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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new type of T cell therapy for treating triple-negative breast cancer (TNBC) that has either returned after treatment or does not respond to treatment. The therapy engineers a patient's own T cells to recognize and attack cancer cells with a specific protein called NY-ESO-1. Known as Anti-HLA-A2/NY-ESO-1 TCR-transduced Autologous T Lymphocytes, this therapy aims to determine the safest dose and understand potential side effects. Women with advanced or metastatic TNBC, showing this specific protein and experiencing frequent relapses or resistance to past treatments, may be eligible. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a new treatment using modified immune cells has been studied for safety in treating certain cancers. Some studies reported serious side effects, including low levels of important blood cells that help fight infections. Increased levels of pancreatic enzymes, indicating potential stress to the organ, were also noted.

Despite these side effects, the treatment effectively identified and destroyed cancer cells in the lab. As this treatment is being tested in a Phase 1 clinical trial, researchers are still assessing its safety in humans, but they have found enough evidence to continue their investigation. This treatment is part of a new approach that aims to train the body's immune cells to better target cancer cells. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for breast cancer, like chemotherapy and hormone therapy, work by attacking rapidly dividing cancer cells or altering hormone levels. But the engineered T cell therapy, specifically anti-HLA-A2/NY-ESO-1 TCR-transduced autologous T lymphocytes, works differently by harnessing the body's immune system. This treatment modifies a patient's own T cells to specifically recognize and attack cancer cells, potentially leading to a more targeted and powerful immune response. Researchers are excited because this approach could offer a more personalized treatment option with the potential for fewer side effects and improved effectiveness compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that specially engineered T cells, called A2-ESO-1 TCR-T cells, can locate and attack cancer cells with a specific marker known as NY-ESO-1. In this trial, participants will receive these modified T cells, which previous studies have demonstrated can mount an immune response specifically targeting cancer cells with this marker. This suggests potential effectiveness against cancers like triple negative breast cancer (TNBC), which often exhibit this marker. Early results indicate that modifying these T cells enhances their ability to find and destroy the targeted cancer cells. This treatment aims to strengthen the body's immune system to better combat cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Daphne Stewart, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05989828

NCT05989828 | A2-ESO-1 TCR-Engineered T Cells for ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4361810/

A pilot trial using lymphocytes genetically engineered with ... In the current study we provide evidence that the adoptive transfer of autologous T cells transduced with a high avidity anti-NY-ESO-1 TCR can ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/anti-hla-a2-ny-eso-1-tcr-transduced-autologous-t-lymphocytes

Clinical Trials Using Anti-HLA-A2/NY-ESO-1 TCR- ... Review the clinical trials studying anti-hla-a2/ny-eso-1 tcr-transduced autologous t lymphocytes on this list and use the filters to refine the results by ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/29/24/5069/731661/Safety-and-Efficacy-of-NY-ESO-1-Antigen-Specific-T

Safety and Efficacy of NY-ESO-1 Antigen-Specific T-Cell ... This phase I/II trial of eight patients with advanced SS employed new technologies that specifically downregulate endogenous TCR and provide similar efficacy ...

5. apps.dtic.mil apps.dtic.mil/sti/trecms/pdf/AD1209087.pdf

NY-ESO-1 Specific TCR-Engineered T Cell ... - DTIC These results indicate that the modification of A2-ESO-1 TCR-T cells did not affect their specificity, but enhanced the ability to recognize the target cells ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2174604/

Primary Human Lymphocytes Transduced with NY-ESO-1 ... The transduced lymphocytes could efficiently recognize and kill HLA-A2- and NY-ESO-1-positive melanoma cell lines in a 4-h 51 Cr release assay.