A2B395 CAR T-Cell Therapy for Colorectal Cancer

(DENALI-1 Trial)

Recruiting at 6 trial locations

Overseen By Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: A2 Biotherapeutics Inc.

Disqualifiers: Prior transplants, Recent cancer therapy, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

240 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to test A2B395, an allogeneic logic-gated Tmod™ CAR T-cell product in subjects with solid tumors including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC) and other solid tumors that express EGFR and have lost HLA-A\*02 expression. The main questions this study aims to answer are: * Phase 1: What is the recommended dose of A2B395 that is safe for patients * Phase 2: Does the recommended dose of A2B395 kill the solid tumor cells and protect the patient's healthy cells Participants will be required to perform study procedures and assessments, and will also receive the following study treatments: * Enrollment in BASECAMP-1 (NCT04981119) * Preconditioning lymphodepletion (PCLD) regimen * A2B395 Tmod CAR T cells at the assigned dose

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that you should not have had cancer therapy within 3 weeks or 3 half-lives of the A2B395 infusion, and no radiotherapy within 28 days of the infusion. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment A2B395 CAR T-Cell Therapy for Colorectal Cancer?

Research shows that T cells engineered to target specific cancer markers can lead to significant reductions in cancer markers and even regression of tumors in some colorectal cancer patients. This suggests that similar CAR T-cell therapies, like A2B395, might also be effective in treating colorectal cancer. ^{1 2 3 4 5}

Is A2B395 CAR T-Cell Therapy safe for humans?

There is no specific safety data available for A2B395 CAR T-Cell Therapy in the provided research articles. ^{2 6 7 8 9}

What makes A2B395 CAR T-Cell Therapy unique for treating colorectal cancer?

A2B395 CAR T-Cell Therapy is unique because it uses genetically engineered T cells to target specific antigens on cancer cells without relying on traditional immune recognition pathways, potentially overcoming the limitations of conventional treatments that require specific immune markers. This approach is particularly promising for colorectal cancer, which often has limited treatment options and poor response to standard immunotherapies. ^{1 2 10 11 12}

Research Team

John Welch, MD, PhD

Principal Investigator

A2 Biotherapeutics

Eligibility Criteria

This trial is for people with certain solid tumors (like colorectal, lung, breast, kidney cancers) that have a specific protein called EGFR and lack another marker known as HLA-A*02. Details on who can join are not fully provided but typically include meeting health standards and having the type of cancer being studied.

Inclusion Criteria

I am fully active or can carry out light work.

My organs are functioning well.

Life expectancy of ≥3 months

Exclusion Criteria

I haven't had cancer treatment within 3 weeks or before A2B395 infusion.

My condition can be treated with standard therapy aimed at curing, not just easing symptoms.

I have not had radiotherapy in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preconditioning Lymphodepletion (PCLD)

Participants receive a preconditioning lymphodepletion regimen before the main treatment

1 week

Treatment

Participants receive a single dose of A2B395 intravenously

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• A2B395

Trial Overview The study tests A2B395, an experimental CAR T-cell therapy designed to target cancer cells in patients with specific tumor types. It includes two phases: finding a safe dose (Phase 1) and seeing if this dose can effectively kill tumor cells while sparing healthy ones (Phase 2).

Participant Groups

Group I: A2B395 Experimental Treatment 2 Interventions

Participants receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B395 intravenously on day 0

Who Is Running the Clinical Trial?

A2 Biotherapeutics Inc.

Lead Sponsor

Trials

5

Recruited

1,200+

Findings from Research

Genetically engineered T lymphocytes targeting carcinoembryonic antigen (CEA) led to significant reductions in serum CEA levels (74-99%) in three patients with metastatic colorectal cancer, with one patient showing a notable regression of cancer in the lungs and liver.

All patients experienced severe transient inflammatory colitis as a dose-limiting toxicity, highlighting both the potential efficacy and the risks associated with using CEA as a target in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Parkhurst, MR., Yang, JC., Langan, RC., et al.[2023]

In a study of 108 patients with advanced colorectal cancer and high MSI expression, the combination of PD-1 customization and autoimmune T-cell therapy resulted in a treatment efficiency of 90.74%, significantly higher than the 61.11% efficiency observed in the control group.

The study also found that after treatment, the levels of immune markers like CD107a, perforin, and GranB cells increased in both groups, but the study group showed a more pronounced expression of PD-1, particularly in patients with more advanced cancer stages (grade III-IV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of PD-1 Customization and Autoimmune T Cells for Advanced Colorectal Cancer with High MSI Expression. Li, N., Zhang, X., Zhang, Y., et al.[2022]

Immunotherapy shows promise in treating colorectal cancer, with agents like the monoclonal antibody 17-1A and anti-EGFR antibodies demonstrating the immune system's ability to target and destroy cancer cells.

Clinical trials are currently evaluating various immunotherapeutic strategies, including dendritic cell vaccines and anti-idiotypic antibodies, with some showing potential to enhance anti-tumor responses, although challenges remain due to tumor evasion mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current concepts in immunotherapy for the treatment of colorectal cancer. Indar, A., Maxwell-Armstrong, CA., Durrant, LG., et al.[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]

In a pilot clinical trial involving 11 participants with advanced colorectal cancer, vaccination with CEA and Her2 peptides was found to be well tolerated, with 82% of adverse events being mild (Grade 1-2), primarily fatigue and injection site reactions.

The vaccination induced immune responses in 70% of participants and resulted in a median overall survival of 16 months, suggesting potential benefits that warrant further investigation, especially in combination with existing checkpoint-blockade therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer. Lynch, KT., Squeo, GC., Kane, WJ., et al.[2021]

The study developed a fourth-generation CAR T cell therapy targeting the MUC1 antigen, which is highly expressed in cholangiocarcinoma (CCA) and linked to poor patient outcomes, showing promise as a new treatment option.

Anti-MUC1-CAR4 T cells demonstrated significant cytotoxic activity against CCA cell lines, achieving up to 66% cell killing, while sparing normal cholangiocytes, indicating a targeted and potentially safer therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. Supimon, K., Sangsuwannukul, T., Sujjitjoon, J., et al.[2021]

References

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

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. [2023]

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

γδ T cells and their clinical application in colon cancer. [2023]

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

Study of PD-1 Customization and Autoimmune T Cells for Advanced Colorectal Cancer with High MSI Expression. [2022]

4. Scotland pubmed.ncbi.nlm.nih.gov

Current concepts in immunotherapy for the treatment of colorectal cancer. [2019]

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

Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. [2021]

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

T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager. [2022]