CAR-monocytes for HER2 Positive Cancer

Overseen By Daniel Cushing

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Carisma Therapeutics Inc

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

6 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a 'washout period' (time without taking certain medications) before starting. You must stop cytotoxic chemotherapy, tyrosine kinase inhibitors, and radiation therapy for 2 weeks, and biologic therapy for 4 weeks before joining. Check with the trial team about other medications you are taking.

What data supports the effectiveness of the treatment CT-0525 for HER2 Positive Cancer?

Research on similar treatments, like HER2-specific CAR-T cells, shows they can effectively target and kill cancer cells in conditions like metastatic colorectal cancer. Additionally, CAR-engineered natural killer (NK) cells have shown strong anti-tumor activity against HER2-expressing cancers, suggesting that CAR-based therapies, including CAR-monocytes, could be promising for HER2 Positive Cancer. ^{1 2 3 4 5}

Is CAR-monocyte therapy for HER2 positive cancer safe?

CAR therapies, including those targeting HER2, have shown potential safety concerns like cytokine release syndrome (a severe immune reaction) and off-tumor toxicity (damage to healthy tissues). However, recent studies suggest that using CAR-engineered NK cells may offer a safer alternative with fewer side effects compared to traditional CAR-T cells. ^{4 5 6 7 8}

How is the treatment CT-0525 unique for HER2 positive cancer?

CT-0525 is unique because it uses CAR-monocytes, a type of immune cell engineered to specifically target and attack HER2 positive cancer cells, potentially offering a new approach for treating solid tumors where traditional CAR-T cell therapies have been less effective. ^{4 5 9 10 11}

What is the purpose of this trial?

This is a first-in-human open-label study to evaluate the safety and tolerability, and manufacturing feasibility of anti-HER2 CAR-monocytes (CT-0525) in participants with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 whose disease has progressed on standard approved therapies.

Research Team

Daniel Cushing

Principal Investigator

Carisma Therapeutics Inc

Eligibility Criteria

This trial is for people with advanced or metastatic solid tumors that have high levels of HER2 and who haven't responded to standard treatments. Specific details about who can join are not provided, but typically participants need to meet certain health standards.

Inclusion Criteria

Must have at least one measurable lesion according to RECIST v1.1

Must have an O2 saturation > 85%

My cancer has returned or spread, tests positive for HER2, and cannot be cured with treatment.

Exclusion Criteria

Known allergy or hypersensitivity to specific medications

Pregnant or lactating women

Active hepatitis B or hepatitis C infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single IV administration of CT-0525 on Day 1

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Multiple visits (in-person)

Treatment Details

Interventions

• CT-0525

Trial Overview The study is testing a new treatment called CT-0525, which involves CAR-monocytes targeting the HER2 protein on cancer cells. It's an early-phase trial assessing safety, how well patients tolerate the treatment, and if it can be made reliably.

Participant Groups

Group I: CT-0525 Experimental Treatment 1 Intervention

Cohort 1: 3 participants will be treated with a single IV administration of CT-0525 (3 billion CAR positive cells) on Day 1. Cohort 2: 3 participants will be treated with a single IV administration of CT-0525 (10 billion CAR positive cells) on Day 1.

Who Is Running the Clinical Trial?

Carisma Therapeutics Inc

Lead Sponsor

Trials

2

Recruited

50+

Findings from Research

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]

HER2 CAR T-cell therapy shows promise for treating solid tumors, particularly in cancers like breast cancer, but it carries significant risks of severe side effects, such as cytokine release syndrome due to targeting HER2 on non-cancerous tissues.

The review highlights ongoing efforts to enhance the safety of HER2 CAR therapies through novel designs and alternative CAR host selections, aiming to minimize the risk of toxicities while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving better and safer HER2-specific CARs for cancer therapy. Liu, X., Zhang, N., Shi, H.[2019]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

CAR-T cells targeting HER2 can cause significant off-tumor toxicities in a mouse model, with the severity of these toxicities being influenced by the type of co-stimulatory domain used, particularly CD28, which was found to be the most toxic.

The study identified that CD4+ CAR-T cells are the main contributors to these toxicities, and variations in donor T cell sources can further affect the toxicity profile, suggesting that both intrinsic CAR-T cell characteristics and donor-specific factors play a role in the safety of CAR-T therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity. Hammill, JA., Kwiecien, JM., Dvorkin-Gheva, A., et al.[2020]

The study successfully developed CAR-T cells that target the ERBB2 antigen, which is overexpressed in aggressive breast cancer cells, demonstrating increased apoptosis in the SKBR3 breast cancer cell line when co-cultured with these engineered T-cells.

This approach shows promise as a universal immunotherapy by enhancing T-cell activation and cytotoxicity without relying on traditional immune recognition mechanisms, suggesting potential for effective treatment of ERBB2-positive breast cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells. Munisvaradass, R., Kumar, S., Govindasamy, C., et al.[2018]

CAR-engineered NK-92 cells targeting the ErbB2 antigen showed effective tumor cell killing in laboratory tests and maintained their antitumor activity in live models, indicating their potential for cancer treatment.

Using γ-irradiation as a safety measure can prevent the replication of these NK cells while still allowing them to effectively attack tumors, making them a promising candidate for clinical use in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Schönfeld, K., Sahm, C., Zhang, C., et al.[2021]

References

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

Biomarkers for Predicting Response to Anti-HER2 Agents. [2020]

2. England pubmed.ncbi.nlm.nih.gov

HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. [2022]

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

Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Ex Vivo Generation of CAR Macrophages from Hematopoietic Stem and Progenitor Cells for Use in Cancer Therapy. [2022]

5. 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]

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

Driving better and safer HER2-specific CARs for cancer therapy. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

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

A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells. [2018]

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

Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Induced CAR-Macrophages as a Novel Therapeutic Cell Type for Cancer Immune Cell Therapies. [2022]