Engineered T Cell Therapy for Breast Cancer

Overseen By Kimberly Arieli, RN

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University of Southern California

Must not be taking: Steroids, Complementary medicines

Disqualifiers: Cardiac disease, Brain metastases, others

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

Compensation: Varies

Number of Visits: 5

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects and best dose of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-T cells) in treating patients with NY-ESO-1 overexpression positive triple negative breast cancer (TNBC) that has come back after a period of improvement (relapsed/recurrent) or that does not respond to treatment (refractory), and that may have spread from where it first started (primary site) to nearby tissue, lymph nodes (advanced) or to other places in the body (metastatic). NY-ESO-1 is an antigen found on the surface of many different types of tumor cells including TNBC. Antigens make it possible for immune cells to recognize and kill germ cells that invade the body, however, it is more difficult for immune cells to recognize antigens on tumor cells. T cells are a special type of immune cell in the blood. These T cells may be trained to recognize the NY-ESO-1 antigen on tumor cells, allowing the T cells to attack and kill those tumor cells. The A2-ESO-1 TCR-T cells are T cells that have been removed from the patient's blood through a process called leukapheresis and then changed in the laboratory to recognize NY-ESO-1 on tumor cells. When given back to the patient, these A2-ESO-1 TCR-T cells find and attack tumor cells that express NY-ESO-1. Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They are given before the T cells to support optimum activity of the A2-ESO-1 TCR-T cells. IL-2 (aldesleukin) is in a class of drugs known as cytokines. It is a man-made version of a naturally occurring protein that stimulates the body to produce other chemicals which increase the body's ability to fight cancer. A2-ESO-1 TCR-T cells may kill more tumor cells in patients with recurrent or refractory advanced or metastatic TNBC that overexpresses NY-ESO-1.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot use medications that interact with or compromise the immune system, such as high-dose steroids, within 2 weeks before the start of the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Engineered T Cell Therapy for Breast Cancer?

Research shows that engineered T cells, like those used in this treatment, have been effective in targeting and reducing tumors in other cancers, such as acute myeloid leukemia and in mouse models. These studies suggest that similar approaches could potentially be effective in treating breast cancer. ^{1 2 3 4 5}

What safety data exists for engineered T cell therapy in humans?

Engineered T cell therapies have shown potential in treating cancer, but there are safety concerns. In one study, two patients experienced severe heart damage and died shortly after receiving T cell therapy, highlighting the risk of serious, unpredictable side effects. This underscores the need for better methods to ensure the safety of these treatments. ^{1 5 6 7 8}

How is the treatment Anti-HLA-A2/NY-ESO-1 TCR-transduced Autologous T Lymphocytes different from other breast cancer treatments?

This treatment is unique because it involves engineering a patient's own T cells to specifically target a protein called NY-ESO-1, which is found on some cancer cells. This personalized approach aims to enhance the immune system's ability to fight cancer, unlike traditional treatments that may not be as targeted. ^{1 2 3 5 6}

Research Team

Daphne Stewart, MD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for women over 18 with advanced or metastatic triple negative breast cancer that's resistant to standard treatments. They must have a certain immune system status, organ function, and life expectancy. Participants need HLA-A2+ status and NY-ESO-1 tumor expression. Pregnant or breastfeeding women can't join, nor those with recent heart issues, brain metastases, severe medical conditions, or allergies to the study drugs.

Inclusion Criteria

My heart pumps blood effectively.

Willing to provide biopsy tissues and blood samples as required by the study

You have a disease that can be measured using a specific set of guidelines.

Exclusion Criteria

I am not pregnant or breastfeeding.

I am not on high-dose steroids or other drugs that weaken my immune system.

I haven't had a heart attack, stroke, or serious heart rhythm problems in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Pre-treatment

Leukapheresis procedure to collect T cells from patients

1 day

1 visit (in-person)

Chemotherapy

Patients receive cyclophosphamide and fludarabine to prepare for T cell infusion

7 days

Daily visits (in-person)

T Cell Infusion

Infusion of A2-ESO-1 TCR-T cells followed by aldesleukin administration

3 days

Daily visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Visits at 3, 6, 12 months, then yearly

Treatment Details

Interventions

• Aldesleukin
• Anti-HLA-A2/NY-ESO-1 TCR-transduced Autologous T Lymphocytes
• Cyclophosphamide
• Fludarabine

Trial Overview The trial tests engineered T cells designed to target NY-ESO-1 on tumor cells in patients whose cancer has returned or doesn't respond to treatment. It includes chemotherapy (cyclophosphamide and fludarabine) before T cell infusion and aldesleukin after to boost effectiveness.

Participant Groups

Group I: Treatment (A2-ESO-1 TCR-T cells) Experimental Treatment 13 Interventions

Patients undergo leukapheresis on day -28 then receive cyclophosphamide IV over 1 hour on days -7 and -6 followed by fludarabine IV over 30 minutes on days -5 to -1. Patients then receive A2-ESO-1 TCR-T cells IV over 30 minutes on day 0 followed by aldesleukin IV over 15 minutes on days 0 to 2. Patients also undergo blood sample collection and CT scans throughout the study. Additionally, patients may undergo a breast biopsy, a mammogram, breast MRI, and breast US at screening and follow up, and ECHO or MUGA at screening.

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

This study demonstrates that allogeneic T cells engineered with a novel siTCR vector can effectively target tumors while minimizing the risk of graft-versus-host disease (GVHD), making them a safer option for adoptive immunotherapy.

The engineered T cells showed significant anti-tumor efficacy in mouse models without triggering GVHD, suggesting that this 'off-the-shelf' therapy could be a viable treatment for cancer patients, expanding the application of genetically engineered T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor gene-modified allogeneic T cells with siRNA for endogenous T cell receptor induce efficient tumor regression without graft-versus-host disease. Okada, S., Muraoka, D., Yasui, K., et al.[2023]

Adoptive cell transfer (ACT) using TCR-engineered T cells showed significant antitumor activity in mice with large tumors, especially when combined with lymphodepletion, dendritic cell vaccination, and high-dose IL-2.

The study utilized advanced imaging techniques to track T cell distribution and confirmed that these engineered T cells initially targeted antigen-matched tumors effectively, providing insights that could help translate this therapy for human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Koya, RC., Mok, S., Comin-Anduix, B., et al.[2022]

Engineered natural killer T cells (NKT) expressing a functional T-cell receptor (TCR) demonstrated effective antitumor activity in mouse models without causing graft-versus-host disease, suggesting a safer alternative for adoptive T-cell therapy.

The study revealed that the engineered TCR can displace the invariant TCR (iTCR) in NKT cells, allowing for effective targeting of cancer cells while minimizing the risk of autoreactivity, making these cells promising candidates for 'off-the-shelf' immunotherapy products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. Landoni, E., Smith, CC., Fucá, G., et al.[2020]

The study developed triple-knockout T cells that lack HLA class I, HLA class II, and T-cell receptor (TCR), allowing these allogeneic T cells to persist better in the presence of immune cells while avoiding graft-versus-host disease, making them safer for use in adoptive immunotherapy.

When these engineered T cells were modified with a CD19 chimeric antigen receptor (CAR), they maintained their ability to attack tumors effectively, suggesting that this approach could lead to more standardized and accessible cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy. Kagoya, Y., Guo, T., Yeung, B., et al.[2021]

In a small trial, T cells modified to target the Wilms tumor antigen 1 were effective in preventing relapse in patients with acute myeloid leukemia after they underwent an allogeneic stem-cell transplant.

This approach highlights the potential of engineered T cell therapies in enhancing post-transplant outcomes for leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR Gene Therapy Improves AML Prognosis. [2020]

Engineered T-cells targeting the NY-ESO-1 cancer-testis antigen showed increased activation and cytotoxicity against NY-ESO-1-positive tumor cells, indicating their potential effectiveness in treating solid tumors.

The study demonstrated that these modified T-cells not only proliferated and activated in response to the tumor cells but also produced key cytokines associated with cancer cell killing, suggesting a strong mechanism of action for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. Alsalloum, A., Alrhmoun, S., Shevchenko, J., et al.[2023]

Engineered T cells with an affinity-enhanced T-cell receptor (TCR) against MAGE-A3 led to severe cardiogenic shock and death in two patients, indicating serious and unpredictable off-target effects despite preclinical safety assessments.

Autopsy results showed significant heart damage and T-cell infiltration, but no MAGE-A3 expression was found in heart tissues, suggesting that the T cells may have targeted an unrelated peptide from a muscle protein, highlighting the need for better specificity testing in TCR engineering.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Linette, GP., Stadtmauer, EA., Maus, MV., et al.[2023]

The T2EVOLVE consortium aims to enhance the development and accessibility of engineered T-cell immunotherapies for cancer, focusing on both rare blood cancers and common solid tumors.

The review emphasizes the importance of improving preclinical models to better predict the safety and efficacy of CAR and TCR T-cell therapies, which could accelerate their transition to clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time 2EVOLVE: predicting efficacy of engineered T-cells - how far is the bench from the bedside? Guedan, S., Luu, M., Ammar, D., et al.[2022]

References

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

T cell receptor gene-modified allogeneic T cells with siRNA for endogenous T cell receptor induce efficient tumor regression without graft-versus-host disease. [2023]

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

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. [2022]

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

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. [2020]

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

Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy. [2021]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. [2023]

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

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. [2023]

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

Time 2EVOLVE: predicting efficacy of engineered T-cells - how far is the bench from the bedside? [2022]