CAR T Cell Therapy for Breast Cancer
Recruiting in Palo Alto (17 mi)
Overseen byJulia Tchou, MD, PhD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: University of Pennsylvania
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Active cancer, Hepatitis, Autoimmune, others
No Placebo Group
Trial Summary
What is the purpose of this trial?Phase 1 - Safety and Proof of Concept
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are on high-dose corticosteroids or systemic immunosuppressive treatment, you may need to adjust your medication as per the trial's exclusion criteria.
What data supports the effectiveness of the treatment huCART-meso cells for breast cancer?
Research shows that meso-CAR-T cells, which target a protein called mesothelin found in breast cancer, can reduce tumor growth. Combining this treatment with another therapy called rAd.sT enhances its effectiveness, suggesting it could be a promising strategy for breast cancer.
12345Is CAR T-cell therapy targeting mesothelin safe for humans?
CAR T-cell therapy targeting mesothelin has been generally well tolerated in humans, with one serious side effect (sepsis) reported in a study. Overall, it has shown a high safety profile, although its effectiveness in treating solid tumors is still being improved.
12356What makes huCART-meso cells treatment unique for breast cancer?
The huCART-meso cells treatment is unique because it uses genetically engineered T-cells to specifically target and attack cancer cells by recognizing a protein called mesothelin, which is often found on the surface of breast cancer cells. This approach is different from traditional treatments like surgery or chemotherapy, as it aims to harness the body's immune system to fight the cancer.
35789Eligibility Criteria
This trial is for adults over 18 with advanced triple-negative breast cancer that can't be removed by surgery or has spread, and whose tumors have a protein called mesothelin. They must be relatively healthy, not pregnant, and agree to use birth control. People with autoimmune diseases needing strong meds, other cancers, hepatitis B or C, serious infections or heart/lung problems can't join.Inclusion Criteria
I am fully active or can carry out light work.
My organs and bone marrow are working well.
My breast cancer is advanced, cannot be surgically removed, and lacks certain hormone receptors and HER2.
+7 more
Exclusion Criteria
I currently have an infection.
I do not have serious heart problems that could interfere with the study.
I am taking strong medication for an autoimmune disease.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive intratumoral injections of CAR T cells at different dose levels
6 weeks
Weekly visits for treatment administration
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Bi-weekly visits for monitoring
Participant Groups
The study is testing the safety of a new therapy using CAR T cells (huCART-meso cells) designed to target mesothelin in breast cancer. It's an early-phase trial to see if this approach could work as a treatment. Participants will also undergo tests to confirm their tumor expresses mesothelin.
2Treatment groups
Experimental Treatment
Group I: Dose Level 1Experimental Treatment2 Interventions
3.00 x 10\^7 CAR T cells administered intratumoral
Group II: Dose Level -1Experimental Treatment2 Interventions
3.00 x 10\^6 CAR T cells administered intratumoral
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who Is Running the Clinical Trial?
University of PennsylvaniaLead Sponsor
References
Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers. [2023]This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.
Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. [2021]Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors.
New approaches in chimeric antigen receptor T-cell therapy for breast cancer. [2020]Chimeric antigen receptor (CAR) T-cells has gained remarkable effect in hematologic malignancy. Breast cancer (BC) is the most popular malignancy tumor in women. Although surgical treatment, radiotherapy, endocrine therapy and molecular targeted therapy increase cure ratio of BC, it is still the major cause for cancer death among women. CAR-T cells can promote anti-breast cancer activity in vivo and in vitro preclinical studies. At present, some studies attempt to push the boundary of CAR T-cell therapy in the BC area. The results indicate that CAR-T cells may be an effective method for BC.
Oncolytic adenovirus targeting TGF-β enhances anti-tumor responses of mesothelin-targeted chimeric antigen receptor T cell therapy against breast cancer. [2021]Chimeric antigen receptor (CAR)-modified T cell therapy evokes only modest antitumor responses in solid tumors. Meso-CAR-T cells are CAR-T cells targeted mesothelin, which are over-expressed in tumor tissues of breast cancer patients. To improve the therapeutic effects, we combined it with rAd.sT, a transforming growth factor β signaling-targeted oncolytic adenovirus, to therapy breast cancer. In subcutaneous MDA-MB-231 xenograft of NSG mice, both rAd.sT and meso-CAR-T inhibited tumor growth, however combination therapy produced stronger inhibitory effects. Interestingly, rAd.sT reduced tumor burden at initial stage following vector treatments, while meso-CAR-T cells decreased tumor burden at a later stage. Moreover, meso-CAR-T could target tumor microenvironments, and combination therapy could enhance cytokines production, such as interleukin (IL)-6 and IL-12 in tumor microenvironment. In conclusion, combination of rAd.sT with meso-CAR-T produced much more impressive antitumor responses to breast cancer and its metastasis, which could be developed as a promising therapeutic strategy.
Challenges of Anti-Mesothelin CAR-T-Cell Therapy. [2023]Chimeric antigen receptor (CAR)-T-cell therapy is a kind of adoptive T-cell therapy (ACT) that has developed rapidly in recent years. Mesothelin (MSLN) is a tumor-associated antigen (TAA) that is highly expressed in various solid tumors and is an important target antigen for the development of new immunotherapies for solid tumors. This article reviews the clinical research status, obstacles, advancements and challenges of anti-MSLN CAR-T-cell therapy. Clinical trials on anti-MSLN CAR-T cells show that they have a high safety profile but limited efficacy. At present, local administration and introduction of new modifications are being used to enhance proliferation and persistence and to improve the efficacy and safety of anti-MSLN CAR-T cells. A number of clinical and basic studies have shown that the curative effect of combining this therapy with standard therapy is significantly better than that of monotherapy.
Driving better and safer HER2-specific CARs for cancer therapy. [2019]Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from "on-target, off-tumor" recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity. Furthermore, we also discuss the main strategies for improving the safety of HER2 CAR-based cancer therapies.
New Approaches in CAR-T Cell Immunotherapy for Breast Cancer. [2018]Despite significant advances in surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of death from malignant tumors among women. Immunotherapy has recently become a critical component of breast cancer treatment with encouraging activity and mild safety profiles. CAR-T therapy using genetically modifying T cells with chimeric antigen receptors (CAR) is the most commonly used approach to generate tumor-specific T cells. It has shown good curative effect for a variety of malignant diseases, especially for hematological malignancies. In this review, we briefly introduce the history and the present state of CAR research. Then we discuss the barriers of solid tumors for CARs application and possible strategies to improve therapeutic response with a focus on breast cancer. At last, we outlook the future directions of CAR-T therapy including managing toxicities and developing universal CAR-T cells.
Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer. [2021]Redirected chimeric antigen receptor (CAR) T-cells can recognize and eradicate cancer cells in a major histocompatibility complex independent manner. Genetic engineering of T cells through CAR expression has yielded great results in the treatment of hematological malignancies compared with solid tumors. There has been a constant effort to enhance the effectiveness of these living drugs, due to their limited success in targeting solid tumors. Poor T cell trafficking, tumor-specific antigen selection, and the immunosuppressive tumor microenvironment are considered as the main barriers in targeting solid tumors by CAR T-cells. Here, we reviewed the current state of CAR T-cell therapy in breast cancer, as the second cancer-related death in women worldwide, as well as some strategies adopted to keep the main limitations of CAR T-cells under control. Also, we summarized various approaches that have been developed to enhance the therapeutic outcomes of this treatment in solid tumors targeting.
Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer. [2023]Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.