CAR-T Cell Therapy for Gastrointestinal Cancers
Recruiting in Palo Alto (17 mi)
+4 other locations
Overseen byMichael R Bishop, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Chimeric Therapeutics
Must not be taking: Corticosteroids, Antibiotics
Disqualifiers: CNS metastases, Autoimmune disorders, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to evaluate CHM-2101, an autologous CDH17 CAR T-cell therapy for the treatment of advanced gastrointestinal (GI) cancers that are relapsed or refractory to at least 1 standard treatment regimen in the metastatic or locally advanced setting.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but ongoing treatment with high-dose corticosteroids is not allowed. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment CHM-2101, Autologous Cadherin 17 Chimeric Antigen Receptor (CAR) T Cell Therapy for gastrointestinal cancers?
Research shows that CDH17 CAR T cells can effectively target and kill tumor cells in gastrointestinal cancers without harming normal tissues, suggesting promising potential for this treatment.
12345Is CAR-T cell therapy safe for gastrointestinal cancers?
Research on CDH17CAR T cells for gastrointestinal cancers shows they can effectively target cancer cells without harming normal tissues, suggesting a promising safety profile.
36789How is the treatment CHM-2101 unique for gastrointestinal cancers?
CHM-2101 is a novel CAR-T cell therapy that targets Cadherin 17 (CDH17), a protein found on gastrointestinal cancer cells, allowing it to attack cancer cells without harming normal tissues. This approach is unique because it uses a llama-derived nanobody to specifically bind to CDH17, making it a promising and safer option for treating these cancers compared to traditional therapies.
12357Eligibility Criteria
This trial is for adults aged 18-85 with advanced GI cancers, including neuroendocrine tumors and colorectal or stomach cancer, that didn't respond to at least one standard treatment. Participants must have measurable disease (except in early phase), provide tissue samples, and be physically able to undergo the therapy.Inclusion Criteria
Left ventricular ejection fraction of at least 50%
Availability of unstained tumor tissue slides from archived tumor tissue or a new tumor biopsy
Documented informed consent of the participant and/or legally authorized representative
+10 more
Exclusion Criteria
I do not have uncontrolled Crohn's, ulcerative colitis, or similar GI disorders.
Half or more of my liver is affected by cancer.
I am currently on high-dose corticosteroid therapy.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis and Manufacturing
Eligible participants undergo leukapheresis to collect PBMCs for product manufacturing, including enrichment of T cells, lentiviral transduction, ex vivo expansion, and cryopreservation of the CHM-2101 cell product.
4-6 weeks
Bridging Chemotherapy
Bridging chemotherapy is permitted to maintain disease stability during CHM-2101 manufacturing time, but is prohibited within the 2 weeks prior to leukapheresis and 2 weeks prior to planned CHM-2101 infusion.
Variable
Treatment
Participants receive three daily doses of IV fludarabine and cyclophosphamide, followed by a single dose of IV CHM-2101.
1 week
Follow-up
Participants are monitored for safety and effectiveness after treatment, with follow-up continuing for 18 months or until disease progression.
18 months
Participant Groups
CHM-2101 CAR-T cell therapy is being tested on patients with specific gastrointestinal cancers. This personalized treatment involves modifying a patient's own immune cells to target and destroy cancer cells.
1Treatment groups
Experimental Treatment
Group I: Autologous CDH17 CAR T-cell TherapyExperimental Treatment1 Intervention
After receiving three daily doses of IV fludarabine and cyclophosphamide, participants will receive a single dose of IV CHM-2101.
The dose of CHM-2101 during Phase 1 will be based on "3+3" rules of dose escalation.
The recommended Phase 2 dose will be based on results from the Phase 1.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sarah Cannon Research InstituteNashville, TN
University of PennsylvaniaPhiladelphia, PA
MD Anderson Cancer CenterHouston, TX
Emory UniversityAtlanta, GA
More Trial Locations
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Who Is Running the Clinical Trial?
Chimeric TherapeuticsLead Sponsor
References
Gastric Cancer CAR T-cell Target Antigen ID'd. [2022]Chimeric antigen receptor (CAR) T-cell therapy has had limited efficacy against solid tumors, but a CAR T-cell therapy targeting isoform 2 of the tight junction membrane protein claudin 18, preferentially expressed on stomach mucosal cells, showed acceptable safety and promising efficacy against advanced digestive system cancers in a phase I trial.
Targeting CDH17 with Chimeric Antigen Receptor-Redirected T Cells in Small Cell Lung Cancer. [2023]Chimeric antigen receptor T cell (CAR-T) therapy stands as a precise and targeted approach in the treatment of malignancies. In this study, we investigated the feasibility of targeting Cadherin 17 (CDH17) with CDH17 CAR-T cells as a therapeutic modality for small cell lung cancer (SCLC).
Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. [2022]Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal epithelial cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is 'masked' in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.
111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis. [2020]Label="OBJECTIVE" NlmCategory="OBJECTIVE">Cadherin-17 (CDH17) is a transmembrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas, including gastric cancer. CDH17 may be an effective diagnostic marker for the staging of gastric cancer. Here, we developed an 111In-labeled anti-CDH17 monoclonal antibody (Mab) as an imaging tracer and performed biodistribution and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies using mice with CDH17-positive gastric cancer xenografts. CDH17 expression in gastric cancer specimens was also analyzed.
Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. [2022]Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.
Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors. [2023]Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.
Antitumor responses in gastric cancer by targeting B7H3 via chimeric antigen receptor T cells. [2022]Gastric cancer (GC) has a poor prognosis and limited therapeutic options. As a new promising cancer therapeutic approach, chimeric antigen receptor (CAR)-T cells represent a potential GC treatment. We investigated the antitumor activity of CAR-T cells target-B7H3 in GC.
Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling. [2021]Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.
c-Met-Specific Chimeric Antigen Receptor T Cells Demonstrate Anti-Tumor Effect in c-Met Positive Gastric Cancer. [2021]Chimeric antigen receptor (CAR) technology has been highlighted in recent years as a new therapeutic approach for cancer treatment. Although the impressive efficacy of CAR-based T cell adoptive immunotherapy has been observed in hematologic cancers, limited effect has been reported on solid tumors. Approximately 20% of gastric cancer (GC) patients exhibit a high expression of c-Met. We have generated an anti c-Met CAR construct that is composed of a single-chain variable fragment (scFv) of c-Met antibody and signaling domains consisting of CD28 and CD3ζ. To test the CAR construct, we used two cell lines: the Jurkat and KHYG-1 cell lines. These are convenient cell lines, compared to primary T cells, to culture and to test CAR constructs. We transduced CAR constructs into Jurkat cells by electroporation. c-Met CAR Jurkat cells secreted interleukin-2 (IL-2) only when incubated with c-Met positive GC cells. To confirm the lytic function of CAR, the CAR construct was transduced into KHYG-1, a NK/T cell line, using lentiviral particles. c-Met CAR KHYG-1 showed cytotoxic effect on c-Met positive GC cells, while c-Met negative GC cell lines were not eradicated by c-Met CAR KHYG-1. Based on these data, we created c-Met CAR T cells from primary T cells, which showed high IL-2 and IFN-γ secretion when incubated with the c-Met positive cancer cell line. In an in vivo xenograft assay with NSG bearing MKN-45, a c-Met positive GC cell line, c-Met CAR T cells effectively inhibited the tumor growth of MKN-45. Our results show that the c-Met CAR T cell therapy can be effective on GC.