A2B694 CAR T-Cells for Solid Cancers

(EVEREST-2 Trial)

Recruiting at 14 trial locations

Overseen By Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: A2 Biotherapeutics Inc.

Disqualifiers: Prior transplants, Cardiac disease, Lung disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

230 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called A2B694, which uses modified immune cells (CAR T-cells) to target and kill cancer cells while sparing healthy ones. The focus is on solid tumors, such as colorectal, pancreatic, lung, and ovarian cancers, and others with specific markers. Researchers aim to first determine the safest dose and then assess its effectiveness against tumors. Suitable candidates are those with these cancers that have returned or spread and who have already tried standard treatments but need new options. Participants will undergo specific procedures and receive the treatment as part of the study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cancer therapy within 3 weeks or 3 half-lives of the A2B694 infusion, and radiotherapy within 28 days of the infusion.

Is there any evidence suggesting that A2B694 is likely to be safe for humans?

Previous studies have tested A2B694, a specialized CAR T-cell therapy, for safety in patients with solid tumors. Research shows that this treatment targets cancer cells while minimizing harm to healthy cells, reducing the risk of common side effects seen in similar therapies.

Reports from these studies indicate that A2B694 lowers the chance of mistakenly attacking healthy cells, focusing its attack on cancer cells. Although specific safety data from these trials is not detailed, ongoing research aims to ensure that the treatment is well-tolerated by patients.

Since this trial is in the early stages of human testing, it likely focuses on finding a safe dose and monitoring for side effects. If successful, it may demonstrate that A2B694 is safe for human use and a promising treatment option for solid tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for solid tumors, which often involve chemotherapy or radiation, A2B694 uses a novel approach called CAR T-cell therapy. This method involves genetically modifying a patient's own T-cells to better target and attack cancer cells. Researchers are excited about A2B694 because it has the potential to specifically hone in on cancer cells while sparing healthy ones, potentially leading to fewer side effects and more effective results. This personalized treatment could change the way we tackle solid tumors by offering a more targeted and adaptable solution.

What evidence suggests that A2B694 might be an effective treatment for solid tumors?

Research has shown that A2B694 CAR T-cells, which participants in this trial will receive, could effectively treat solid tumors. These cells are specially designed to find and attack cancer cells with a protein called MSLN, while sparing healthy cells. Early results suggest that A2B694 is safe and can successfully target tumors with MSLN. This treatment aims to minimize damage to non-cancerous cells, a common issue with cancer treatments. Initial data from patients with solid tumors, such as colorectal and pancreatic cancer, indicated that this method might help shrink tumors. ^{1 3 6 7 8}

Who Is on the Research Team?

John Welch, MD, PhD

Principal Investigator

A2 Biotherapeutics

Are You a Good Fit for This Trial?

This trial is for adults with certain advanced solid tumors like colorectal, lung, pancreatic, ovarian cancer or mesothelioma. These cancers must express a protein called MSLN and lack HLA-A*02 due to mutation. Participants need measurable disease over 1 cm by CT scan, good organ function, an ECOG status of 0-1 (fully active to restricted in physically strenuous activity), and a life expectancy over 3 months.

Inclusion Criteria

I am enrolled in the BASECAMP-1 study, my tests show LOH of HLA-A*02, and I have enough stored cells for Tmod CAR T-cell therapy.

My cancer is advanced, cannot be surgically removed, and shows MSLN.

I have completed the necessary treatment for my solid tumor as outlined.

Exclusion Criteria

I need extra oxygen at home.

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

I have had lung conditions needing long-term steroids or immune suppressants in the past year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preconditioning Lymphodepletion (PCLD) Regimen

Participants receive a preconditioning lymphodepletion regimen before the infusion of A2B694

1 week

Treatment

Participants receive a single dose of A2B694 intravenously on day 0

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

What Are the Treatments Tested in This Trial?

Interventions

• A2B694

Trial Overview The study tests A2B694 CAR T-cell therapy after patients undergo preconditioning lymphodepletion. Phase 1 determines the safe dosage while Phase 2 checks if this dose effectively targets tumor cells without harming healthy ones. Patients previously enrolled in BASECAMP-1 are given A2B694 at the determined safe dose.

How Is the Trial Designed?

Group I: A2B694 Experimental Treatment 2 Interventions

Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B694 intravenously on day 0

Who Is Running the Clinical Trial?

A2 Biotherapeutics Inc.

Lead Sponsor

Trials

5

Recruited

1,200+

Tempus AI

Industry Sponsor

Trials

18

Recruited

20,700+

Tempus Labs

Industry Sponsor

Trials

17

Recruited

20,200+

Published Research Related to This Trial

Chimeric antigen receptor (CAR) T-cell therapies have been successfully approved for treating certain blood cancers, specifically targeting CD19-positive B-cell lymphomas and multiple myeloma with BCMA, showcasing their efficacy in hematological malignancies.

Despite advancements, CAR-T therapies for solid tumors are still in development and have not yet received approval, indicating ongoing challenges in effectively targeting these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Development of Novel Gene-Modified T-Cell Therapies(CAR-T, TCR-T)]. Kitano, S.[2023]

The FDA has approved two types of CAR-T cells for treating blood cancers, marking a significant advancement in immunotherapy, but challenges like antigen escape and off-tumor toxicities remain.

Using Boolean logic gates to create multi-antigen-targeted CAR-T cells may enhance their effectiveness and safety, potentially leading to better treatment outcomes in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. Han, X., Wang, Y., Wei, J., et al.[2020]

The Tmod™ dual-receptor system enhances T cell therapy for solid tumors by using a unique mechanism that targets the genetic difference between tumor and normal cells, specifically loss of heterozygosity (LOH).

In vitro studies show that Tmod can effectively manage variations in antigen levels on target cells, demonstrating two key pharmacologic mechanisms: it reduces the sensitivity of the activator and decreases the overall activation magnitude, which may improve the selectivity and efficacy of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy. Manry, D., Bolanos, K., DiAndreth, B., et al.[2022]

Genetically engineered T cells, particularly CAR T cells, have shown great success in treating blood cancers, improving survival rates, but have struggled with solid tumors due to challenges like tumor heterogeneity.

Biological logic gating in T cells is a promising new approach that could enhance the effectiveness and safety of CAR T therapies for solid tumors by allowing targeted, localized treatment and the ability to attack multiple tumor antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

To go or not to go? Biological logic gating engineered T cells. Abbott, RC., Hughes-Parry, HE., Jenkins, MR.[2022]

TCR-T cell therapy shows great promise for treating solid tumors by recognizing a wider range of target antigens compared to CAR-T cells, which are primarily effective against CD19+ B cell-derived cancers.

Currently, there are 56 clinical trials worldwide investigating the efficacy of TCR-T cell therapy, highlighting the growing interest and potential for this approach in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. Chen, L., Qiao, D., Wang, J., et al.[2020]

CD7-CAR T cells, which are modified to avoid fratricide by using naturally occurring CD7- T cells, showed strong antitumor activity against T-cell acute lymphoblastic leukemia (T-ALL) in both laboratory and mouse models.

In a comparison of CD19-CAR T cells, those derived from CD7- T cells demonstrated enhanced antitumor effects, and a higher presence of CD7-low expressing T cells was associated with better patient responses in a clinical study, suggesting a promising avenue for immunotherapy in hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. Freiwan, A., Zoine, JT., Crawford, JC., et al.[2023]

The development of a new CAR T cell platform called LINK CAR, which uses proximal T cell signaling molecules instead of traditional CD3ζ domains, shows promise in effectively targeting tumors while minimizing on-target, off-tumor toxicity, a common issue with existing CAR T therapies.

In vivo studies demonstrate that LINK CAR T cells can activate T cells and eradicate tumors more effectively than previous systems, potentially allowing for safer treatments for solid tumors and other diseases like autoimmunity and fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-opting signalling molecules enables logic-gated control of CAR T cells. Tousley, AM., Rotiroti, MC., Labanieh, L., et al.[2023]

T cell receptor-engineered T cell (TCR-T) therapy shows promise as a cancer treatment because it is not limited by the surface antigen expression of target cells, making it a potential option for solid tumors as well as hematologic malignancies.

However, the overall efficacy of TCR-T therapy in solid tumors remains lower compared to its success in blood cancers, highlighting the need to address specific barriers and develop strategies to enhance its effectiveness in these challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-T Immunotherapy: The Challenges and Solutions. Liu, Y., Yan, X., Zhang, F., et al.[2022]

CAR T cell therapy has shown great promise in treating blood cancers but faces challenges in effectively targeting solid tumors due to factors like the lack of specific antigens and a suppressive tumor environment.

Innovative strategies, such as combining CAR T cells with oncolytic viruses and gene editing, are being explored to enhance the efficacy and safety of CAR T cell therapy for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in CAR-T cell therapy for malignant solid tumors. Liu, J., Tu, X., Liu, L., et al.[2023]

In a phase 1 trial involving 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia, a defined CD19 CAR T cell product achieved an impressive 89% rate of minimal residual disease-negative (MRD-) remission, indicating strong efficacy.

The trial demonstrated a favorable safety profile, with no deaths or severe toxicities like cerebral edema, although 23% of patients experienced reversible severe cytokine release syndrome or neurotoxicity, suggesting manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Gardner, RA., Finney, O., Annesley, C., et al.[2022]

In a phase I study involving 16 patients with CD19-positive relapsed/refractory B-cell lymphoma, the novel AbTCR T-cell therapy (ET019003) demonstrated promising efficacy, with 50% of treated patients achieving a complete response and an overall response rate of 83%.

The therapy was well-tolerated, showing a favorable safety profile with no severe cytokine release syndrome and only one case of mild neurotoxicity, indicating its potential for low toxicity compared to traditional CAR T-cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma. He, P., Liu, H., Zimdahl, B., et al.[2023]

The novel CAR structure using KIRS2/Dap12 with a 4-1BB co-stimulation domain significantly enhances anti-tumor efficacy against B cell acute lymphoblastic leukemia (B-ALL) by increasing IL-2 production, as shown in both laboratory and clinical settings.

In a phase I clinical trial, all 4 adult patients with relapsed/refractory B-ALL treated with CD19-KIRS2/Dap12-BB CAR-T cells achieved complete responses without experiencing neurotoxicity or severe cytokine release syndrome, highlighting the safety and effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL. Sun, M., Xu, P., Wang, E., et al.[2021]

The Tmod system is a novel approach that uses engineered immune cells with NOT-gated signal integrators to selectively target solid tumors, potentially improving therapeutic selectivity in cancer treatment.

This method is being developed for patients with specific tumor genomic features, such as loss of heterozygosity, and is supported by extensive preclinical data, indicating a promising pathway toward effective cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. DiAndreth, B., Hamburger, AE., Xu, H., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06051695

NCT06051695 | A Study to Evaluate the Safety and ... The goal of this study is to test A2B694, an autologous logic-gated Tmod™ CAR T-cell product in subjects with solid tumors including colorectal cancer (CRC) ...

2. a2bio.com a2bio.com/a2-bio-to-present-early-safety-and-efficacy-data-from-everest-2-study-during-2025-annual-meeting-of-the-society-for-immunotherapy-of-cancer/

A2 Bio Announces First Patient Dosed in Phase 1/2 ... EVEREST-2 (NCT06051695) is a seamless Phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B694, an autologous ...

3. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A721

627 EVEREST-2: a seamless phase 1/2 study of A2B694 ... A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1556086425021525

Phase 1/2 Study of Logic-Gated Tmod CAR T A2B694 in ... A2B694 has manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The dose-escalation ...

5. a2bio.com a2bio.com/wp-content/uploads/EVEREST-2_AACR-2025_Poster_Final.pdf

EVEREST‐2: A seamless phase 1/2 study of A2B694, a ... open‑label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with solid tumors ... Tmod cells kill tumor equivalent to CAR Ts.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3040

EVEREST-2: Initial data of the logic-gated Tmod chimeric ... EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN.

7. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/CT186/761647

EVEREST-2: A seamless phase 1/2 study of A2B694, a logic ... A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by ...

8. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A670

588 EVEREST-1: initial safety data from a seamless phase ... Tmod CAR T therapy addresses challenges of on-target, off-tumor toxicity by combining a CEA-targeted CAR-activating receptor with a blocking ...