TROP2-CAR-NK Cells for Platinum-Resistant Ovarian Cancer

Overseen by Amir A. Jazaeri

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticancer, Immunosuppressants, Steroids, others

Disqualifiers: Pregnancy, Autoimmune, CNS metastases, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment where specially modified immune cells are injected into the abdomen of patients with advanced ovarian cancer that hasn't responded to other treatments. These immune cells are designed to find and destroy cancer cells by recognizing a specific marker on them. This approach has shown promise in treating ovarian cancer.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you must be at least 3 weeks from your last cytotoxic chemotherapy and 4 weeks from any systemic anti-cancer therapy before starting the trial treatment.

What data supports the effectiveness of the TROP2-CAR-NK Cells treatment for platinum-resistant ovarian cancer?

Research shows that natural killer (NK) cells, like those used in the TROP2-CAR-NK treatment, can effectively reduce tumor burden in ovarian cancer models. Studies have demonstrated that NK cells derived from different sources, including stem cells, can improve survival in mice with ovarian cancer, suggesting potential benefits for patients with platinum-resistant ovarian cancer. ^{1 2 3 4 5}

Is the TROP2-CAR-NK cell treatment safe for humans?

Research on similar NK cell treatments, including those engineered with CARs and IL-15, shows they can be safe for humans, with built-in safety measures like a suicide gene to limit toxicity. These treatments have been tested in various models and have shown promising safety profiles, although specific data on TROP2-CAR-NK cells is limited. ^{1 2 6 7 8}

What makes the TROP2-CAR-NK treatment unique for platinum-resistant ovarian cancer?

The TROP2-CAR-NK treatment is unique because it uses genetically modified natural killer (NK) cells derived from cord blood to specifically target and kill ovarian cancer cells that are resistant to platinum-based chemotherapy, offering a novel approach compared to traditional treatments. ^{1 3 4 5 8}

Research Team

Amir A. Jazaeri

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with certain types of cancer (high-grade serous ovarian, mesonephric-like adenocarcinoma, or pancreatic) that are resistant to standard treatments. Participants must have an ECOG performance status of 0 or 1, agree to contraception if applicable, and have adequate organ function. They should not be pregnant/breastfeeding and must have failed previous chemotherapy lines.

Inclusion Criteria

My cancer can be measured and is present in my abdomen or lymph nodes near my spine.

My cancer, originating from the female reproductive tract or peritoneal lining, has been confirmed as mesonephric-like adenocarcinoma by MD Anderson Cancer Center.

I have had platinum-based chemotherapy before and it did not work.

Exclusion Criteria

My tumor is affecting a major blood vessel or has cavities inside it.

I have not had any cancer treatment or experimental drugs in the last 4 weeks.

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine for 3 days

1 week

3 visits (in-person)

Treatment

Participants receive 1 dose of TROP2-CAR-NK cells delivered intraperitoneally

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness, including objective response rates at week 12

12 weeks

Up to 16 visits (in-person)

Treatment Details

Interventions

• Cyclophosphamide (Anti-metabolites)
• Fludarabine (Anti-metabolites)
• TROP2-CAR-NK (CAR T-cell Therapy)

Trial Overview The study tests TROP2-CAR-NK cells delivered into the abdomen combined with Cyclophosphamide and Fludarabine in patients with specific cancers. It aims to find the optimal dose for those whose cancer hasn't responded well to other treatments.

Participant Groups

Group I: TROP2-CAR-NK Experimental Treatment 3 Interventions

Participants will receive 1 dose of TROP2-CAR-NK and will visit the study clinic up to 16 times to have tests and procedures (such as blood draws, biopsies, and CT scans). Participants will receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days in a row. Participants will receive cyclophosphamide and fludarabine by vein over about 3 hours total.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

Natural killer (NK) cells, whether derived from induced pluripotent stem cells (iPSCs) or activated peripheral blood (PB), significantly reduced tumor burden in a mouse model of ovarian cancer, demonstrating their potential as effective immunotherapy.

Mice treated with three doses of iPSC-derived or expanded PB-NK cells showed improved median survival (98 and 97 days, respectively) compared to untreated mice (73 days), indicating that iPSC-derived NK cells are as effective as PB-NK cells for treating ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer. Hermanson, DL., Bendzick, L., Pribyl, L., et al.[2021]

This phase I safety trial involves 12 patients with recurrent ovarian cancer, aiming to evaluate the safety and toxicity of intraperitoneal infusions of natural killer (NK) cells derived from umbilical cord blood, with or without prior immunosuppressive treatment.

The study will assess whether these NK cells can safely expand and remain active in the body, potentially offering a new therapeutic strategy for patients with a poor prognosis, especially if no severe toxicity is observed in the initial cohorts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal infusion of ex vivo-cultured allogeneic NK cells in recurrent ovarian carcinoma patients (a phase I study). Hoogstad-van Evert, J., Bekkers, R., Ottevanger, N., et al.[2022]

A novel dual-effect cord blood natural killer cell (CBNKC) was developed that co-expresses high-affinity PD-1 (HAPD1) and a chimeric antigen receptor (CAR) targeting CD19, showing enhanced anti-tumor effects compared to standard CAR19 CBNKCs.

In both in vitro and in vivo tests, the HAPD1 CAR CBNKCs demonstrated significantly stronger cytotoxicity against CD19-positive tumor cells, indicating their potential as an effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and evaluation of dual-effect cord blood natural killer cells expressing highaffinity PD-1 and chimeric antigen CD19 receptor]. Zhong, H., Zou, Q., Liu, H., et al.[2023]

In newly diagnosed high-grade serous carcinoma (HGSC), specific subpopulations of decidual-like natural killer (dl-NK) cells were identified that correlate with tumor characteristics, indicating a potential immune evasion mechanism.

The study found that HGSC tumor cells can suppress the activity of NK cells through a process called trogocytosis, where NK cells acquire CD9 from tumor cells, leading to reduced anti-tumor responses; targeting CD9 may enhance NK cell effectiveness in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment. Gonzalez, VD., Huang, YW., Delgado-Gonzalez, A., et al.[2023]

Cytokine-induced killer lymphocytes (CIK) generated from patients with epithelial ovarian cancer (EOC) showed strong antitumor activity against platinum-resistant ovarian cancer cells in both laboratory tests and animal models, indicating their potential as a new treatment option.

The study demonstrated that CIK could effectively target and kill patient-derived ovarian cancer cells, even those that survived previous treatment with carboplatin, suggesting a promising avenue for immunotherapy in challenging cases of EOC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer. Capellero, S., Erriquez, J., Melano, C., et al.[2021]

Engineered cord blood-derived natural killer (NK) cells, modified with CAR-CD19 and IL-15, showed effective targeting and killing of leukemia cells in laboratory tests and improved survival in a mouse model of lymphoma.

This approach not only enhances the efficacy of NK cells in treating cancers but also includes a safety mechanism (the iC9 suicide gene) to eliminate the cells if necessary, reducing the risk of adverse effects like graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Liu, E., Tong, Y., Dotti, G., et al.[2021]

Intraperitoneal (IP) delivery of interleukin-2 activated natural killer (NK) cells in a mouse model of ovarian cancer resulted in effective tumor clearance and stable engraftment, with NK cells persisting for up to 54 days post-injection.

The study demonstrated that NK cells maintained their ability to kill ovarian cancer cells after IP infusion, suggesting that this delivery method could enhance the therapeutic potential of NK cell treatments in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Geller, MA., Knorr, DA., Hermanson, DA., et al.[2021]

A novel CAR targeting CD44 was developed and shown to effectively kill CD44-positive ovarian cancer cells, demonstrating strong potential for treating ovarian cancer stem cells that contribute to recurrence.

The engineered NK-92 cells with the CD44 CAR maintained their effectiveness even in the presence of cisplatin, and combining CD44NK treatment with cisplatin resulted in greater anti-tumor activity than using them sequentially.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44. Klapdor, R., Wang, S., Morgan, MA., et al.[2021]

References

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

Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer. [2021]

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

Intraperitoneal infusion of ex vivo-cultured allogeneic NK cells in recurrent ovarian carcinoma patients (a phase I study). [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Construction and evaluation of dual-effect cord blood natural killer cells expressing highaffinity PD-1 and chimeric antigen CD19 receptor]. [2023]

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

High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. [2021]

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

Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44. [2021]