T cells might offer a viable option for treating ovarian cancer that doesn't respond to standard treatments. Although studies are ongoing, this approach appears promising for future therapy. ^{1 2 4 6 7}

Who Is on the Research Team?

Lorna Rodriguez, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with ovarian cancer that didn't respond to platinum therapy. They must have a certain level of physical fitness, no severe allergies to study drugs, and agree to use birth control. People can't join if they haven't recovered from previous treatments' side effects, have significant heart rhythm problems, active autoimmune diseases requiring steroids or other immunosuppressants, uncontrolled infections including hepatitis B/C or HIV, bleeding disorders on anticoagulants, recent strokes or brain hemorrhages.

Inclusion Criteria

My bilirubin levels are within the required range.

Your liver enzyme levels are not more than 5 times the upper limit of normal. This will be checked within 42 days before you agree to join the study.

Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable exceptions may be granted with study principal investigator (PI) approval

Exclusion Criteria

I am on medication to suppress my immune system due to an autoimmune disease.

I am currently experiencing symptoms of a blocked intestine.

I have had a gastrointestinal perforation or symptomatic diverticular disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Patients receive fludarabine and cyclophosphamide intravenously to prepare for CAR T cell infusion

3 days

3 visits (in-person)

Treatment

Patients receive TAG72-CAR T cells intraperitoneally

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Multiple visits at 1, 7, 14, 21, 28, 60, and 90 days, then 6, 9, and 12 months

Long-term follow-up

Participants are monitored for long-term safety and survival outcomes

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• TAG72-CAR T Cells

Trial Overview The trial tests TAG72-CAR T cells in patients with resistant epithelial ovarian cancer. Patients' own T cells are modified to target TAG72 protein on tumor cells. The safety and optimal dose of these engineered T cells will be evaluated alongside standard therapies like Fludarabine and Cyclophosphamide.

How Is the Trial Designed?

Group I: Treatment (TAG72-CAR T cells) Experimental Treatment 3 Interventions

Patients receive fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients receive TAG72-CAR T cells IP on day 0.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The TAG72-BBζ CAR T cell therapy demonstrated strong effectiveness against ovarian cancer by significantly reducing tumor growth and improving survival in mouse models, indicating its potential as a treatment option.

However, challenges remain, such as reduced TAG72 expression in recurring tumors and limited T cell persistence, which could affect the long-term success of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells. Murad, JP., Kozlowska, AK., Lee, HJ., et al.[2019]

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 mouse model with human Her2 expression, both high-affinity and low-affinity chimeric antigen receptor T cells (CARTs) caused liver damage, but low-affinity CARTs resulted in less toxicity and lower systemic inflammation compared to high-affinity CARTs.

Surprisingly, low-affinity CARTs showed better antitumor efficacy against Her2-positive tumors, likely due to their ability to migrate out of the liver and infiltrate tumors more effectively than high-affinity CARTs, suggesting that tuning T cell affinity can enhance safety and effectiveness in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A rational mouse model to detect on-target, off-tumor CAR T cell toxicity. Castellarin, M., Sands, C., Da, T., et al.[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]

Adoptive transfer of genetically modified T cells, specifically those expressing chimeric antigen receptors (CARs), shows promise as a novel treatment for ovarian cancer, which is known for its poor prognosis after standard therapies.

Ovarian tumors are relatively immunogenic, meaning they can provoke a natural immune response, making them suitable candidates for T cell immunotherapy, which is currently being explored in both pre-clinical and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. Chekmasova, AA., Brentjens, RJ.[2022]

Genetically-modified T cells targeting the L1-CAM protein, which is over-expressed in ovarian cancer, showed promising results in laboratory tests and mouse models, indicating their potential as an immunotherapy for this deadly disease.

When administered intraperitoneally, these CE7R+ T cells significantly reduced tumor growth and ascites formation in mice, leading to improved survival rates compared to control groups, suggesting a new effective treatment strategy for advanced ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice. Hong, H., Brown, CE., Ostberg, JR., et al.[2020]

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]

Dual CAR-T cells targeting both TAG-72 and a truncated CD47 antigen show promise in improving the effectiveness of immunotherapy for ovarian cancer, potentially overcoming the limitations of single-target therapies.

The design of the truncated CD47 CAR minimizes damage to healthy tissues while enhancing the elimination of TAG-72 positive cancer cells, suggesting a safer approach for treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer. Shu, R., Evtimov, VJ., Hammett, MV., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7868933/

Engineered CAR-T cells targeting TAG-72 and CD47 in ... In this study, we hypothesize that CAR-T cells with TAG-72/CD47 dual specificity would more effectively target ovarian cancer cells than single-target CAR-T ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05225363

NCT05225363 | Modified Immune Cells (TAG72-CAR T ... This phase I trial tests the safety, side effects, and best dose of TAG72-chimeric antigen receptor (CAR) T cells in treating patients with epithelial ...

3. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02268/full

Effective Targeting of TAG72 + Peritoneal Ovarian Tumors ... These preclinical findings support TAG72-BBζ CAR T cells as a viable therapeutic option for ovarian cancers, and also highlight its broader ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6254427/

Effective Targeting of TAG72+ Peritoneal Ovarian Tumors ... In vitro, TAG72-BBζ CAR T cells demonstrate potent antigen-dependent cytotoxicity against multiple TAG72-expressing human ovarian cancer cell ...

5. cell.com cell.com/molecular-therapy-family/oncology/fulltext/S2950-3299(25)00031-1

CRISPR-Cas9 knockout of DGKα/ζ improves the anti- ... We targeted tumor-associated glycoprotein 72 (TAG-72), an oncofetal antigen highly expressed in adenocarcinomas like ovarian cancer, by engineering TAG-72 CAR-T ...

6. reporter.nih.gov reporter.nih.gov/search/4XyziBYl1UWdXrzp2wpt8w/project-details/10914190

Project Details TAG72 is highly over- expressed in EOC and other solid tumors with little or no expression in normal tissues, making it an ideal target for CAR T cell therapy.

7. jitc.bmj.com jitc.bmj.com/content/5/1/22

T cells specific for TAG-72 in colorectal cancer Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. Author ...