CAR NK Cells for B-Cell Cancers
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Nkarta, Inc.
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a single arm, open-label, multi-center, Phase 1 study to determine the safety and tolerability of an experimental therapy called NKX019 (allogeneic CAR NK cells targeting CD19) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) or B cell acute lymphoblastic leukemia (B-ALL)
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you need to stop your current medications. However, it mentions that recent use of any cancer-directed therapy within a specified window before the first dose of NKX019 is not allowed. It's best to discuss your current medications with the trial team.
What data supports the idea that CAR NK Cells for B-Cell Cancers is an effective treatment?The available research shows that CAR NK Cells, specifically those targeting CD19, have demonstrated high effectiveness against B-cell cancers. In one study, these cells showed strong activity against cancer cells in laboratory settings, similar to CAR-T cells, but with fewer side effects. Another study highlighted that CAR NK cells could be produced efficiently and used as an 'off-the-shelf' treatment, making them more accessible. These findings suggest that CAR NK Cells are a promising and potentially safer alternative to other treatments like CAR-T cells for B-cell cancers.23578
Is NKX019 a promising treatment for B-cell cancers?Yes, NKX019, which uses engineered natural killer (NK) cells to target cancer cells, shows promise as a treatment for B-cell cancers. It can effectively attack cancer cells that are usually resistant to natural killer cells, offering a safer alternative to other therapies without severe side effects.12678
What safety data exists for CAR NK cell treatment for B-cell cancers?CAR NK cells, including those targeting CD19, have shown a safer clinical profile compared to CAR-T cells, with no risk of graft-versus-host disease. Preclinical studies and early clinical trials indicate that CAR NK cells have potent antileukemic activity with a lower toxicity profile. The safety and efficacy of allogeneic cord blood-derived CD19 CAR-NK cell therapy have been reported, although the durability of clinical effects is still under investigation. Overall, CAR NK cells are considered promising for their safety and effectiveness in treating hematological malignancies.45679
Eligibility Criteria
Adults with certain B-cell cancers like non-Hodgkin lymphoma, chronic lymphocytic leukemia, or acute lymphoblastic leukemia that have come back or didn't respond to treatment can join. They must have had at least two prior treatments (one for some cases), be in fairly good health, and not pregnant. People with active brain cancer, recent other cancer treatments, or specific types of lymphoma aren't eligible.Inclusion Criteria
My diagnosis is a type of B cell blood cancer, as confirmed by lab tests.
I have taken medication for leukemia that targets specific proteins.
My cancer still shows CD19 or CD20 positivity after previous treatments targeting these.
I am fully active and can carry on all pre-disease activities without restriction.
My cancer can be measured by tests.
I have been treated with a specific antibody and chemotherapy for my lymphoma.
I have taken Venetoclax for my CLL/SLL.
I have been treated with a BTK inhibitor for my cancer.
Exclusion Criteria
My condition is either Burkitt Lymphoma, primary CNS lymphoma, or has transformed to Hodgkin lymphoma.
I have lasting side effects from previous treatments that are moderate to severe.
I have non-Hodgkin lymphoma with signs of cancer in my brain or spinal cord.
My leukemia has spread outside of my bone marrow.
Treatment Details
The trial is testing NKX019, a new type of cell therapy using modified natural killer cells aimed at CD19 on cancer cells. It's an early-phase study to see if it's safe and how well patients tolerate it. All participants receive the same experimental treatment without a comparison group.
1Treatment groups
Experimental Treatment
Group I: NKX019 - CAR NK cell therapyExperimental Treatment1 Intervention
All subjects will receive fludarabine/cyclophosphamide lymphodepletion followed by 3 weekly doses of NKX019 on Day 0, 7, and 14 of a 28-day cycle. Combination cohorts (if opened) will additionally receive rituximab with each cycle.
Find a clinic near you
Research locations nearbySelect from list below to view details:
The Cleveland Clinic FoundationCleveland, OH
Colorado Blood Cancer InstituteDenver, CO
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Who is running the clinical trial?
Nkarta, Inc.Lead Sponsor
Nkarta Inc.Lead Sponsor
References
CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. [2021]Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The 'first generation' CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.
Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. [2019]Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19+ targets, and maintained their intrinsic degranulation response toward CD19- K562 cells. The response of redirected NK-cell subsets against CD19+ targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA-specific KIR(s), displayed superior ability to kill CD19+, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells. Cancer Immunol Res; 6(4); 467-80. ©2018 AACR.
Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer. [2019]Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are bone marrow-derived innate lymphocytes that can eliminate tumors directly, with their activity governed by the integration of signals from activating and inhibitory receptors and from cytokines including IL-15, IL-12, and IL-18. NK cells do not cause GVHD or other alloimmune or autoimmune toxicities and thus, can provide a potential source of allogeneic "off-the-shelf" cellular therapy, mediating major anti-tumor effects without inducing potentially lethal alloreactivity such as GVHD. Given the multiple unique advantages of NK cells, researchers are now exploring the use of CAR-engineered NK cells for the treatment of various hematological and non-hematological malignancies. Herein, we review preclinical data on the development of CAR-NK cells, advantages, disadvantages, and current obstacles to their clinical use.
CAR-Expressing Natural Killer Cells for Cancer Retargeting. [2020]Since the approval in 2017 and the outstanding success of Kymriah® and Yescarta®, the number of clinical trials investigating the safety and efficacy of chimeric antigen receptor-modified autologous T cells has been constantly rising. Currently, more than 200 clinical trials are listed on clinicaltrial.gov. In contrast to CAR-T cells, natural killer (NK) cells can be used from allogeneic donors as an "off the shelf product" and provide alternative candidates for cancer retargeting. This review summarises preclinical results of CAR-engineered NK cells using both primary human NK cells and the cell line NK-92, and provides an overview about the first clinical CAR-NK cell studies targeting haematological malignancies and solid tumours, respectively.
Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. [2021]We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective "off-the-shelf" immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.
Recent advances in chimeric antigen receptor natural killer cell therapy for overcoming intractable hematological malignancies. [2021]Natural killer (NK) cells have a potent cytotoxic activity against leukemia and lymphoma without recognition of human leukocyte antigen (HLA) molecules. Chimeric antigen receptor-engineered NK cells (CAR-NK cells) can be produced from the NK92 cell line, peripheral blood, cord blood, and induced pluripotent stem cells for immunotherapy of malignant tumor cells. Recently, the safety and efficacy of HLA-mismatched allogeneic cord blood-derived CD19 CAR-NK cell therapy for CD19-positive hematological malignancies have been reported. However, the durability of clinical effects has not been clarified. The characteristics of CAR-NK cells with a strong antileukemia/lymphoma effect and better proliferative capacity without severe adverse effects may be promising for overcoming intractable hematological malignancies as an off-the-shelf allogeneic cellular therapy.
Selective Cytotoxicity of Single and Dual Anti-CD19 and Anti-CD138 Chimeric Antigen Receptor-Natural Killer Cells against Hematologic Malignancies. [2022]Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients' antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.
[Construction and evaluation of dual-effect cord blood natural killer cells expressing highaffinity PD-1 and chimeric antigen CD19 receptor]. [2023]To obtain novel dual-effect cord blood natural killer cells (CBNKCs) expressing high-affinity PD-1 (HAPD1) and chimeric antigen CD19 receptor (CAR) to improve the effect of CAR-based immunotherapy.
Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. [2022]Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.