A2B530 CAR T Therapy for Solid Cancers

(EVEREST-1 Trial)

Recruiting at 9 trial locations

Overseen By Wen-Kai Weng, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: A2 Biotherapeutics Inc.

Disqualifiers: Local therapy, Stem cell transplant, Organ transplant, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

160 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests A2B530, a treatment using modified immune cells from the patient, in adults with hard-to-treat cancers like colorectal, pancreatic, and lung cancer. The treatment aims to target and kill cancer cells while protecting healthy cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot have had cancer therapy within 3 weeks or 3 half-lives of the A2B530 infusion. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment A2B530 CAR T Therapy for Solid Cancers?

CAR T-cell therapies have shown success in treating blood cancers, but they face challenges with solid tumors due to the complex environment around these tumors. Some studies suggest that combining CAR T-cell therapy with other treatments might improve its effectiveness for solid cancers. ^{1 2 3 4 5}

Is A2B530 CAR T Therapy safe for humans?

A systematic review of CAR T-cell therapy for solid tumors found no serious specific toxicities, suggesting it is generally safe in humans. ^{5 6 7 8 9}

How is A2B530 CAR T therapy different from other treatments for solid cancers?

A2B530 CAR T therapy is unique because it uses specially engineered T-cells to target and attack solid tumors, which is challenging due to the tumor's complex environment. Unlike traditional treatments, this therapy aims to overcome barriers like tumor heterogeneity and immune suppression, potentially offering a more personalized and effective approach for solid cancers. ^{1 3 10 11 12}

Research Team

Eric Ng, MD

Principal Investigator

A2 Biotherapeutics Inc.

Eligibility Criteria

This trial is for adults with certain solid tumors like colorectal, pancreatic, or non-small cell lung cancer that express CEA and lack HLA-A*02. They must have a life expectancy of at least 3 months, be able to follow the study plan including long-term safety checks, and have completed necessary prior treatments. Pregnant or breastfeeding individuals are excluded as well as those not using birth control.

Inclusion Criteria

I can carry out all my daily activities without help.

You are expected to live for at least 3 more months.

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

Exclusion Criteria

I haven't had a new blood clot in my lungs or legs in the last 3 months.

I am not pregnant or breastfeeding.

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

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 A2B530 Tmod CAR T cells

1 week

Treatment

Participants receive a single dose of A2B530 intravenously on day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and dose limiting toxicities

24 months

Treatment Details

Interventions

• A2B530

Trial Overview The study tests A2B530 CAR T-cells in patients with specific solid tumors. It's divided into two phases: Phase 1 determines the safest dose; Phase 2 checks if this dose effectively targets tumor cells while sparing healthy ones. Participants will undergo a preconditioning regimen before receiving the A2B530 treatment.

Participant Groups

Group I: A2530 Experimental Treatment 2 Interventions

Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B530 intravenously on day 0

A2B530 is already approved in United States for the following indications:

Approved in United States as A2B530 for:

• Colorectal cancer with germline heterozygous HLA-A*02-positive disease expressing carcinoembryonic antigen and lost HLA-A*02 expression

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

CAR T-cell therapies have shown promising and potentially curative effects in treating blood cancers, but their effectiveness as standalone treatments for solid tumors has been limited.

Combining CAR T-cell therapy with other treatments, such as chemotherapy or radiotherapy, may enhance therapeutic efficacy for solid tumors, suggesting that combination strategies could be more effective than monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy: A feasibility strategy for CAR-T cell therapy in the treatment of solid tumors. Xu, J., Wang, Y., Shi, J., et al.[2022]

CAR T-cell immunotherapy, which involves genetically modifying T cells to target cancer cells, has shown promising results, especially in treating B-cell malignancies with several patients achieving complete and durable responses.

Current research is expanding CAR T-cell therapy to solid tumors, specifically targeting members of the ErbB family, indicating a potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ErbB-targeted CAR T-cell immunotherapy of cancer. Whilding, LM., Maher, J.[2022]

CAR T-cell therapy has shown remarkable success in treating blood cancers, with two therapies, Kymriah and Yescarta, receiving FDA and EMA approval.

However, applying CAR T-cell therapy to solid tumors faces significant challenges, such as the diverse nature of tumor antigens and the suppressive environment around tumors, which hinder T-cell effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors. Alcantara, M., Du Rusquec, P., Romano, E.[2021]

CAR-T therapy has shown great promise in treating blood cancers by using modified T cells to target specific tumor antigens, but its effectiveness against solid tumors is still limited due to challenges like the tumor microenvironment and lack of specific targets.

Recent advancements, including CRISPR-based modifications and the use of progenitor-like T cells, are being explored to enhance CAR-T therapy's application in solid tumors, with several studies expected to enter clinical trials soon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cells applied to solid tumors. Zhou, Z., Tao, C., Li, J., et al.[2022]

A study involving 163 patients with metastatic solid cancers identified 78 with TP53 mutations, leading to the development of a library of 39 T-cell receptors (TCRs) that target these shared mutations, which could potentially broaden the use of adoptive cellular therapy (ACT) in cancer treatment.

While initial treatments using tumor-infiltrating lymphocytes (TILs) showed limited clinical responses, one patient treated with engineered T cells targeting a specific TP53 mutation experienced a significant tumor regression, suggesting that TCRs targeting shared neoantigens may be a promising avenue for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor-Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors. Kim, SP., Vale, NR., Zacharakis, N., et al.[2022]

The study demonstrated that an optimized single-chain T cell receptor (scTCR) targeting the p53 tumor antigen can effectively eradicate tumors without causing harmful autoimmunity, indicating a high safety profile for this TCR gene therapy.

Adoptive T cell transfer (ACT) using the scTCR led to complete tumor protection and the development of a long-lasting, antigen-specific memory T cell response in mouse models, showcasing its therapeutic efficacy against p53-associated cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Potent Tumor-Reactive p53-Specific Single-Chain TCR without On- or Off-Target Autoimmunity In Vivo. Echchannaoui, H., Petschenka, J., Ferreira, EA., et al.[2020]

CD22-targeting CAR T-cell therapies show high complete response rates, with 68% in acute lymphoblastic leukemia (ALL) and 64% in non-Hodgkin's lymphoma (NHL), indicating their efficacy in treating these malignancies.

The incidence of severe side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is low, suggesting that these therapies are relatively safe, especially with dual-targeting CAR T-cells not increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. Fergusson, NJ., Adeel, K., Kekre, N., et al.[2023]

CAR-T cell therapy shows promising efficacy in treating solid tumors, with a 100% clinical benefit in epithelial ovarian cancer and varying success rates in other cancers, such as 70-82% in gastrointestinal tumors and 63% in small-cell lung cancer, based on a review of 29 studies involving 265 patients.

The therapy appears to be safe, as no serious CAR-T cell specific toxicities were reported in the studies reviewed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy for Solid Tumors: Are we Still That Far? a Systematic Review of Literature. Karam, A., Mjaess, G., Martinez Chanza, N., et al.[2022]

In a study of 170 patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), TP53 mutations were found to be a poor prognostic factor for overall survival in patients receiving conventional therapies, with a median survival of 12 months for those with mutations compared to not reached for those without.

However, in patients treated with CAR T-cell therapy, TP53 mutation status did not significantly impact overall survival, suggesting that CAR T-cell therapy may overcome the negative effects of TP53 mutations seen in conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era. Porpaczy, E., Wohlfarth, P., Königsbrügge, O., et al.[2021]

CAR T cell therapy has shown strong effectiveness against leukemia and lymphoma, but faces challenges in treating solid tumors due to issues like T cell persistence and the tumor microenvironment.

Current research is focused on improving CAR T cell design and strategies to enhance T cell longevity and overcome tumor heterogeneity, with the goal of making this therapy effective for solid cancers, although it remains unproven at this stage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers. Kyte, JA.[2022]

Engineered T-cell receptor (TCR) and CAR T therapies have shown promising clinical responses in select solid tumors, building on the success seen in hematological malignancies with CAR T treatments.

Recent advancements in target selection, T-cell activation, and overcoming the immunosuppressive tumor environment are expected to enhance the efficacy of these therapies in solid tumors, although healthcare facilities will need to adapt to implement these treatments effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor and chimeric antigen receptor in solid cancers: current landscape, preclinical data and insight into future developments. Azizi, AA., Pillai, M., Thistlethwaite, FC.[2020]

Chimeric antigen receptor (CAR) T-cell therapies have shown great success in treating hematological cancers, but their effectiveness against solid tumors is limited due to the challenging tumor microenvironment.

To improve CAR T-cell efficacy in solid tumors, future strategies may involve combination therapies that target both the tumor and its immunosuppressive mechanisms, as well as next-generation CAR designs that enhance targeting precision and resistance to T-cell exhaustion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches for refining and furthering the development of CAR-based T cell therapies for solid malignancies. Hull, CM., Maher, J.[2022]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Combination therapy: A feasibility strategy for CAR-T cell therapy in the treatment of solid tumors. [2022]

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

ErbB-targeted CAR T-cell immunotherapy of cancer. [2022]

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

Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors. [2021]

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

Chimeric antigen receptor T cells applied to solid tumors. [2022]

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

Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor-Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors. [2022]

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

A Potent Tumor-Reactive p53-Specific Single-Chain TCR without On- or Off-Target Autoimmunity In Vivo. [2020]

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

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. [2023]

8. England pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy for Solid Tumors: Are we Still That Far? a Systematic Review of Literature. [2022]

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

Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers. [2022]

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

T-cell receptor and chimeric antigen receptor in solid cancers: current landscape, preclinical data and insight into future developments. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Approaches for refining and furthering the development of CAR-based T cell therapies for solid malignancies. [2022]