Engineered NK Cells for Recurrent Glioblastoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Bevacizumab, Gliadel wafers
Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 and NR3C1 (cord blood \[CB\]-NK-TGF-betaR2-/NR3C1-) in treating patients with glioblastoma that has come back (recurrent). CB-NK-TGF-betaR2-/NR3C1- cells are genetically changed immune cells that may help to control the disease.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on immunosuppressive therapy within 7 days prior to the study, and you should not have had chemotherapy or targeted therapy within 2 weeks before starting the trial.
What data supports the effectiveness of the treatment using engineered NK cells for recurrent glioblastoma?
Research shows that natural killer (NK) cells, which are part of the body's immune system, can be activated to attack glioblastoma cells, a type of aggressive brain cancer. Studies have found that NK cells from cord blood can be expanded and enhanced to improve their ability to target and kill cancer cells, suggesting potential effectiveness in treating glioblastoma.12345
Is the treatment with engineered NK cells generally safe for humans?
How is the treatment with engineered NK cells for recurrent glioblastoma different from other treatments?
This treatment uses engineered natural killer (NK) cells derived from cord blood, which are modified to resist the suppressive effects of the tumor environment, specifically targeting the TGF-β pathway that often hinders immune response in glioblastoma. Unlike traditional therapies, these NK cells do not require prior antigen presentation, making them a potentially more effective option for targeting glioblastoma stem cells that are resistant to standard treatments.12379
Eligibility Criteria
Adults with recurrent glioblastoma who've had prior radiation and temozolomide therapy can join this trial. They must have a stable health status, including normal organ function and blood counts, not be pregnant or breastfeeding, agree to use contraception, and understand the study's requirements. Excluded are those with severe allergies to monoclonal antibodies, certain infections or immunodeficiencies, recent immunosuppressive therapy, other active cancers requiring treatment, bleeding disorders or full-dose anticoagulation.Inclusion Criteria
My blood counts meet the required levels for treatment.
I agree to use two effective birth control methods during and for 3 months after the study.
I am 18 years or older.
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Exclusion Criteria
I have been treated with Gliadel wafers before.
I have had cancer treatment directly into the tumor or nearby area.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive CB-NK-TGF-betaR2-/NR3C1- intratumorally every 4 weeks for up to 8 doses
32 weeks
8 visits (in-person)
Surgical Resection (Group 2)
Participants undergo surgical resection of the tumor with Ommaya catheter management
2 weeks
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
2 visits (in-person)
Treatment Details
Interventions
- Cord Blood-derived Expanded Allogeneic Natural Killer Cells (CAR T-cell Therapy)
- Resection (Surgery)
Trial OverviewThe trial is testing genetically engineered NK cells designed to fight cancer by deleting TGF-betaR2 and NR3C1 in patients with recurrent glioblastoma. It aims to determine the optimal dose of these modified cells while monitoring for any potential benefits or side effects.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)Experimental Treatment2 Interventions
Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.
Group II: Group 1 (CB-NK-TGF-betaR2-/NR3C1- )Experimental Treatment1 Intervention
Participants will receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every four weeks for up to 8 doses in the absence of disease progression or unacceptable toxicity.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. [2021]Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.
Cytokines impact natural killer cell phenotype and functionality against glioblastoma in vitro. [2023]Label="Objective">Natural killer (NK) cells are a part of the innate immune system and first-line defense against cancer. Since they possess natural mechanisms to recognize and kill tumor cells, NK cells are considered as a potential option for an off-the-shelf allogeneic cell-based immunotherapy. Here, our objective was to identify the optimal cytokine-based, feeder-free, activation and expansion protocol for cytotoxic NK cells against glioblastoma in vitro.
Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles. [2021]Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56+ NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34+ hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs). UCB56-NK cells also displayed a more potent cytotoxicity compared to UCB34-NK cells. NK cells derived from iPSCs (iPSC-NK cells) were found to have variable KIR expression, with certain iPSC-NK cell populations expressing high levels of KIRs and others not expressing KIRs. Notably, KIR expression on UCB56 and iPSC-NK cells had limited effect on cytotoxic activity when stimulated by tumor target cells that express high levels of cognate HLA class I, suggesting that in vitro differentiation and expansion may override the KIR-HLA class I mediated inhibition when used across HLA barriers. Together our results give a better understanding of the cell surface receptor, transcriptional, and functional differences between NK cells present in umbilical cord blood and hematopoietic progenitor-derived NK cells which may prove important in selecting the most active NK cell populations for treatment of cancer or other therapies.
[Enhanced cytotoxicity against leukemia cells of natural Killer cells from cord blood after expansion in vitro]. [2013]To investigate the enhanced cytotoxicity against leukemia cells of natural Killer (NK) cells from cord blood (CB) after expansion in vitro.
CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. [2020]Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
An efficient feeder-free and chemically-defined expansion strategy for highly purified natural killer cells derived from human cord blood. [2023]Natural killer cells (NKCs) are immune cells that can attack cancer cells through the direct recognition of ligands without prior sensitization. Cord blood-derived NKCs (CBNKCs) represent a promising tool for allogenic NKC-based cancer immunotherapy. Efficient NKC expansion and decreased T cell inclusion are crucial for the success of allogeneic NKC-based immunotherapy without inducing graft-versus-host reactions. We previously established an efficient ex vivo expansion system consisting of highly purified-NKCs derived from human peripheral blood. Herein, we evaluated the performance of the NKC expansion system using CB and characterized the expanded populations.
Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. [2022]Adoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor microenvironment. Expanded autologous T cells, particularly T cells with engineered T cell receptors (TCR) and chimeric antigen receptor-T cells have had success in various hematologic malignancies but have faced challenges when applied to solid tumors. As a result, other immune subpopulations may provide valuable and orthogonal options for treatment. Natural killer (NK) cells offer the possibility of significant tumor clearance and recruitment of additional immune subpopulations without the need for prior antigen presentation like in T or B cells that could require removal of endogenous antigen specificity mediated via the T cell receptor (TCR and/or the B ecll receptor (BCR). In recent years, NK cells have been demonstrated to be increasingly important players in the immune response against cancer. Here, we review multiple avenues for allogeneic NK cell therapy, including derivation of NK cells from peripheral blood or umbilical cord blood, the NK-92 immortalized cell line, and induced pluripotent stem cells (iPSCs). We also describe the potential of engineering iPSC-derived NK cells and the utility of this platform. Finally, we consider the benefits and drawbacks of each approach and discuss recent developments in the manufacturing and genetic or metabolic engineering of NK cells to have robust and prolonged antitumor responses in preclinical and clinical settings.
High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. [2021]Immunotherapy based on natural killer (NK) cell infusions is a potential adjuvant treatment for many cancers. Such therapeutic application in humans requires large numbers of functional NK cells that have been selected and expanded using clinical grade protocols. We established an extremely efficient cytokine-based culture system for ex vivo expansion of NK cells from hematopoietic stem and progenitor cells from umbilical cord blood (UCB). Systematic refinement of this two-step system using a novel clinical grade medium resulted in a therapeutically applicable cell culture protocol. CD56(+)CD3(-) NK cell products could be routinely generated from freshly selected CD34(+) UCB cells with a mean expansion of >15,000 fold and a nearly 100% purity. Moreover, our protocol has the capacity to produce more than 3-log NK cell expansion from frozen CD34(+) UCB cells. These ex vivo-generated cell products contain NK cell subsets differentially expressing NKG2A and killer immunoglobulin-like receptors. Furthermore, UCB-derived CD56(+) NK cells generated by our protocol uniformly express high levels of activating NKG2D and natural cytotoxicity receptors. Functional analysis showed that these ex vivo-generated NK cells efficiently target myeloid leukemia and melanoma tumor cell lines, and mediate cytolysis of primary leukemia cells at low NK-target ratios. Our culture system exemplifies a major breakthrough in producing pure NK cell products from limited numbers of CD34(+) cells for cancer immunotherapy.
Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β. [2022]Cord blood (CB)-derived natural killer (NK) cells that are genetically engineered to express a chimeric antigen receptor (CAR) are an attractive off-the-shelf therapy for the treatment of cancer, demonstrating a robust safety profile in vivo. For poor prognosis brain tumors such as glioblastoma multiforme (GBM), novel therapies are urgently needed. Although CAR-T cells demonstrate efficacy in preclinical GBM models, an off-the-shelf product may exhibit unwanted side effects like graft-versus-host disease. Hence, we developed an off-the-shelf CAR-NK cell approach using a B7H3 CAR and showed that CAR-transduced NK cells have robust cytolytic activity against GBM cells in vitro. However, transforming growth factor (TGF)-β within the tumor microenvironment has devastating effects on the cytolytic activity of both unmodified and CAR-transduced NK cells. To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF-β dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF-β. This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.