CAR-GPC3 T Cell Therapy for Cancer
(DUET-1 Trial)
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Sotio Biotech Inc.
Must not be taking: Antineoplastics, Corticosteroids
Disqualifiers: CNS tumors, Cardiovascular disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a first-in-human (FIH), Phase 1/2, open-label, multicenter study to assess safety and determine the recommended Phase 2 dose (RP2D) of BOXR1030 administration after lymphodepleting chemotherapy (LD chemotherapy) in subjects with glypican-3 positive (GPC3+) advanced solid tumors.
Do I need to stop my current medications to join the trial?
The trial requires a washout period for certain medications before starting treatment. You may need to stop some medications, especially antineoplastic treatments, for a specific time before the trial begins. It's best to discuss your current medications with the trial team to understand what changes might be necessary.
What data supports the effectiveness of the treatment BOXR1030 T Cells for cancer?
Research shows that T cells engineered to target glypican-3 (GPC3), a protein found on some cancer cells, can effectively attack and reduce tumors in models of lung and liver cancer. These studies suggest that similar GPC3-targeted treatments, like BOXR1030 T Cells, might also be effective against cancers expressing GPC3.
12345Is CAR-GPC3 T Cell Therapy safe for humans?
CAR T cell therapies, including those targeting glypican-3 (GPC3), have shown potential in treating certain cancers, but they can also cause serious side effects like cytokine release syndrome (CRS) and neurological issues. Safety strategies are being developed to manage these risks, and some studies suggest that modifying the therapy can reduce side effects. However, it's important to monitor for severe reactions, especially shortly after treatment.
13678What makes the CAR-GPC3 T Cell Therapy treatment unique compared to other cancer treatments?
CAR-GPC3 T Cell Therapy is unique because it uses specially engineered T cells to target glypican-3 (GPC3), a protein found on certain cancer cells, allowing for precise attack on tumors while sparing normal cells. This approach is particularly promising for solid tumors, which have been challenging to treat with traditional CAR-T therapies.
12349Eligibility Criteria
Adults aged 18-80 with advanced solid tumors positive for GPC3, such as liver cancer or lung squamous cell carcinoma. They must have a life expectancy over 16 weeks, good organ function, and no severe complications like major untreated brain metastasis. Women of childbearing age and men with partners must agree to effective contraception.Inclusion Criteria
My cancer is advanced, cannot be surgically removed, and tests show high levels of GPC3.
My liver cancer is not fibrolamellar or mixed hepatocellular cholangiocarcinoma.
I may have had radiation for symptom relief or hormone treatment, but it's been over a week since.
+13 more
Exclusion Criteria
I have a heart condition that affects my daily life.
I do not have severe diseases like uncontrolled bleeding, serious infections, or active hepatitis.
I have untreated brain tumors or metastasis.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis
Eligible subjects undergo leukapheresis to obtain T cells for BOXR1030 manufacturing
1 week
Lymphodepleting Chemotherapy
Subjects receive a 3-day LD chemotherapy regimen with fludarabine and cyclophosphamide
1 week
Treatment
Subjects receive BOXR1030 administration and remain hospitalized for 10 days post-infusion
4 weeks
Inpatient stay for 10 days post-infusion
Post-treatment Evaluation
Subjects are monitored for safety and effectiveness with regular visits and assessments
6 months
Daily visits for the first week, then weekly visits up to 6 months
Long-term Follow-up
Subjects are monitored for long-term safety and disease status for up to 15 years
15 years
Visits at Months 7, 9, 11, 13, 15, 18, 21, 24, every 6 months until Year 5, then annually
Participant Groups
The trial is testing BOXR1030 T Cells after chemotherapy in patients with GPC3-positive tumors. It's the first time this treatment is being used on humans (Phase 1), aiming to find the safest dose for Phase 2 trials while monitoring its safety across multiple centers.
1Treatment groups
Experimental Treatment
Group I: GPC3+ solid tumorsExperimental Treatment1 Intervention
One time intravenous administration of BOXR1030 after completion of cyclophosphamide and fludarabine LD chemotherapy
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Froedtert and Medical College of WisconsinMilwaukee, WI
University of Texas MD Anderson Cancer CenterHouston, TX
Baylor Scott and White Research InstituteDallas, TX
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Who Is Running the Clinical Trial?
Sotio Biotech Inc.Lead Sponsor
SOTIO, LLCLead Sponsor
SOTIO Biotech a.s.Industry Sponsor
SOTIO Biotech AGIndustry Sponsor
SOTIO BiotechIndustry Sponsor
References
Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. [2020]There are unmet medical needs for patients with lung squamous cell carcinoma (LSCC). Therefore, in this study, we explored the antitumor potential of third-generation glypican 3 (GPC3)-redirected chimeric antigen receptor (CAR)-engineered T lymphocytes (CARgpc3 T cells) in tumor models of LSCC. First, we demonstrated by immunohistochemistry (IHC) that GPC3 was expressed in 66.3% of LSCC samples and in 3.3% of lung adenocarcinoma (LAD) samples but not in normal lung tissues. In the presence of GPC3-positive LSCC cells, CARgpc3 T cells were highly activated and increased in number. CARgpc3 T cells could specifically lyse GPC3-positive LSCC cells in vitro. In two established LSCC xenograft models, CARgpc3 T cells could almost completely eliminate the growth of GPC3-positive cells. Additionally, the CARgpc3 T cells were able to persist in vivo and efficiently infiltrate the cancerous tissues. Taken together, these findings indicate that CARgpc3 T cells might be a novel potential therapeutic agent for the treatment of patients with LSCC.
[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. [2020]Adoptive immunotherapy based on chimeric antigen receptor-modified T cells (CAR-T) is one of the most promising strategies to treat malignant tumors, but its application in solid tumors is still limited. Glypican-3 (GPC3) is a meaningful diagnostic, therapeutic, and prognostic biomarker for hepatocellular carcinoma (HCC). The second/third generation GPC3-targeted CAR-T cells are generated to treat HCC. In order to improve the therapeutic effect, we constructed a fourth-generation lentiviral vector to express GPC3 CAR, human interleukin-7 (IL-7) and CCL19. Then the lentiviral vector and packaging plasmids were co-transfected into HEK293T cells to generate CAR lentiviral particles. Human T lymphocyte cells were transduced with CAR lentiviral to develop the fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19). In vitro, we used cell counting, transwell assay, luciferase bioluminescence assay and flow cytometry to compare the proliferation, chemotaxis, cytotoxicity and subtype distribution between GPC3-BBZ-7×19 CAR-T cells and the second generation GPC3-targeted CAR-T cells (GPC3-BBZ). In vivo, we established GPC3-positive HCC xenograft model in immunodeficient mice, then untransduced T cells (non-CAR-T) or GPC3-BBZ-7×19 CAR-T cells were injected. Tumor growth in mice was observed by bioluminescence imaging. Results showed that compared with GPC3-BBZ CAR-T, GPC3-BBZ-7×19 CAR-T cells had stronger proliferation, chemotactic ability, and higher composition of memory stem T cells (Tscm) (P values
Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. [2020]Adoptive immunotherapy based on chimeric antigen receptor-modified T (CAR-T) cells has been demonstrated as one of the most promising therapeutic strategies in the treatment of malignancies. However, CAR-T cell therapy has shown limited efficacy for the treatment of solid tumors. This is, in part, because of tumor heterogeneity and a hostile tumor microenvironment, which could suppress adoptively transferred T cell activity. In this study, we, respectively, engineered human- or murine-derived-armored glypican-3 (GPC3)-specific CAR-T cells capable of inducibly expressing IL-12 (GPC3-28Z-NFAT-IL-12) T cells. The results showed that GPC3-28Z-NFAT-IL-12 T cells could lyse GPC3+ tumor cells specifically and increase cytokine secretion compared with GPC3-28Z T cells in vitro. In vivo, GPC3-28Z-NFAT-IL-12 T cells augmented the antitumor effect when encountering GPC3+ large tumor burdens, which could be attributed to IL-12 increasing IFN-γ production, favoring T cells infiltration and persistence. Furthermore, in immunocompetent hosts, low doses of GPC3-m28Z-mNFAT-mIL-12 T cells exerted superior antitumor efficacy without prior conditioning in comparison with GPC3-m28Z T cells. Also, mIL-12 secretion decreased regulatory T cell infiltration in established tumors. In conclusion, these findings demonstrated that the inducible expression of IL-12 could boost CAR-T function with less potential side effects, both in immunodeficient and immunocompetent hosts. The inducibly expressed IL-12-armored GPC3-CAR-T cells could broaden the application of CAR-T-based immunotherapy to patients intolerant of lymphodepletion chemotherapy and might provide an alternative therapeutic strategy for patients with GPC3+ cancers.
Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. [2022]The aim of our study is to elucidate whether T cells expressing GPC3-targeted chimeric antigen receptor (CAR) can efficiently eliminate GPC3-positive HCC cells and their potential in the treatment of HCC.
CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity. [2021]Adoptive cell-transfer therapy (ACT) has been reported to suppress growing tumors and to overcome tumor escape in animal models. As a candidate ACT effector, γ9δ2T cells can be activated and expanded in vitro and in vivo and display strong antitumor activity against colorectal, lung, prostate, ovarian and renal cell carcinomas. However, it is difficult to obtain a large enough number of γδT cells to meet the need for immunotherapy that can overcome the cancer patients' immune suppressive tumor microenvironment. In previous studies, our lab confirmed that γ9δ2T cells recognized tumor cells via the CDR3δ region of the γδ-T-cell receptor (TCR). We constructed full-length human peripheral blood mononuclear cell (PBMC)-derived γ9 and δ2 chains in which the CDR3 region was replaced by an ovarian epithelial carcinoma (OEC)-derived CDR3. We transferred the CDR3δ-grafted γ9δ2TCR into peripheral blood lymphocytes (PBLs) to develop genetically modified γ9δ2T cells. In vitro studies have shown that these CDR3δ-grafted γ9δ2T cells can produce cytokines after stimulation with tumor cell extracts and exhibit cytotoxicity towards tumor cells, including human OEC and cervical adenocarcinoma. CDR3δ-grafted γ9δ2T cells adoptively transferred into nude mice bearing a human OEC cell line demonstrated significant antitumor effects. These results indicate that CDR3δ-grafted γ9δ2T cells might be candidates for clinical tumor immunotherapy.
Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR T cell toxicity. Findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.
Engineering Next-Generation CAR-T Cells for Better Toxicity Management. [2023]Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy-notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.
Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. [2021]Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC025 , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n = 1378, IC025  = 4.24), neurological disorders (n = 963, IC025  = 2.42), hematological disorders (n = 532, IC025  = 3.32), infections (n = 287, IC025  = 2.38), cardiovascular disorders (n = 256, IC025  = 2.81), pulmonary disorders (n = 186, IC025  = 3.80), reno-metabolic disorders (n = 123, IC025  = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC025  = 5.01) and hepatic disorders (n = 32, IC025  = 2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.
Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. [2022]T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3ζ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors.