ADP-A2M4CD8 + Immunotherapy for Advanced Cancers

Not currently recruiting at 25 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ADP-A2M4CD8, a type of immunotherapy, to determine its safety and tolerability in people with certain advanced cancers. It targets cancers such as melanoma and some lung cancers that express a specific protein called MAGE-A4. The treatment uses genetically modified cells designed to target cancer more effectively. Suitable participants have one of these cancers and have tested positive for a specific HLA type related to the treatment. 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 new therapy.

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.

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

Research has shown that ADP-A2M4CD8 T-cell therapy is generally safe, based on previous studies. These studies included patients with various cancers, such as those affecting the stomach and throat. The treatment uses the patient's own cells, reducing the risk of severe reactions. Early results indicate that most patients tolerate this therapy well, and serious side effects are uncommon. However, as with any treatment, some side effects may occur, so discussing these with a healthcare professional is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ADP-A2M4CD8 because it offers a novel approach to treating advanced cancers. Unlike standard treatments like chemotherapy and radiation, which target rapidly dividing cells, ADP-A2M4CD8 is a type of immunotherapy that uses genetically modified T cells to specifically target and attack cancer cells. This treatment is unique because it combines engineered T cells with CD8, a molecule that enhances the immune system's ability to fight cancer, potentially leading to more effective and targeted cancer cell destruction. This targeted approach could minimize damage to healthy cells and reduce side effects compared to traditional therapies.

What evidence suggests that ADP-A2M4CD8 T-cell therapy might be an effective treatment for advanced cancers?

Research has shown that ADP-A2M4CD8 T-cell therapy, which participants in this trial may receive, offers promising results for treating some advanced cancers. In earlier studies, patients with cancers such as ovarian and bladder cancer experienced a 44% objective response rate (ORR) after just one dose of this therapy. Nearly half of these patients saw a significant decrease in tumor size. Additionally, patients with cancers of the esophagogastric junction (EGJ) and head and neck also showed positive results, suggesting the therapy might be effective for different types of tumors. Overall, the therapy has been generally safe and well-tolerated by patients. ^{1 2 3 6 7}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.TPS363

A phase 2, open-label study of ADP-A2M4CD8 SPEAR T ... SURPASS-2 (NCT04752358) is a phase 2, open-label, single-arm trial to assess safety and efficacy of ADP-A2M4CD8 SPEAR T-cells in HLA-A*02–positive patients.

2. jitc.bmj.com jitc.bmj.com/content/8/Suppl_3/A231.1

379 Initial safety, efficacy, and product attributes from the ... Conclusions ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile and pts with EGJ cancer and head and neck cancer have demonstrated ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11815873/

Adoptive T Cell Therapy Targeting MAGE-A4 - PMC Though the ADP A2M4 TCR demonstrated excellent effectiveness against certain MAGE A4-associated tumors in recent trials, further advances in the development of ...

4. adaptimmune.com adaptimmune.com/investors-and-media/news-center/press-releases/detail/231/adaptimmune-reports-positive-data-in-its-surpass-trial

Adaptimmune Reports Positive Data in its SURPASS Trial 44% Objective Response Rate (ORR) with a single dose of ADP-A2M4CD8 in 25 heavily pre-treated patients with late-stage ovarian, urothelial, ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT395724

Preliminary clinical outcomes of ADP-A2M4CD8, a next- ... ADP-A2M4CD8 has demonstrated an acceptable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859)in HLA A*02–eligible patients with unresectable or ...

6. d1io3yog0oux5.cloudfront.net d1io3yog0oux5.cloudfront.net/adaptimmune/files/pages/adaptimmune/db/336/description/ADP-A2M4CD8/2020/SURPASS_eposter_SITC_2020_D_Hong_et_al_%28cm08%29_FINAL_UPLOAD.pdf

Initial Safety, Efficacy, and Product Attributes from • ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile, and ... Diagnosis of advanced gastroesophageal cancers, HNSCC, non-small cell lung cancer,.

7. researchgate.net researchgate.net/publication/346800970_379_Initial_safety_efficacy_and_product_attributes_from_the_SURPASS_trial_with_ADP-A2M4CD8_a_SPEAR_T-cell_therapy_incorporating_an_affinity_optimized_TCR_targeting_MAGE-A4_and_a_CD8a_co-receptor

379 Initial safety, efficacy, and product attributes from the ... Background The ongoing SURPASS trial ( NCT04044859 ) evaluates safety and efficacy of next-generation ADP-A2M4CD8 SPEAR T-cells ...