TROP2-CAR-NK Cells + Cetuximab for Colorectal Cancer

Overseen By Maria Pia Morelli, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Live vaccines, Steroids

Disqualifiers: Active disease, Pregnancy, Immunodeficiency, others

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

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of a new treatment that combines TROP2-CAR-NK cells (a type of cell therapy) with cetuximab for colorectal cancer. It focuses on patients with minimal residual disease (MRD) after surgical removal of cancer and completion of standard treatments. Participants should show no visible signs of cancer on scans but have cancer DNA in their bloodstream. As a Phase 1 trial, this research seeks to understand 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. However, you cannot have received systemic anticancer therapy within 2 weeks or 3 half-lives before starting the trial's chemotherapy, and you must have recovered from any side effects of previous treatments.

Is there any evidence suggesting that TROP2-CAR-NK Cells combined with cetuximab are likely to be safe for humans?

Research has shown that TROP2-CAR-NK cells, when combined with cetuximab, might be safe and manageable for patients with minimal residual colorectal cancer. These cells are designed to enhance the immune system's ability to locate and destroy cancer cells more effectively.

Studies have demonstrated that this treatment merges the natural cancer-killing ability of NK (natural killer) cells with a precise targeting system. This approach aims to attack cancer cells while sparing healthy cells.

Other research on similar CAR-NK cell treatments has found them to be safe and effective, with efforts underway to make these therapies affordable and accessible. However, as this treatment remains in early testing, the complete safety profile is not yet known. Participants should be aware that researchers are closely monitoring side effects to determine the safest dose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for colorectal cancer, like chemotherapy and targeted therapies, work by attacking rapidly dividing cells or specific cancer-causing proteins. But TROP2-CAR-NK cells work differently, leveraging the patient's own immune system to fight the cancer. This treatment involves engineering natural killer (NK) cells to specifically target and destroy cancer cells that express the TROP2 protein, which is often found in colorectal cancer. Researchers are excited because this approach could potentially offer a more precise and less toxic treatment option compared to traditional therapies. Additionally, combining TROP2-CAR-NK cells with cetuximab, a current cancer therapy, may enhance their effectiveness, offering hope for improved outcomes.

What evidence suggests that TROP2-CAR-NK Cells combined with cetuximab could be an effective treatment for colorectal cancer?

Research has shown that combining TROP2-CAR-NK cells with cetuximab might help the immune system fight colorectal cancer more effectively than using cetuximab alone. In this trial, participants will receive TROP2-CAR-NK cells in a dose escalation and expansion phase to determine the optimal dose. NK cells, a type of immune cell, are known for their safety and generally cause fewer side effects compared to other treatments. Early results suggest this combination could effectively target small amounts of cancer that remain after treatment. Although still under study, this treatment appears promising based on current evidence. ^{1 2 6 7 8}

Who Is on the Research Team?

Maria Pia Morelli, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with colorectal cancer who have minimal residual disease, meaning small amounts of cancer cells that remain after treatment. Participants should be able to receive lymphodepleting chemotherapy.

Inclusion Criteria

I have colorectal cancer with no visible tumors after surgery but still have cancer DNA in my blood.

I am not able to have children or will follow strict birth control for 6 months after treatment.

I agree to follow the study's birth control advice and will inform my doctor if I father a child during the study or within 6 months after.

Exclusion Criteria

I haven't had major heart problems in the last year.

I have had genetically modified T or NK cell therapy before.

I have received an organ or tissue transplant from another person.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of TROP2-CAR-NK cells combined with cetuximab to determine the maximum tolerated dose

Varies per participant group

Multiple visits for dose administration and monitoring

Dose Expansion

Participants receive the recommended dose of TROP2-CAR-NK cells combined with cetuximab to further evaluate safety and efficacy

Until dose level is confirmed

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• TROP2-CAR-NK Cells

Trial Overview The study is testing the highest tolerable dose of TROP2-CAR-NK cells combined with cetuximab in patients. It involves pre-treatment with fludarabine and cyclophosphamide, followed by the experimental therapy.

How Is the Trial Designed?

Group I: Dose Escalation + Dose Expansion Experimental Treatment 6 Interventions

Up to 5 dose levels of TROP2-CAR-NK cells will be tested in the Dose Escalation phase. Up to 12 participants maximum will be enrolled at any dose level, in groups of 3 participants at a time. 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 recommended dose of TROP2-CAR-NK cells is found. When that dose level is confirmed, the final group of 12 participants will be enrolled at that dose level.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Bellicum Pharmaceuticals, Inc.

Collaborator

Trials

1

Recruited

40+

Published Research Related to This Trial

The combination of cetuximab, a monoclonal antibody targeting HER1, with NK cell-stimulatory cytokines (IL-2, IL-12, IL-21) significantly enhances the production of IFN-gamma and antibody-dependent cellular cytotoxicity (ADCC) by NK cells, improving their ability to attack tumor cells.

In a murine model, the addition of IL-21 to cetuximab treatment not only boosted NK cell activity but also showed greater efficacy in reducing tumor growth, suggesting that these cytokines could serve as effective adjuvants in treating HER1-positive cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Roda, JM., Joshi, T., Butchar, JP., et al.[2018]

Infusing expanded autologous NK cells alongside trastuzumab in patients with HER2-positive tumors was well tolerated, with no maximum tolerated dose reached, indicating a favorable safety profile for this combination therapy.

While no objective responses were observed, 6 out of 19 patients experienced stable disease for at least 6 months, suggesting potential antitumor activity, particularly in a patient with a specific CD16 variant who had a partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Lee, SC., Shimasaki, N., Lim, JSJ., et al.[2021]

Natural killer (NK) cells from colorectal cancer (CRC) patients show a significantly altered phenotype, with reduced expression of activating receptors and increased expression of inhibitory receptors, which impairs their ability to attack cancer cells.

Combining IL-2 and IL-15 with cetuximab can enhance the cytotoxic activity of NK cells against CRC, suggesting potential therapeutic strategies to improve immune responses in CRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic and Functional Dysregulated Blood NK Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15. Rocca, YS., Roberti, MP., Juliá, EP., et al.[2022]

In a multicentric study of metastatic colorectal cancer patients treated with cetuximab, a high density of FcγRIIIA+ (CD16) immune cells, primarily tumor-associated neutrophils, was linked to better treatment responses, suggesting their role in enhancing antibody-dependent cellular cytotoxicity (ADCC).

The study also found that HLA-E/β2m was overexpressed in metastatic tumors and associated with poor overall survival, indicating that targeting this immune checkpoint with therapies like monalizumab could improve outcomes when combined with bispecific antibodies in RAS wild-type mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Density of FcγRIIIA+ (CD16+) Tumor-Associated Neutrophils in Metastases Improves the Therapeutic Response of Cetuximab in Metastatic Colorectal Cancer Patients, Independently of the HLA-E/CD94-NKG2A Axis. Denis Musquer, M., Jouand, N., Pere, M., et al.[2021]

The combination of expanded natural killer (NK) cells with IgG1 antibodies in patients with advanced gastric or colorectal cancers was well tolerated, showing no severe adverse events during the trial involving 9 participants.

Preliminary results indicated that this therapy could induce anti-tumor activity, with 4 out of 6 evaluable patients achieving stable disease and some showing a decrease in tumor size, alongside enhanced immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Ishikawa, T., Okayama, T., Sakamoto, N., et al.[2018]

CAR-NK-92 cells engineered to target EpCAM-positive colorectal cancer cells demonstrated specific recognition and effective immune responses, including the release of cytokines and cytotoxicity in vitro.

Combining CAR-NK-92 cells with the drug regorafenib significantly improved tumor growth suppression in a mouse model of colorectal cancer compared to using either treatment alone, suggesting a promising new strategy for enhancing cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models. Zhang, Q., Zhang, H., Ding, J., et al.[2019]

Reovirus-activated NK cells significantly enhance the anti-tumor effects of cetuximab against colorectal cancer (CRC) cells, showing improved cytotoxicity compared to either treatment alone, regardless of KRAS mutation status.

The mechanism behind this enhanced efficacy involves Toll-like receptor 3 (TLR3) signaling, indicating that targeting this pathway could be a promising strategy for improving cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway. Long, S., Gu, Y., An, Y., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06358430

NCT06358430 | Dose Escalation and Expansion Study of ... To find the highest and/or recommended dose of TROP2-CAR-NK cells combined with cetuximab in participants with MRD CRC.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-03107

TROP2-CAR-NK cells in Combination with Cetuximab for ... Giving TROP2-CAR-NK cells in combination with cetuximab may be safe, tolerable, and/or effective in patients with MRD CRC.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12367655/

Recent advances in tumor immunotherapy based on NK cells Compared to chimeric antigen receptor T (CAR-T) cell therapy, NK cell-based immunotherapy demonstrates superior safety and tolerability. However, the clinical ...

4. withpower.com withpower.com/trial/phase-1-neoplasm-residual-9-2024-7fbf0

TROP2-CAR-NK Cells + Cetuximab for Colorectal Cancer This combination aims to enhance the immune response against colorectal cancer, potentially offering a more effective approach than using cetuximab alone. Show ...

5. crcmrd.com crcmrd.com/?avada_portfolio=trop2-car-nk-cells-in-combination-with-cetuximab-in-patients-with-minimal-residual-colorectal-cancer

TROP2-CAR-NK Cells with Cetuximab - CRC Minimal ... This study Phase I study designed to find the highest and/or recommended dose of TROP2-CAR-NK cells combined with cetuximab in participants with MRD CRC.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12162902/

CAR-NK cells: harnessing the power of natural killers for ... Arming NK cells with CARs merges their innate natural cytotoxicity with the refined precision of targeted antigen recognition.

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

Safety, efficacy and determinants of response of allogeneic ... There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable.

8. clin.larvol.com clin.larvol.com/trial-detail/NCT06358430

Transduced Cord Blood-derived NK Cells in Combination ... Dose escalation and expansion study of TROP2 CAR engineered IL-15- transduced cord blood-derived NK cells in combination with cetuximab in patient with ...