ADP-A2M4CD8 + Immunotherapy for Advanced Cancers

Recruiting at 22 trial locations

Overseen By David Hong, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Adaptimmune

Disqualifiers: Autoimmune disease, CNS metastases, Cardiovascular, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2.5 years

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment ADP-A2M4CD8 + Immunotherapy for Advanced Cancers?

Research shows that certain CD8 T cells, which are part of the immune system, can effectively target and kill cancer cells in various tumors. Additionally, enhancing CD8+ T-cell responses with specific proteins has shown improved antitumor activity in mice, suggesting potential benefits for similar treatments in humans. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment ADP-A2M4CD8 + Immunotherapy for Advanced Cancers?

Research shows that enhancing CD8+ T-cell responses, like those in the ADP-A2M4CD8 treatment, can improve antitumor activity by increasing T-cell proliferation and reducing tumor-induced immune suppression. Additionally, tumor-reactive CD8 T cells are linked to better survival in cancer patients, suggesting potential benefits of this treatment approach. ^{1 2 3 4 5}

What makes the treatment ADP-A2M4CD8 unique for advanced cancers?

ADP-A2M4CD8 is a novel treatment that uses genetically engineered T-cells to specifically target and attack cancer cells expressing the MAGE-A4 antigen, which is not commonly targeted by other treatments. This approach is unique because it combines the specificity of targeting a cancer testis antigen with the potential for enhanced immune response by including CD8alpha, potentially leading to better control of tumor growth. ^{6 7 8 9 10}

What makes the treatment ADP-A2M4CD8 unique for advanced cancers?

ADP-A2M4CD8 is a novel treatment that uses genetically engineered T-cells to specifically target and attack cancer cells expressing the MAGE-A4 antigen, which is found in various solid tumors. This approach is unique because it combines the specificity of targeting a cancer testis antigen with the potential for enhanced immune response by including CD8alpha, which may improve the treatment's effectiveness against advanced cancers. ^{6 7 8 9 10}

What is the purpose of this trial?

This trial tests a new therapy that uses modified immune cells to fight various cancers in patients with specific markers. The treatment aims to boost the immune system by using trained cells to target and destroy cancer cells.

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults aged 18-75 with certain cancers (like esophageal, stomach, lung, bladder, melanoma) that are HLA-A2+ and MAGE-A4+. They should have a good performance status and normal heart function. Excluded are those with uncontrolled illnesses, pregnant or breastfeeding women, history of severe allergies to study drugs, active autoimmune diseases, brain metastases or another cancer not in remission.

Inclusion Criteria

The pumping function of your heart is at least 50% or within the normal range set by the hospital.

I have at least one HLA-A*02 gene variant.

I am fully active or can carry out light work.

Exclusion Criteria

You have had allergic reactions to drugs similar to fludarabine or cyclophosphamide in the past.

I have a serious heart condition.

I have another cancer that is not fully in remission.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ADP-A2M4CD8 T-cell therapy as monotherapy or in combination with either nivolumab or pembrolizumab

2.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• ADP-A2M4CD8
• Nivolumab
• Pembrolizumab

Trial Overview The trial tests ADP-A2M4CD8 T-cell therapy alone or combined with nivolumab every four weeks or pembrolizumab every six weeks. It aims to assess the safety and effectiveness of these treatments in patients whose tumors express a specific protein (MAGE-A4) and have a particular human leukocyte antigen (HLA).

Participant Groups

Group I: Autologous genetically modified ADP-A2M4CD8 cells Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Adaptimmune

Lead Sponsor

Trials

25

Recruited

10,000+

ICON plc

Industry Sponsor

Trials

88

Recruited

28,900+

Dr. Steve Cutler

ICON plc

Chief Executive Officer since 2017

PhD from the University of Sydney, MBA from the University of Birmingham

Dr. Greg Licholai

ICON plc

Chief Medical Officer since 2023

Degrees from Harvard Business School, Yale School of Medicine, Columbia University, and Boston College

Findings from Research

Patients with Ewing's sarcoma exhibit tumor-specific immunity, as their circulating T cells can proliferate and effectively kill tumor cells, indicating that immune tolerance may not be as prevalent as previously thought.

The study highlights the importance of 4-1BBL costimulation in activating tumor-reactive T cells, suggesting that therapies targeting this pathway could enhance anti-tumor immunity and improve outcomes in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor expression of 4-1BB ligand sustains tumor lytic T cells. Zhang, H., Merchant, MS., Chua, KS., et al.[2020]

MC-CAR T cells, which include MyD88 and CD40 costimulatory endodomains, demonstrated greater proliferation and antitumor activity compared to traditional CAR T cells with CD28 and 41BB endodomains in both laboratory and animal models.

Transcriptomic analysis indicated that MC-CAR T cells maintained a less differentiated state after activation, which may contribute to their enhanced effectiveness in targeting solid tumors, suggesting a potential improvement in CAR T cell therapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MyD88/CD40 signaling retains CAR T cells in a less differentiated state. Prinzing, B., Schreiner, P., Bell, M., et al.[2022]

The development of a fusion protein (CD8α:MyD88) significantly enhances CD8+ T-cell responses to weakly immunogenic tumor antigens, leading to increased T-cell proliferation and activation in a tumor-specific manner.

In mouse models, CD8α:MyD88-engineered T cells demonstrated improved antitumor activity, characterized by better T-cell infiltration into tumors, reduced T-cell exhaustion, and a favorable cytokine/chemokine profile, suggesting a promising strategy to overcome immunosuppression in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Synthetic CD8α:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens. Kaczanowska, S., Joseph, AM., Guo, J., et al.[2018]

CD103+CD39+ tumor-infiltrating CD8 T cells are enriched in tumor-reactive cells across various cancers and are associated with a better overall survival in head and neck cancer patients.

These T cells have a unique T-cell receptor repertoire and can effectively kill tumor cells, suggesting their potential role in enhancing immunotherapy strategies and developing adoptive T-cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Duhen, T., Duhen, R., Montler, R., et al.[2019]

In a study of 26 metastatic melanoma patients undergoing adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs), 106 neoepitopes were identified, with a strong correlation between the frequency of neoepitope-specific CD8+ T cells in TIL infusion products and improved patient survival.

Patients who responded positively to TIL-ACT had a unique presence of neoepitope-specific CD8+ T cells in their post-treatment blood samples, suggesting that the expansion of these specific T cells is crucial for the effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma. Kristensen, NP., Heeke, C., Tvingsholm, SA., et al.[2022]

A novel staining approach revealed that a specific CTL line targeting the MAGE-1 HLA-A24 peptide showed a significant increase in response after dendritic cell vaccine therapy, with the proportion of specific CTLs rising from 0.04% to 18.6%.

The expanded CTL line demonstrated strong cytotoxic activity against MAGE-1+ cancer cells, and for the first time, a specific T-cell receptor (TCR) cDNA was identified, confirming its effectiveness in transduced naive T-cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of a MAGE-1-derived HLA-A24 epitope-specific CTL line from a Japanese metastatic melanoma patient. Akiyama, Y., Maruyama, K., Tai, S., et al.[2011]

ADP-A2M10, a genetically engineered T-cell therapy targeting MAGE-A10-positive tumors, demonstrated an acceptable safety profile with no off-target toxicity in a phase 1 trial involving 10 patients with advanced cancers.

The therapy showed persistence in the bloodstream and the ability to infiltrate tumors, particularly in higher dose groups, although the best clinical responses were stable disease in four patients and progressive disease in five.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors. Hong, DS., Butler, MO., Pachynski, RK., et al.[2022]

The study developed a synthetic artificial antigen presenting cell (APC) system that effectively stimulates T cells, leading to the generation of high yields of functional cytotoxic T lymphocytes (CTLs) suitable for anticancer immunotherapy.

By using a specific ratio of costimulatory signals (3:1 ratio of anti-4-1BB to anti-CD28), the system achieved strong costimulatory synergy, resulting in the production of a large number of effector memory CTLs, which are crucial for effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent costimulation of human CD8 T cells by anti-4-1BB and anti-CD28 on synthetic artificial antigen presenting cells. Rudolf, D., Silberzahn, T., Walter, S., et al.[2020]

ADP-A2M10, a genetically engineered T cell therapy targeting MAGE-A10 in advanced non-small cell lung cancer (NSCLC), showed an acceptable safety profile with no off-target toxicity, although some patients experienced significant adverse events like lymphopenia and cytokine release syndrome.

The therapy demonstrated persistence in the bloodstream and tumor tissue, with higher doses leading to better persistence, indicating potential for effective antitumor activity, although only one patient achieved a partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10+ advanced non-small cell lung cancer. Blumenschein, GR., Devarakonda, S., Johnson, M., et al.[2022]

In a phase I trial, autologous T cells engineered to target the MAGE-A4 cancer testis antigen (ADP-A2M4) demonstrated significant efficacy, particularly in synovial sarcoma, achieving a disease control rate of approximately 90%.

The therapy was associated with a manageable toxicity profile, indicating that it is a potentially safe treatment option for patients with a variety of solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cells Targeting MAGE-A4 Shrink Tumors. [2021]

References

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

Tumor expression of 4-1BB ligand sustains tumor lytic T cells. [2020]

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

MyD88/CD40 signaling retains CAR T cells in a less differentiated state. [2022]

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

A Synthetic CD8α:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. [2019]

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

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Characterization of a MAGE-1-derived HLA-A24 epitope-specific CTL line from a Japanese metastatic melanoma patient. [2011]

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

Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Potent costimulation of human CD8 T cells by anti-4-1BB and anti-CD28 on synthetic artificial antigen presenting cells. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10+ advanced non-small cell lung cancer. [2022]

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

T Cells Targeting MAGE-A4 Shrink Tumors. [2021]