Trial Summary
What is the purpose of this trial?This is single center, open-label phase 1 dose escalation trial that uses modified 3+3 design to identify a recommended phase 2 dose (RP2D) of CAR.B7-H3 T cell product. An expansion cohort will enroll additional subjects at the RP2D for a total enrollment of up to 21 subjects on the protocol.
Do I need to stop taking my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are using systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent, you may not be eligible. Please discuss your current medications with the trial investigator for more details.
What data supports the idea that CAR T-Cell Therapy for Ovarian Cancer is an effective treatment?
The available research shows that CAR T-Cell Therapy targeting B7-H3 can effectively control the growth of ovarian cancer in laboratory and animal studies. Specifically, the therapy was able to manage tumor growth in models that mimic human ovarian cancer without causing significant side effects. This suggests that CAR T-Cell Therapy could be a promising treatment option for ovarian cancer, potentially offering better outcomes compared to traditional methods like surgery and chemotherapy. However, it's important to note that while these findings are promising, further studies and clinical trials are needed to confirm its effectiveness and safety in humans.
12345What safety data exists for CAR T-Cell Therapy in ovarian cancer?
CAR T-Cell Therapy for ovarian cancer, particularly targeting B7-H3, has shown promise in preclinical and early clinical trials. B7-H3-targeted CAR-T cells have demonstrated antitumor activity with minimal toxicity in some models, but there are concerns about potential 'on-target, off-tumor' toxicities. B7-H4 CAR T-cell therapy showed delayed, lethal toxicity due to expression in normal tissues. Overall, while initial trials suggest safety, long-term effects and specific toxicities need further evaluation.
13467Is the treatment CAR.B7-H3 a promising treatment for ovarian cancer?
Yes, CAR.B7-H3 is a promising treatment for ovarian cancer. It targets a specific protein, B7-H3, which is found in high amounts on cancer cells but not much on normal cells. This makes it a good target for treatment. Studies have shown that CAR.B7-H3 can effectively control tumor growth in ovarian cancer and other cancers, making it a strong candidate for future treatments.
13489Eligibility Criteria
This trial is for adults over 18 with recurrent ovarian cancer that's resistant to platinum-based chemotherapy and PARP inhibitors if they have BRCA mutations. Participants must be in good enough health to undergo procedures, agree to use two forms of contraception, and not be pregnant or breastfeeding. They can't join if they have certain other cancers, brain metastases, active infections like HIV or hepatitis, or recent bowel complications.Inclusion Criteria
I am older than 18 years.
I am willing to have multiple biopsies as my doctor thinks it's safe.
Written informed consent to undergo cell procurement is explained to, understood by, and signed by the subject; the subject is given a copy of the informed consent form for cell procurement
+13 more
Exclusion Criteria
I have had a gastrointestinal perforation in the past.
I had an abscess inside my belly in the last 3 months.
I have had signs or symptoms of a blocked intestine recently.
+9 more
Participant Groups
The study tests CAR T-cells targeting B7-H3 antigen in patients with ovarian cancer using a '3+3 design' to find the safest dose for phase 2 trials. Up to 21 people will receive this treatment after being screened for eligibility. The process includes placing an intraperitoneal port and multiple biopsies before and after treatment.
1Treatment groups
Experimental Treatment
Group I: CAR.B7-H3 T cell productExperimental Treatment3 Interventions
Up to 12 patients will receive three weekly CAR.B7-H3 T cell product infusions at the same dose. To determine the recommended phase 2 dose (RP2D), a modified 3+3 dose escalation design will be used to evaluate two dose levels: Dose Level 1 (7.5x10\^7 cells/infusion), Dose Level 2 (2x10\^8 cells/infusion). If this dose is not tolerated, then a lower dose of 3.75 × 10\^6 cells/infusion will be explored. Up to 3 dose levels of CAR.B7-H3 cells will be tested with at least 3 patients enrolled at each dose cohort before dose escalation is considered based on the incidence of dose limiting toxicity (DLT). An expansion cohort will enroll up to 9 patients at the recommended phase 2 dose. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and cyclophosphamide.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lineberger Comprehensive Cancer CenterChapel Hill, NC
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Who Is Running the Clinical Trial?
UNC Lineberger Comprehensive Cancer CenterLead Sponsor
National Institutes of Health (NIH)Collaborator
National Cancer Institute (NCI)Collaborator
References
Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. [2021]The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.
A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. [2022]A number of members of the B7 superfamily of ligands have been implicated in tumor immunogenicity and cancer development. Two of these recently characterized ligands, B7-H4 and B7-H3, have been linked to ovarian tumors. B7-H4 is consistently overexpressed in ovarian tumor specimens, and its tissue and serum levels have been found to be a potential biomarker for ovarian cancer, either alone or in combination with CA125. More recently, B7-H3 has been found to be overexpressed in a large series of ovarian cancer tumor specimens and similar to other types of carcinomas, B7-H3 overexpression has been correlated with poor survival. On the basis of the results obtained by knocking down B7-H3 protein using siRNA, researchers have suggested that blocking the action of B7-H3 could reduce tumor growth, metastatic potential, and improve survival. Because siRNA knock-down is not an ideal clinical therapeutic vehicle, additional studies using antibody-mediated suppression of the B7-H3 protein are necessary to fully evaluate the clinical potential of this molecule as a therapeutic target.
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.
CAR-T cell therapy in ovarian cancer: from the bench to the bedside. [2019]Ovarian cancer (OC) is the most lethal gynecological malignancy and is responsible for most gynecological cancer deaths. Apart from conventional surgery, chemotherapy, and radiotherapy, chimeric antigen receptor-modified T (CAR-T) cells as a representative of adoptive cellular immunotherapy have received considerable attention in the research field of cancer treatment. CARs combine antigen specificity and T-cell-activating properties in a single fusion molecule. Several preclinical experiments and clinical trials have confirmed that adoptive cell immunotherapy using typical CAR-engineered T cells for OC is a promising treatment approach with striking clinical efficacy; moreover, the emerging CAR-Ts targeting various antigens also exert great potential. However, such therapies have side effects and toxicities, such as cytokine-associated and "on-target, off-tumor" toxicities. In this review, we systematically detail and highlight the present knowledge of CAR-Ts including the constructions, vectors, clinical applications, development challenges, and solutions of CAR-T-cell therapy for OC. We hope to provide new insight into OC treatment for the future.
Targeting immunotherapy for bladder cancer using anti-CD3× B7-H3 bispecific antibody. [2021]B7-H3 is attractive for cancer immunotherapy with B7-H3 overexpressed tumors. To explore whether B7-H3 is an effective target for patients with bladder cancer, anti-CD3× anti-B7-H3 bispecific antibodies (B7-H3Bi-Ab) was armed with activated T cells (ATC) to kill bladder cancer cells.
Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy. [2022]B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo.
B7-H3-targeted CAR-T cell therapy for solid tumors. [2022]Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors.
T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review. [2021]Ovarian cancer, in particularly high-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS), are highly aggressive and deadly female cancers with limited treatment options. These tumors are generally unresponsive to immune check-point inhibitor (ICI) therapy and are referred to as immunologically "cold" tumors. Cell-based therapy, in particular, adoptive T-cell therapy, is an alternative immunotherapy option that has shown great potential, especially chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies. However, the efficacy of CAR-T therapy in solid tumors has been modest. This review explores the potential of another cell-based therapy, T-cell receptor therapy (TCR-T) as an alternate treatment option for immunological "cold" OC and OCS tumors.
The challenge of selecting tumor antigens for chimeric antigen receptor T-cell therapy in ovarian cancer. [2022]Ovarian cancer (OC) is one of the most common cancers in women, with a high mortality rate and very few available and effective treatments. Evidence shows that immunotherapy in OC has not been very successful because immune checkpoint blockers have not achieved satisfactory clinical outcomes. On the other hand, as one of the effective treatment approaches, chimeric antigen receptor T-cell (CAR T-cell) therapy has gained a moral position, especially in blood malignancies. Although in solid tumors, CAR T-cell therapy faces various complications and challenges. One of these challenges is selecting the appropriate tumor antigen targeted by CAR T cells, making the selection difficult due to the expression of antigens by tumor cells and normal cells. In addition, the rate of tumor antigen expression and CAR T-cell access to the desired antigen and proper stimulation of CAR T cells can be other important points in antigen selection. This review summarized common tumor antigens and the challenges of selecting them in CAR T cells therapy of OC.