CAR T-Cell Therapy for Breast Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Minerva Biotechnologies Corporation
Must not be taking: Corticosteroids, Immunosuppressives
Disqualifiers: Autoimmune, Organ dysfunction, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This trial uses a patient's own immune cells, which are modified in a lab to better recognize and attack cancer cells. The treatment targets patients with advanced breast cancer that expresses a specific protein called MUC1*. The modified T cells are designed to find and destroy these cancer cells by recognizing the MUC1* marker. MUC1 is a cancer-associated antigen that is overexpressed and modified by tumor cells in over half of all cancer cases, and it has been pursued as a target for immunotherapy.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does exclude patients who require ongoing daily corticosteroid therapy at a dose of more than 15 mg of prednisone per day. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment huMNC2-CAR44 CAR T cells for breast cancer?
Research shows that CAR T-cell therapy, similar to huMNC2-CAR44, has been effective in targeting and killing breast cancer cells, particularly those overexpressing certain proteins like HER2. Studies have demonstrated that CAR T-cells can promote anti-breast cancer activity in both laboratory and animal models, suggesting potential effectiveness for breast cancer treatment.12345
What safety data exists for CAR T-Cell Therapy in humans?
CAR T-Cell Therapy has been associated with several safety concerns, including cytokine release syndrome (a severe immune reaction), neurotoxicity, and other organ-related toxicities. These adverse effects can vary in severity and are influenced by factors like the type of CAR T-cell used and the patient's condition.678910
What makes the huMNC2-CAR44 CAR T-cell treatment unique for breast cancer?
The huMNC2-CAR44 CAR T-cell treatment is unique because it involves genetically modified T-cells that are designed to specifically target and attack breast cancer cells, potentially offering a new approach for patients who do not respond to traditional therapies like surgery, chemotherapy, or radiation.234511
Eligibility Criteria
This trial is for adults with advanced breast cancer that tests positive for a specific protein, MUC1*. Participants must have tried standard treatments and be in good enough health to give consent. Women of childbearing age need a negative pregnancy test and all fertile participants must agree to use contraception. People can't join if they're on high-dose steroids, have certain blood counts or organ dysfunction, untreated brain metastases, active infections, other cancers needing treatment, severe heart issues or are HIV positive.Inclusion Criteria
I can understand and sign a consent form.
I have had at least 3 treatments for HER2 positive breast cancer.
My breast cancer diagnosis and hormone receptor status are confirmed by a pathology review.
See 9 more
Exclusion Criteria
Treatment with investigational agent(s) within 30 days of planned lymphodepletion.
I have another cancer that is getting worse or needs treatment.
Breast-feeding women.
See 13 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either huMNC2-CAR44 or huMNC2-CAR22 T cells, which are autologous T cells engineered to target MUC1*
35 days
1 visit (in-person) for T cell infusion
Follow-up
Participants are monitored for safety and effectiveness after treatment, including in vivo persistence of CAR T cells
365 days
Long-term follow-up
Participants are monitored for antitumor activity and long-term safety
Up to 15 years
Treatment Details
Interventions
- huMNC2-CAR44 CAR T cells (CAR T-cell Therapy)
Trial OverviewThe study is testing two types of CAR T cell therapies (huMNC2-CAR44 or huMNC2-CAR22) designed to target the MUC1* protein on breast cancer cells. It's an early-phase trial to see how safe these therapies are and how well they work against this form of breast cancer.
Participant Groups
4Treatment groups
Experimental Treatment
Group I: Triple NegativeExperimental Treatment1 Intervention
Dose Expansion - 15 patients will be enrolled with triple negative metastatic breast cancer.
Group II: LuminalExperimental Treatment1 Intervention
Dose Expansion - 15 patients will be enrolled with luminal (hormone receptor positive, HER2 negative) metastatic breast cancer.
Group III: HER2+Experimental Treatment1 Intervention
Dose Expansion - 15 patients will be enrolled with HER2+ metastatic breast cancer.
Group IV: Dose EscalationExperimental Treatment1 Intervention
Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
Minerva Biotechnologies CorporationLead Sponsor
City of Hope Medical CenterCollaborator
References
Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells. [2018]Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours.
Selectively targeting myeloid-derived suppressor cells through TRAIL receptor 2 to enhance the efficacy of CAR T cell therapy for treatment of breast cancer. [2022]Successful targeting of solid tumors such as breast cancer (BC) using chimeric antigen receptor (CAR) T cells has proven challenging, largely attributed to the immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs) inhibit CAR T cell function and persistence within the breast TME. To overcome this challenge, we have developed CAR T cells targeting tumor-associated mucin 1 (MUC1) with a novel chimeric costimulatory receptor that targets tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TR2) expressed on MDSCs.
Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer. [2023]There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
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.
[Specific cytotoxicity of a novel HER2-based chimeric antigen receptor modified T lymphocytes against HER2-positive tumor cells]. [2019]Objective: To construct the third generation chimeric antigen receptor based on a novel humanized anti-HER2 H1-2 scFv, and to investigate the specific cytotoxicity of H1-2 CAR modified T lymphocytes(CAR-T) against HER2(+) tumor cells. Method: The expression cassette of the third generation CAR gene and anti-HER2 H1-2 scFv were constructed and cloned into lentivirus transfer plasmid, and then the third generation H1-2 CAR was transduced into human T lymphocytes using lentivirus.Enzyme linked immunosorbent assay was used to detect the expression of cytokines IL2, and LDH release assay was used to detect the cytotoxic effect of the H1-2 CAR-T.Finally, NOD/SCID mice and HER2(+) breast cancer cell line SKBR3 were used to detect the anti-tumor effect of H1-2 CAR-T in vivo. Results: The third generation H1-2 CAR was successfully constructed.H1-2 CAR-T secreted high dose of IL2 after confrontation with HER2(+) breast cancer cells.In vitro, the cytolytic rate of H1-2 CAR-T on high expression HER2(+) tumor cells was significantly higher than that in low expression HER2 or non-expression HER2 tumor cells. At the efficacy to target ratio of 20, the cytolytic rate of H1-2 CAR-T against breast cancer cell SK-BR-3 could reach (90.1±2.8)%, while the cytolytic rate of H1-2 CAR-T against HER2(-) breast cancer cell MDA-MB-231 was only (13.5±4.7)%. In the mouse xenograft tumor model, H1-2 CAR-T cells inhibited breast cancer growth in vivo.At the end of the experiments, the average tumor weight in the H1-2 CAR-T cell treatment group was (0.7±0.1) g, the non-transfected T cell therapeutic group was (1.2±0.2) g, and the PBS group was (1.2±0.2) g. There was significant difference between the H1-2 CAR-T therapeutic group and the non-transfected T cell therapeutic group (P<0.05). However, there was no significant difference between the non-transfected T cell therapeutic group and the PBS treatment group (P>0.05). Conclusion: The HER2-sepcific H1-2 CAR-T cells specifically kill HER2 positive cells, and further studies on CAR-T cells for the treatment of HER2(+) cancers are useful.
Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications. [2023]Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.
A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity. [2020]Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4+-to-CD8+ T cell ratio in the adoptive transfer product. CD4+ CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4+ CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity.
Complications after CD19+ CAR T-Cell Therapy. [2020]Clinical trials demonstrated that CD19+ chimeric antigen receptor (CAR) T-cells can be highly effective against a number of malignancies. However, the complete risk profile of CAR T-cells could not be defined in the initial trials. Currently, there is emerging evidence derived from post approval studies in CD19+ CAR T-cells demonstrating both short-term and medium-term effects, which were unknown at the time of regulatory approval. Here, we review the incidence and the current management of CD19+ CAR T-cell complications. We highlight frequently occurring events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cardiotoxicity, pulmonary toxicity, metabolic complications, secondary macrophage-activation syndrome, and prolonged cytopenia. Furthermore, we present evidence supporting the hypothesis that CAR T-cell-mediated toxicities can involve any other organ system and we discuss the potential risk of long-term complications. Finally, we discuss recent pre-clinical and clinical data shedding new light on the pathophysiology of CAR T-cell-related complications.
[Complications other than infections, CRS and ICANS following CAR T-cells therapy: Recommendations of the Francophone Society of bone marrow transplantation and cell therapy (SFGM-TC)]. [2022]CAR-T cells are an innovative treatment for an increasing number of patients, particularly since the extension of their indication to mantle lymphoma and multiple myeloma. Several complications of CAR T-cell therapy, that were first described as exceptional, have now been reported in series of patients, since its first clinical use in 2011. Among them, cardiac complications, delayed cytopenias, acute and chronic Graft versus Host Disease, and tumoral lysis syndrome are recognized as specific potent complications following CAR T-cells infusion. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of these complications with focuses the epidemiology, the physiopathology and the risk factors of these 4 side effects. Our recommendations apply to commercial CAR-T cells, in order to guide strategies for the management of complications associated with this new therapeutic approach.
From bench to bedside: the history and progress of CAR T cell therapy. [2023]Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.
An In Vitro Comparison of Costimulatory Domains in Chimeric Antigen Receptor T Cell for Breast Cancer Treatment. [2022]Adoptive cellular therapy with chimeric antigen receptor (CAR) T cells has emerged as a potential novel treatment for various cancers. In this study, we have generated CAR T cells targeting mucin-1 (MUC1), which is an aberrantly glycosylated antigen overexpressed on breast cancer cells. Two different signaling domains, including CD28 and 41BB, were incorporated and directly compared the superiority of different costimulatory signals. Two different CAR MUC1 constructs were transduced into primary T cells and evaluated their characteristics and antitumor activities against MUC1+ cancer cells. CAR MUC1 T cells showed high transduction efficiency and antigen specificity toward MUC1+ cancer cell lines and primary breast cancer cells. When coculturing with target cells, the transduced cells exhibited potent antitumor activity in vitro and secrete proinflammatory cytokines. Upon antigen stimulation, incorporation of the 41BB signaling domain was able to improve T cell proliferation and reduce surface PD1 expression and the upregulation of suppressive cytokines, when compared with CAR MUC1 containing the CD28 domain. Our findings show that CAR T cell targeting MUC1 can be effective against MUC1+ breast cancer cell and support the further development of CAR MUC1 T cells containing 41BB signaling in preclinical and clinical studies of breast cancer treatment.