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

Trial Summary

What is the purpose of this trial?

To find the highest and/or recommended dose of TROP2-CAR-NK cells combined with cetuximab in participants with MRD CRC.

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.

What data supports the effectiveness of the treatment TROP2-CAR-NK Cells + Cetuximab for Colorectal Cancer?

Research shows that natural killer (NK) cells can be activated by cetuximab, especially when combined with cytokines like IL-15, enhancing their ability to fight colorectal cancer. Additionally, similar CAR-NK cell therapies have shown promise in targeting and killing cancer cells, suggesting potential effectiveness for this treatment combination. ^{1 2 3 4 5}

Is the combination of TROP2-CAR-NK Cells and Cetuximab safe for humans?

A Phase I clinical trial involving NK cells combined with cetuximab for colorectal cancer showed that the treatment was well tolerated with no severe side effects reported. This suggests that the combination therapy is generally safe for humans. ^{1 2 3 5 6}

What makes the TROP2-CAR-NK Cells + Cetuximab treatment unique for colorectal cancer?

This treatment is unique because it combines TROP2-CAR-NK cells, which are engineered immune cells designed to specifically target cancer cells, with cetuximab, an antibody that helps the immune system attack cancer. This combination aims to enhance the immune response against colorectal cancer, potentially offering a more effective approach than using cetuximab alone. ^{1 3 5 6 7}

Research Team

Maria Pia Morelli, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

References

1. Egypt pubmed.ncbi.nlm.nih.gov

Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models. [2019]

2. Switzerland 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. [2022]

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

Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway. [2022]

4. Switzerland 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. [2021]

5. United States 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. [2018]

6. United States 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. [2018]

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

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. [2021]