A2B694 CAR T-Cells for Solid Cancers

(EVEREST-2 Trial)

Recruiting at 13 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

Trial Summary

What is the purpose of this trial?

This trial tests a new immune cell therapy for adults with difficult-to-treat solid tumors. The therapy modifies the patient's own immune cells to target and kill cancer cells while protecting healthy cells. The study aims to find a safe dose and see how well it works.

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.

What data supports the effectiveness of the treatment A2B694 CAR T-Cells for Solid Cancers?

Research shows that using logic-gated CAR T-cells, like A2B694, can potentially improve the treatment of solid tumors by targeting multiple cancer markers and reducing side effects. This approach has shown promise in preclinical studies by enhancing the selectivity and effectiveness of the treatment. ^{1 2 3 4 5}

What safety data exists for A2B694 CAR T-Cells for Solid Cancers?

The research articles provided do not contain specific safety data for A2B694 CAR T-Cells for solid cancers. They discuss safety in the context of other CAR T-cell therapies, primarily for blood cancers, noting issues like cytokine release syndrome and neurotoxicity, but these are not directly related to A2B694. ^{5 6 7 8 9}

How is the A2B694 CAR T-Cell treatment different from other treatments for solid cancers?

The A2B694 CAR T-Cell treatment is unique because it uses a logic-gated Tmod CAR T-cell product, which is designed to improve the targeting of solid tumors by recognizing specific antigens on cancer cells, potentially overcoming the limitations of traditional CAR T-cell therapies that struggle with solid tumors. ^{9 10 11 12 13}

Research Team

John Welch, MD, PhD

Principal Investigator

A2 Biotherapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

To go or not to go? Biological logic gating engineered T cells. [2022]

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

The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. [2022]

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

Co-opting signalling molecules enables logic-gated control of CAR T cells. [2023]

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

Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy. [2022]

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

Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. [2020]

6. United States 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. [2022]

7. Germany 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. [2023]

8. United States 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. [2021]

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

Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. [2020]

11. Japan pubmed.ncbi.nlm.nih.gov

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

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

TCR-T Immunotherapy: The Challenges and Solutions. [2022]

13. China pubmed.ncbi.nlm.nih.gov

Advances in CAR-T cell therapy for malignant solid tumors. [2023]