SynKIR-110 for Ovarian Cancer
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Verismo Therapeutics
Disqualifiers: Active cancers, Immunodeficiency, Hepatitis, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This first-in-human (FIH) trial is designed to assess the safety, feasibility, and potential activity of a single intravenous (IV) dose of SynKIR-110 administered to subjects with mesothelin-expressing advanced ovarian cancer, mesothelioma, and cholangiocarcinoma.
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify whether you need to stop taking your current medications.
What data supports the idea that SynKIR-110 for Ovarian Cancer is an effective treatment?
The available research shows that SynKIR-110, a type of treatment using modified T cells, has shown promise in fighting ovarian cancer. In a study using mice with ovarian cancer, a single injection of these modified cells helped slow down tumor growth and improved the survival of the mice. When the treatment was given weekly, it further controlled the disease and extended the mice's lives. Importantly, there were no major side effects observed. This suggests that SynKIR-110 could be a potential treatment for ovarian cancer, offering hope for better outcomes compared to some existing options.
12345What safety data is available for SynKIR-110 treatment for ovarian cancer?
The safety data for SynKIR-110, also known as Autologous T cells Transduced with Mesothelin KIR-CAR, indicates that it has been evaluated in various studies targeting mesothelin-expressing cancers. In a murine ovarian cancer model, CARMA-hMeso (a similar treatment) showed no significant off-target toxicities. In a phase I study of CART-meso (another related treatment), it was well tolerated with only one dose-limiting toxicity (grade 4, sepsis) reported. The treatment was generally well tolerated, with stable disease observed in some patients. Further studies are ongoing to evaluate fully human anti-mesothelin CARs to potentially improve safety and efficacy.
12367Is SynKIR-110 a promising treatment for ovarian cancer?
Yes, SynKIR-110 is a promising treatment for ovarian cancer. It uses a special type of T cells that are engineered to target and kill cancer cells that have a protein called mesothelin, which is often found in ovarian cancer. This treatment has shown potential in early studies to control tumor growth and improve survival in animal models, and it has the potential to provide a new option for patients with ovarian cancer.
12358Eligibility Criteria
This trial is for adults over 18 with advanced ovarian cancer, mesothelioma, or cholangiocarcinoma that express a protein called mesothelin. They must have had at least one prior treatment and be in good health otherwise, with no serious heart or lung conditions, other active cancers, immune deficiencies, or autoimmune diseases.Inclusion Criteria
I am fully active or can carry out light work.
My organs and bone marrow are functioning well.
My ovarian cancer or mesothelioma has high mesothelin levels, or my cholangiocarcinoma shows some mesothelin presence.
+4 more
Exclusion Criteria
I have no active cancer except for mesothelioma, cholangiocarcinoma, or ovarian cancer, or any cancer I had has been cured for over 5 years.
My lungs do not have any conditions that would exclude me.
My condition is sarcomatoid or biphasic mesothelioma.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pre-leukapheresis safety/eligibility and leukapheresis visits
Treatment
Administration of non-myeloablative lymphodepleting chemotherapy followed by a single infusion of SynKIR-110
1 day
Single visit for infusion
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
Regular visits until disease progression
Long-term safety follow-up
Participants are invited to participate in a long-term safety follow-up study after disease progression
Participant Groups
The trial is testing SynKIR-110 given through the vein to see if it's safe and works against certain cancers. It involves genetically modifying a patient's own T cells to target cancer cells expressing mesothelin.
1Treatment groups
Experimental Treatment
Group I: SynKIR-110Experimental Treatment1 Intervention
Single dose gravity drip IV administration
Autologous T cells Transduced with Mesothelin KIR-CAR is already approved in United States for the following indications:
🇺🇸 Approved in United States as SynKIR-110 for:
- None approved yet; currently in Phase 1 clinical trials for mesothelin-expressing advanced ovarian cancer, mesothelioma, and cholangiocarcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
MDAndersonHouston, TX
University of Wisconsin Carbone Cancer CenterMadison, WI
University of Kansas Cancer CenterWestwood, KS
MD Anderson Cancer CenterHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Verismo TherapeuticsLead Sponsor
References
Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA-Transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy. [2023]CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to "on-target off-tumor" toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK cells may permit prospective control of "on-target off-tumor" toxicity. To develop a commercial product for solid tumors, mesothelin was selected as an antigen target based on its association with poor prognosis and overexpression in multiple solid cancers. It was hypothesized that selecting, activating, and expanding cells ex vivo prior to mRNA CAR transfection would not be necessary, thus simplifying the complexity and cost of manufacturing. Now, the development of anti-human mesothelin mRNA CAR transfected peripheral blood lymphocytes (CARMA-hMeso) is reported, demonstrating the manufacture and cryopreservation of multiple cell aliquots for repeat administrations from a single human leukapheresis. A rapid, automated, closed system for cGMP-compliant transfection of mRNA CAR in up to 20 × 109 peripheral blood lymphocytes was developed. Here we show that CARMA-hMeso cells recognize and lyse tumor cells in a mesothelin-specific manner. Expression of CAR was detectable over approximately 7 days in vitro, with a progressive decline of CAR expression that appears to correlate with in vitro cell expansion. In a murine ovarian cancer model, a single intraperitoneal injection of CARMA-hMeso resulted in the dose-dependent inhibition of tumor growth and improved survival of mice. Furthermore, repeat weekly intraperitoneal administrations of the optimal CARMA-hMeso dose further prolonged disease control and survival. No significant off-target toxicities were observed. These data support further investigation of CARMA-hMeso as a potential treatment for ovarian cancer and other mesothelin-expressing cancers.
Mesothelin-Specific CAR T Cells Target Ovarian Cancer. [2021]New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coinhibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z- and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8+ T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer. SIGNIFICANCE: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.
Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. [2021]Cancer regression by gene-modified T cells bearing a chimeric antigen receptor (CAR) exodomain of mouse origin can be limited by the induction of transgene immunogenicity resulting in poor persistence and function in vivo. The development of functionally-active CAR of human origin can address this issue. Here, we constructed and evaluated fully human anti-mesothelin CARs comprised of a human mesothelin-specific single-chain antibody variable fragment (P4 scFv) coupled to T cell signaling domains. Primary human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors in vitro. P4 CAR T cells also mediated bystander killing of mesothelin-negative cancer cells during coculture. CAR reactivity was not abrogated by soluble tumor-secreted or recombinant mesothelin protein even at supraphysiological levels. Importantly, adoptive transfer of P4 CAR-expressing T cells mediated the regression of large, established tumor in the presence of soluble mesothelin in a xenogenic model of human ovarian cancer. Thus, primary human T cells expressing fully human anti-mesothelin CAR efficiently kill mesothelin-expressing tumors in vitro and in vivo and have the potential to overcome the issue of transgene immunogenicity that may limit CAR T cell trials that utilize scFvs of mouse origin.
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.
Application of chimeric antigen receptor-engineered T cells in ovarian cancer therapy. [2021]Due to the critical role of T cells in the immune surveillance of ovarian cancer, adoptive T-cell therapies are receiving increased attention as an immunotherapeutic approach for ovarian cancer. Chimeric antigen receptors (CARs), constructed by incorporating the single-chain Fv fragment to a T-cell signaling domain such as CD3 ζ or Fc receptor γ chain, endow T cell with nonmajor histocompatibility complex-restricted specificity. Dual specificity, trans-signaling CARs and affinity-tuned single-chain Fv fragment have broadened the applicability of CAR-engineered T-cell therapy and may be considered preferential to T cell receptor T-cell therapy in clinical care. As new insights into the CAR-engineered T cells have emerged over the last decade, we review the development of CAR T-cell therapy and discuss the progress and safety concerns regarding its translation from basic research into clinical care of ovarian cancer.
Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. [2023]We describe techniques and results of image-guided delivery of mesothelin-targeted chimeric antigen receptor (CAR) T cells in patients with pleural malignancies in a phase I/II trial (ClinicalTrials.gov: NCT02414269).
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.
Cell therapies in ovarian cancer. [2021]Epithelial ovarian cancer (EOC) is the most important cause of gynecological cancer-related mortality. Despite improvements in medical therapies, particularly with the incorporation of drugs targeting homologous recombination deficiency, EOC survival rates remain low. Adoptive cell therapy (ACT) is a personalized form of immunotherapy in which autologous lymphocytes are expanded, manipulated ex vivo, and re-infused into patients to mediate cancer rejection. This highly promising novel approach with curative potential encompasses multiple strategies, including the adoptive transfer of tumor-infiltrating lymphocytes, natural killer cells, or engineered immune components such as chimeric antigen receptor (CAR) constructs and engineered T-cell receptors. Technical advances in genomics and immuno-engineering have made possible neoantigen-based ACT strategies, as well as CAR-T cells with increased cell persistence and intratumoral trafficking, which have the potential to broaden the opportunity for patients with EOC. Furthermore, dendritic cell-based immunotherapies have been tested in patients with EOC with modest but encouraging results, while the combination of DC-based vaccination as a priming modality for other cancer therapies has shown encouraging results. In this manuscript, we provide a clinically oriented historical overview of various forms of cell therapies for the treatment of EOC, with an emphasis on T-cell therapy.