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

Trial Summary

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.

What data supports the effectiveness of the TROP2-CAR-NK Cells treatment for solid cancers?

Research shows that NK cells (a type of immune cell) modified with IL-15 can grow and kill cancer cells more effectively. This approach has been successful in other cancer treatments, suggesting that TROP2-CAR-NK Cells, which use a similar strategy, might also be effective against solid cancers. ^{1 2 3 4 5}

Is TROP2-CAR-NK cell therapy safe for humans?

TROP2-CAR-NK cell therapy is considered to be generally safe in humans, with studies showing it has fewer side effects compared to similar therapies like CAR-T cells. Unlike CAR-T cells, CAR-NK cells do not cause severe side effects such as cytokine release syndrome (CRS) or neurotoxicity, making them a promising option for cancer treatment. ^{5 6 7 8 9}

What makes the TROP2-CAR-NK Cells treatment unique for solid cancers?

TROP2-CAR-NK Cells are unique because they use natural killer (NK) cells engineered with a chimeric antigen receptor (CAR) to target solid tumors, offering a potentially safer and more effective alternative to CAR-T cell therapies, which have shown severe side effects in solid tumors. Additionally, these NK cells are modified to express IL-15, enhancing their growth and tumor-killing ability without the need for external cytokines. ^{1 10 11 12 13}

What is the purpose of this trial?

To find the recommended dose of TROP2- CAR-NK cells that can be given to participants with advanced forms of solid tumors.

Research Team

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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-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]

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]

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]

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]

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]

References

1. Germany 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. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Exploiting Human NK Cells in Tumor Therapy. [2020]

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

Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. [2023]

4. Switzerland 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. [2023]

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

Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-NK as a Rapidly Developed and Efficient Immunotherapeutic Strategy against Cancer. [2023]

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

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. [2022]

8. England pubmed.ncbi.nlm.nih.gov

The tricks for fighting against cancer using CAR NK cells: A review. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

CAR-expressing NK cells for cancer therapy: a new hope. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy. [2020]

11. Italy pubmed.ncbi.nlm.nih.gov

Characterization of interleukin-15 gene-modified human natural killer cells: implications for adoptive cellular immunotherapy. [2022]

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

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. [2021]

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

KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. [2023]