Engineered T Cell Therapy for Breast Cancer
Recruiting in Palo Alto (17 mi)
Overseen byDaphne Stewart, MD
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Southern California
Must not be taking: Steroids, Complementary medicines
Disqualifiers: Cardiac disease, Brain metastases, others
No Placebo Group
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.
12345What 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.
15678How 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.
12356Eligibility 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.
+16 more
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.
+14 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (A2-ESO-1 TCR-T cells)Experimental Treatment13 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
USC / Norris Comprehensive Cancer CenterLos Angeles, CA
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Who Is Running the Clinical Trial?
University of Southern CaliforniaLead Sponsor
National Cancer Institute (NCI)Collaborator
References
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]Adoptive immunotherapy using genetically engineered patient-derived lymphocytes to express tumor-reactive receptors is a promising treatment for malignancy. However, utilization of autologous T cells in this therapy limits the quality of gene-engineered T cells, thereby inhibiting the timely infusion of the cells into patients. In this study, we evaluated the anti-tumor efficacy and the potential to induce graft-versus-host disease (GVHD) in T cell receptor (TCR) gene-engineered allogeneic T cells that downregulate the endogenous TCR and HLA class I molecules with the aim of developing an "off-the-shelf" cell product with expanded application of genetically engineered T cells. We transduced human lymphocytes with a high-affinity TCR specific to the cancer/testis antigen NY-ESO-1 using a novel retrovirus vector with siRNAs specific to the endogenous TCR (siTCR vector). These T cells showed reduced expression of endogenous TCR and minimized reactivity to allogeneic cells in vitro. In non-obese diabetic/SCID/γcnull mice, TCR gene-transduced T cells induced tumor regression without development of GVHD. A lentivirus-based CRISPR/Cas9 system targeting β-2 microglobulin in TCR gene-modified T cells silenced the HLA class I expression and prevented allogeneic CD8+ T cell stimulation without disrupting their anti-tumor capacity. This report is the first demonstration that siTCR technology is effective in preventing GVHD. Adoptive cell therapy with allogeneic T cells engineered with siTCR vector may be useful in developing an "off-the-shelf" therapy for patients with malignancy.
Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. [2022]A key issue in advancing the use of adoptive cell transfer (ACT) of T cell receptor (TCR) engineered lymphocytes for cancer therapy is demonstrating how TCR transgenic cells repopulate lymphopenic hosts and target tumors in an antigen-specific fashion. ACT of splenocytes from fully immunocompetent HLA-A2.1/K(b) mice transduced with a chimeric murine/human TCR specific for tyrosinase, together with lymphodepletion conditioning, dendritic cell (DC)-based vaccination, and high-dose interleukin-2 (IL-2), had profound antitumor activity against large established MHC- and antigen-matched tumors. Genetic labeling with bioluminescence imaging (BLI) and positron emitting tomography (PET) reporter genes allowed visualization of the distribution and antigen-specific tumor homing of TCR transgenic T cells, with trafficking correlated with antitumor efficacy. After an initial brief stage of systemic distribution, TCR-redirected and genetically labeled T cells demonstrated an early pattern of specific distribution to antigen-matched tumors and locoregional lymph nodes, followed by a more promiscuous distribution 1 wk later with additional accumulation in antigen-mismatched tumors. This approach of TCR engineering and molecular imaging reporter gene labeling is directly translatable to humans and provides useful information on how to clinically develop this mode of therapy.
A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. [2020]T-cell receptor (TCR) gene transfer redirects T cells to target intracellular antigens. However, the potential autoreactivity generated by TCR mispairing and occurrence of graft-versus-host disease in the allogenic setting due to the retention of native TCRs remain major concerns. Natural killer T cells (NKT) have shown promise as a platform for adoptive T-cell therapy in cancer patients. Here, we showed their utility for TCR gene transfer. We successfully engineered and expanded NKTs expressing a functional TCR (TCR NKTs), showing HLA-restricted antitumor activity in xenogeneic mouse models in the absence of graft-versus-mouse reactions. We found that TCR NKTs downregulated the invariant TCR (iTCR), leading to iTCR+TCR+ and iTCR-TCR+ populations. In-depth analyses of these subsets revealed that in iTCR-TCR+ NKTs, the iTCR, although expressed at the mRNA and protein levels, was retained in the cytoplasm. This effect resulted from a competition for binding to CD3 molecules for cell-surface expression by the transgenic TCR. Overall, our results highlight the feasibility and advantages of using NKTs for TCR expression for adoptive cell immunotherapies. NKT-low intrinsic alloreactivity that associated with the observed iTCR displacement by the engineered TCR represents ideal characteristics for "off-the-shelf" products without further TCR gene editing.
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]Adoptive immunotherapy can induce sustained therapeutic effects in some cancers. Antitumor T-cell grafts are often individually prepared in vitro from autologous T cells, which requires an intensive workload and increased costs. The quality of the generated T cells can also be variable, which affects the therapy's antitumor efficacy and toxicity. Standardized production of antitumor T-cell grafts from third-party donors will enable widespread use of this modality if allogeneic T-cell responses are effectively controlled. Here, we generated HLA class I, HLA class II, and T-cell receptor (TCR) triple-knockout (tKO) T cells by simultaneous knockout of the B2M, CIITA, and TRAC genes through Cas9/sgRNA ribonucleoprotein electroporation. Although HLA-deficient T cells were targeted by natural killer cells, they persisted better than HLA-sufficient T cells in the presence of allogeneic peripheral blood mononuclear cells (PBMC) in immunodeficient mice. When transduced with a CD19 chimeric antigen receptor (CAR) and stimulated by tumor cells, tKO CAR-T cells persisted better when cultured with allogeneic PBMCs compared with TRAC and B2M double-knockout T cells. The CD19 tKO CAR-T cells did not induce graft-versus-host disease but retained antitumor responses. These results demonstrated the benefit of HLA class I, HLA class II, and TCR deletion in enabling allogeneic-sourced T cells to be used for off-the-shelf adoptive immunotherapy.
TCR Gene Therapy Improves AML Prognosis. [2020]T cells engineered to express a receptor specific for Wilms tumor antigen 1 helped prevent relapse in a small trial of patients with acute myeloid leukemia who had received an allogeneic stem-cell transplant.
TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. [2023]Adoptive T-cell therapies tailored for the treatment of solid tumors encounter intricate challenges, necessitating the meticulous selection of specific target antigens and the engineering of highly specific T-cell receptors (TCRs). This study delves into the cytotoxicity and functional characteristics of in vitro-cultured T-lymphocytes, equipped with a TCR designed to precisely target the cancer-testis antigen NY-ESO-1. Flow cytometry analysis unveiled a notable increase in the population of cells expressing activation markers upon encountering the NY-ESO-1-positive tumor cell line, SK-Mel-37. Employing the NanoString platform, immune transcriptome profiling revealed the upregulation of genes enriched in Gene Ontology Biological Processes associated with the IFN-γ signaling pathway, regulation of T-cell activation, and proliferation. Furthermore, the modified T cells exhibited robust cytotoxicity in an antigen-dependent manner, as confirmed by the LDH assay results. Multiplex immunoassays, including LEGENDplex™, additionally demonstrated the elevated production of cytotoxicity-associated cytokines driven by granzymes and soluble Fas ligand (sFasL). Our findings underscore the specific targeting potential of engineered TCR T cells against NY-ESO-1-positive tumors. Further comprehensive in vivo investigations are essential to thoroughly validate these results and effectively harness the intrinsic potential of genetically engineered T cells for combating cancer.
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. [2023]An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
Time 2EVOLVE: predicting efficacy of engineered T-cells - how far is the bench from the bedside? [2022]Immunotherapy with gene engineered CAR and TCR transgenic T-cells is a transformative treatment in cancer medicine. There is a rich pipeline with target antigens and sophisticated technologies that will enable establishing this novel treatment not only in rare hematological malignancies, but also in common solid tumors. The T2EVOLVE consortium is a public private partnership directed at accelerating the preclinical development of and increasing access to engineered T-cell immunotherapies for cancer patients. A key ambition in T2EVOLVE is to assess the currently available preclinical models for evaluating safety and efficacy of engineered T cell therapy and developing new models and test parameters with higher predictive value for clinical safety and efficacy in order to improve and accelerate the selection of lead T-cell products for clinical translation. Here, we review existing and emerging preclinical models that permit assessing CAR and TCR signaling and antigen binding, the access and function of engineered T-cells to primary and metastatic tumor ligands, as well as the impact of endogenous factors such as the host immune system and microbiome. Collectively, this review article presents a perspective on an accelerated translational development path that is based on innovative standardized preclinical test systems for CAR and TCR transgenic T-cell products.