TROP2-CAR-NK Cells for Solid Cancers

Overseen By Ecaterina Dumbrava, M D

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Pregnancy, Active infection, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose of a new treatment called TROP2-CAR-NK cells for people with advanced solid tumors that have not responded to standard treatments. Researchers will gradually increase doses to find the safest and most effective amount. The trial suits individuals with hard-to-treat cancers like non-small cell lung cancer or certain types of breast cancer. Participants should have tumors that show TROP2 expression and must be willing to stay near the study site for a short period.

As a Phase 1 trial, this 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 does not specify if you need to stop taking your current medications, but you must not have received systemic anticancer therapy within 2 weeks or 5 half-lives before starting the trial's chemotherapy. It's best to discuss your specific medications with the trial team.

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

Research has shown that TROP2-CAR-NK cells hold promise in early studies, particularly for treating cancers like ovarian and pancreatic. These studies suggest that TROP2-CAR-NK cells are generally safe for humans. This cell therapy is designed to locate and attack cancer cells.

In simpler terms, tests in lab settings have shown these cells to be effective, with manageable side effects. The treatment targets cancer cells with a protein called TROP2, common in many solid tumors.

This trial is in its first phase, focusing on determining the treatment's safety and optimal dose. Researchers closely monitor participants to understand any side effects and ensure the treatment is well-tolerated. This early stage is crucial to confirm the therapy's safety before proceeding to larger studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TROP2-CAR-NK cells because they represent a novel approach to treating solid cancers. Unlike traditional therapies like chemotherapy or targeted drugs, which often attack cancer cells directly, TROP2-CAR-NK cells are engineered immune cells that specifically target the TROP2 protein found on the surface of many cancer cells. This targeted approach could lead to more precise attacks on tumors with potentially fewer side effects. Additionally, the use of natural killer (NK) cells, which are part of the body's innate immune system, might enhance the body's ability to fight cancer by boosting its natural defenses. These features make TROP2-CAR-NK cells a promising new option in the fight against cancer.

What evidence suggests that TROP2-CAR-NK Cells might be an effective treatment for solid cancers?

Research has shown that TROP2-CAR-NK cells, which participants in this trial will receive, could help treat certain solid tumors, such as ovarian and pancreatic cancers. These cells are designed to locate and attack cancer cells, potentially stopping tumor growth. Early studies suggest that these NK cells can safely and effectively target cancer cells. They appear particularly effective against tumors with high levels of TROP2, possibly destroying more cancer cells than other treatments. Although further research is needed to confirm these results in humans, this method shows promise for treating advanced solid tumors. ^{1 2 3 5 6}

Who Is on the Research Team?

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced solid tumors who have tried standard treatments or for whom no standard treatment is available. They must have a life expectancy of at least 3 months, measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. Tumors must show TROP2 expression and participants should agree to contraception guidelines.

Inclusion Criteria

Left ventricular ejection fraction >50%

Patients must have adequate organ function as defined below within 10 days prior to the start of lymphodepleting chemotherapy: Table 1. Adequate Organ Function Laboratory Values Systemic Function Test Laboratory Value Hematologic ANC ≥1500/µL Platelets ≥100,000/µL Hemoglobin ≥9.0 g/dLa Renal Creatinine OR CrCl by Cockcroft-Gault formula ≤1.5 × ULNb ≥45 mL/min for patients with creatinine >1.5 × ULNb Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN AST and ALT ≤2.5 × ULN (≤5 × ULN for patients with liver metastases) Coagulation PT/INR aPTT ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of normal

My cancer is advanced, cannot be surgically removed, and has not responded to or I have refused standard treatments.

Exclusion Criteria

I have an immunodeficiency or take more than 10 mg of steroids daily.

I haven't had cancer treatment in the last 2 weeks or 3 weeks for antibody treatments.

I have recovered from side effects of past treatments, except for minor issues like slight nerve pain or hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants are assigned to a dose level of TROP2-CAR-NK cells, starting from the lowest dose and increasing until the maximum tolerated dose is found

8-12 weeks

Dose Expansion

Participants receive TROP2-CAR-NK cells at the recommended dose found in the Dose Escalation phase

8-12 weeks

Follow-up

Participants are monitored for safety, tolerability, and antitumor activity after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine phosphate
• Rimiducid
• TROP2-CAR-NK Cells

Trial Overview The trial is testing the safety and optimal dose of TROP2-CAR-NK cells in patients with advanced solid tumors. It includes a pre-treatment phase with cyclophosphamide and fludarabine phosphate to prepare the body, followed by the experimental NK cell therapy.

How Is the Trial Designed?

Group I: Dose Expansion Cohort 2 Experimental Treatment 4 Interventions

Participants who are enrolled in Dose Escalation, Participants will be assigned to a dose level of TROP2- CAR-NK cells based on when you join this study. Up to 5 dose levels of TROP2-CARNK cells will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of TROP2-CAR-NK cells is found. Participants who are enrolled in the Dose Expansion, Participants will receive TROP2-CAR-NK cells at the recommended dose that was found in the Dose Escalation.

Group II: Dose Expansion Cohort 1 Experimental Treatment 4 Interventions

Participants who are enrolled in Dose Escalation, Participants will be assigned to a dose level of TROP2- CAR-NK cells based on when you join this study. Up to 5 dose levels of TROP2-CARNK cells will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of TROP2-CAR-NK cells is found. Participants who are enrolled in the Dose Expansion, Participants will receive TROP2-CAR-NK cells at the recommended dose that was found in the Dose Escalation.

Group III: Dose Escalation Experimental Treatment 4 Interventions

Participants who are enrolled in Dose Escalation, Participants will be assigned to a dose level of TROP2- CAR-NK cells based on when you join this study. Up to 5 dose levels of TROP2-CARNK cells will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of TROP2-CAR-NK cells is found. Participants who are enrolled in the Dose Expansion, Participants will receive TROP2-CAR-NK cells at the recommended dose that was found in the Dose Escalation.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

Published Research Related to This Trial

CAR-modified T cell therapy has shown great success in treating blood cancers but is associated with significant risks like graft-versus-host disease (GVHD) and cytokine release syndromes (CRS).

CAR-NK cell therapy presents a safer alternative, as it avoids these adverse effects and offers better anti-tumor activity without the need for HLA matching, making it a promising 'off-the-shelf' treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK as a Rapidly Developed and Efficient Immunotherapeutic Strategy against Cancer. Włodarczyk, M., Pyrzynska, B.[2023]

CAR-NK cells, which are genetically engineered natural killer cells, show promise as a safer alternative to CAR-T cell therapy, potentially reducing the risk of severe side effects like cytokine release syndrome and tumor lysis syndrome.

Studies have successfully transduced both human primary NK cells and the NK-92 cell line to express CARs targeting various cancers, indicating their effectiveness in both pre-clinical and clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The tricks for fighting against cancer using CAR NK cells: A review. Vahidian, F., Khosroshahi, LM., Akbarzadeh, M., et al.[2022]

Chimeric antigen receptor-expressing NK cells (CAR-NK cells) show promising anti-tumor activity and have a better safety profile compared to CAR-T cell therapy, making them a potential alternative for cancer treatment.

Despite the success of CAR-T therapies like Kymriah and Yescarta, the high cost and toxicity of allogeneic CAR-T cell production highlight the need for more efficient and safer off-the-shelf cellular therapies, such as CAR-NK cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-expressing NK cells for cancer therapy: a new hope. Xia, J., Minamino, S., Kuwabara, K.[2021]

Interleukin-15 (IL-15) is essential for regulating the immune functions of natural killer (NK) cells, which are important for fighting tumors, making it a key target in cancer therapies.

Current clinical trials are exploring the use of IL-15 and its analogs, as well as genetically modifying NK cells to enhance their effectiveness in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Ma, S., Caligiuri, MA., Yu, J.[2023]

In vivo studies showed that CAR activation in natural killer (NK) cells leads to trogocytosis, where tumor antigens are transferred to NK cells, reducing their ability to target tumors and causing self-destruction among NK cells that express these antigens.

A dual-CAR system was developed that combines an activating CAR for tumor antigens and an inhibitory CAR to prevent fratricide among NK cells, enhancing their overall activity against tumors while maintaining safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Li, Y., Basar, R., Wang, G., et al.[2023]

CAR T cell therapy has shown great success in treating blood cancers, but its effectiveness against solid tumors has not been as promising, prompting research into alternative immune cells.

Alternative immune effectors like γδT cells, natural killer (NK) cells, and cytokine-induced killer (CIK) cells may enhance CAR therapy's efficacy and safety, as they possess unique antitumor activities and can adapt better to the diverse nature of solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy. Rotolo, R., Leuci, V., Donini, C., et al.[2020]

Ectopic expression of IL-15 in human NK cells enhances their growth and cytotoxicity without the need for IL-2, allowing for effective proliferation and activation of these cells.

NK cells modified to express both IL-15 and a chimeric antigen receptor (CAR) targeting cancer cells showed improved selective killing of resistant breast carcinoma cells, indicating a promising strategy for enhancing the efficacy of NK cell-based cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Sahm, C., Schönfeld, K., Wels, WS.[2020]

IL-15 gene-modified NK-92 cells (NK92-IL15) showed enhanced proliferation and cytotoxicity against various tumor cells, indicating their potential as a powerful tool in cancer treatment.

The NK92-IL15 cells produced high levels of IL-15, which improved their growth and activation, suggesting they could be effective in adoptive cellular immunotherapy for malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of interleukin-15 gene-modified human natural killer cells: implications for adoptive cellular immunotherapy. Zhang, J., Sun, R., Wei, H., et al.[2022]

HER2 CAR-engineered natural killer (NK) cells significantly enhance anti-tumor activity against HER2-expressing cancer cells, showing greater cytotoxicity than traditional CAR-T cells, especially in solid tumors.

Unlike CAR-T cells, HER2 CAR-NK cells do not cause harmful effects on non-cancerous cells, making them a safer option for immunotherapy in treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. Portillo, AL., Hogg, R., Poznanski, SM., et al.[2021]

CAR NK cells can be engineered to target tumor cells without the need for HLA matching, making them a promising 'off-the-shelf' option for cancer immunotherapy, as highlighted by recent clinical trials.

The review discusses advancements in CAR NK cell design and identifies challenges in their production and effectiveness, suggesting that improvements in these areas could enhance their therapeutic potential against both solid and liquid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. Yilmaz, A., Cui, H., Caligiuri, MA., et al.[2023]

Natural Killer (NK) cells are crucial in fighting tumors and can be enhanced through immunotherapy, but traditional methods like IL-2 infusion can cause significant toxicity, limiting their use.

Innovative approaches like CAR-engineered NK cells offer a promising 'off-the-shelf' therapy option that avoids complications like graft-versus-host disease (GvHD) and can be sourced from unrelated donors, potentially improving cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploiting Human NK Cells in Tumor Therapy. Vacca, P., Pietra, G., Tumino, N., et al.[2020]

IL-15 modification significantly enhances the expansion, survival, and antitumor activity of CLDN18.2-targeting CAR-T cells in murine models, leading to improved tumor suppression compared to standard CAR-T cells.

In vivo studies showed that IL-15-expressing CAR-T cells not only infiltrated tumors more effectively but also provided a survival advantage in certain tumor models, highlighting their potential for clinical evaluation in patients with CLDN18.2-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models. Shi, H., Li, A., Dai, Z., et al.[2023]

CAR-modified Natural Killer (NK) cells present a promising alternative to CAR T cells for cancer treatment due to their MHC-independency, shorter lifespan, and potential for off-the-shelf use, making them a flexible option for targeting tumors.

The review highlights ongoing challenges in enhancing the efficacy and safety of CAR NK cells, particularly in solid tumors, and discusses strategies to improve their persistence and function in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. Elahi, R., Heidary, AH., Hadiloo, K., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS5626

Phase I/II study of TROP2 CAR engineered IL15 ... Pre-clinical studies have established the efficacy and safety of TROP2 CAR NK cells in ovarian and pancreatic cancers. Methods: This is a ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06066424

Study Details | NCT06066424 | Phase 1 Dose Escalation ... Although the clinical benefit of TROP2-CAR-NK cells has not yet been established, the intent of offering this treatment is to provide a possible therapeutic ...

3. reporter.nih.gov reporter.nih.gov/project-details/11067768

TROP2-Directed CAR-NK Cells for the Immunotherapy ... CAR-NK cells have emerged as a promising cell therapy for cancer due to the NK cells' innate ability to kill tumor cells and their safety in the allogeneic ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05922930

NCT05922930 | Study of TROP2 CAR Engineered IL15- ... Primary Objectives: 1. To determine the safety and optimal cell dose of TROP2-CAR/IL15-transduced CB-NK cells[TROP2-CAR NK cells (KSR)]delivered ...

5. cancer.gov cancer.gov/clinicaltrials/NCI-2023-08351

TROP2-CAR-NK for the Treatment of Patients with ... Giving TROP2-CAR-NK may kill more tumor cells in patients with advanced solid tumors. ... CAR-NK cells in patients with solid tumors with high TROP2 expression.

6. nature.com nature.com/articles/s41591-023-02785-8

Safety, efficacy and determinants of response of allogeneic ... We confirmed that CAR-NK and non-transduced (NT)-NK cells from Opt-Cs had superior long-term cytotoxicity against Raji tumor rechallenges, while ...