NK Cells + Chemotherapy for Blood Cancers
Recruiting in Palo Alto (17 mi)
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Steroids, Antithymocyte globulin
Disqualifiers: HIV, Autoimmune disease, Neurological disorder, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this clinical research study is to learn about the safety of giving immune cells called natural killer (NK) cells with chemotherapy to patients with leukemia, lymphoma, or multiple myeloma.
Immune system cells (such as NK cells) are made by the body to attack foreign or cancerous cells. Researchers think that NK cells you receive from a donor may react against cancer cells in your body, which may help to control the disease.
Will I have to stop taking my current medications?
The trial protocol allows patients to continue certain medications like Hydroxyurea and tyrosine kinase inhibitors until shortly before starting the trial treatment. However, other anti-cancer agents and investigational drugs must be stopped. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment CAR.70/IL15-transduced CB-NK cells for blood cancers?
Research shows that cord blood-derived NK cells engineered to express IL-15 and a chimeric antigen receptor (CAR) can effectively kill cancer cells and prolong survival in animal models, suggesting potential for treating blood cancers. Additionally, a study found that using cord blood-derived NK cells as maintenance therapy after stem cell transplantation improved patient outcomes, indicating their promise in reducing relapse rates and enhancing survival.
12345Is the combination of NK cells and chemotherapy safe for treating blood cancers?
Research shows that NK cells engineered with CAR technology, like CAR.70/IL15-transduced CB-NK cells, have been used safely in humans, with only mild infusion reactions reported in some cases. These cells do not cause graft-versus-host disease (a condition where donor cells attack the recipient's body) and have built-in safety measures to limit toxicity.
12567How is the treatment with CAR.70/IL15-transduced CB-NK cells different from other treatments for blood cancers?
This treatment uses engineered natural killer (NK) cells from cord blood, which are modified to express IL-15 and a chimeric antigen receptor (CAR) targeting CD19, allowing them to effectively attack cancer cells without causing graft-versus-host disease (GVHD), a common issue with other cell therapies. Unlike traditional CAR-T cell therapies, this approach offers an 'off-the-shelf' solution that is easier to produce and administer, potentially improving accessibility and reducing costs.
128910Eligibility Criteria
Adults aged 18-75 with certain blood cancers (like leukemia, lymphoma) that have a specific marker called CD70. They must be at least 3 weeks out from their last chemotherapy, have good organ function, and not be pregnant or fathering a child. Participants need to use effective birth control during the study and for three months after.Inclusion Criteria
My blood cancer cells show a high level of CD70.
I can care for myself but may not be able to do active work.
Patients must meet diseases specific eligibility criteria
+21 more
Exclusion Criteria
I am not on high-dose steroids or certain immune treatments right before joining.
I have not had an active autoimmune disease in the last year.
I am currently on immunosuppressive therapy.
+14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Lymphodepleting Chemotherapy
Participants receive lymphodepleting chemotherapy with Cyclophosphamide and Fludarabine phosphate
1-2 weeks
CAR-NK Cell Treatment
Participants receive a single flat dose of CAR.70/IL15-transduced CB-NK cells
1 day
Follow-up
Participants are monitored for safety and effectiveness after treatment
6 months
Participant Groups
The trial is testing whether donor-derived natural killer (NK) cells engineered with CAR.70/IL15 can fight cancer when given alongside chemo drugs Cyclophosphamide and Fludarabine phosphate. It's in early stages to check safety and how well it works.
3Treatment groups
Experimental Treatment
Group I: Fludarabine phosphateExperimental Treatment2 Interventions
Fludarabine is dosed using actual body weight.
Group II: CyclophosphamideExperimental Treatment2 Interventions
Cyclophosphamide is dosed per adjusted body weight for patients weighing \> 20% above their ideal body weight using the calculation.
Group III: CAR.70/IL15-transduced CB-NK cellsExperimental Treatment1 Intervention
Patients will receive a single flat dose of CAR-NK.
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
References
Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. [2021]Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.
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.
piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. [2021]Promising progress has been made in adoptive transfer of allogeneic natural killer (NK) cells to treat relapsed or refractory acute myeloid leukemia (AML). In this regard, chimeric antigen receptor (CAR)-modification of NK cells is considered as a compelling approach to augment the specificity and cytotoxicity of NK cells against AML. Using a non-viral piggyBac transposon technology and human peripheral blood-derived primary NK cells, we generated CAR-NK cells to target NKG2D ligands and demonstrated their in vitro activity in lysing cancer cells expressing the ligands and in vivo efficacy in inhibiting tumor growth in a xenograft KG-1 AML model. We further generated CAR-NK cells co-expressing transgenes for the NKG2D CAR and interleukin-15 (IL-15). The ectopic expression of IL-15 improved the in vitro and in vivo persistence of NKG2D CAR-NK cells, leading to enhanced in vivo tumor control and significant prolongation of mouse survival in the KG-1 AML model. Collectively, our findings demonstrate the ectopic expression of IL-15 as an important means to improve the antileukemic activity of NKG2D CAR-NK cells. Our study further illustrates the feasibility of using the piggyBac non-viral platform as an efficient and cost-effective way for CAR-NK cell manufacturing.
Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. [2022]The prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence.
A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation. [2023]Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.
Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. [2022]Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative "off-the-shelf" carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.
The tricks for fighting against cancer using CAR NK cells: A review. [2022]Natural killer (NK) cells seem to be the most common innate lymphocyte subtypes, and they're known for their ability to guide anti-tumor and anti-viral responses, making them potentially therapeutic. Since NK cells lack polymorphic clonotypic receptors, they must rely on inhibitory receptors to develop, mature, and distinguish between "self" and "non-self." In the clinic, genetically engineered immune cells expressing a chimeric antigen receptor (CAR) that consists of an extracellular antigen recognizing domain connected to an intracellular signaling domain have gained interest. The U.S. food and drug administration (FDA) approved two CAR-T cells, anti-CD19 CARs, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Nevertheless, CAR-T cell therapy is linked to a series of negative side effects, including fatal cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), as well as a lack of regulatory control. CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells, and their abundance in clinical specimens, according to a growing number of studies. In pre-clinical and clinical trials, human primary NK cells and the NK-92 cell line were effectively transduced to express CARs against hematological cancers and solid tumors. Here, it is tried to summarize the development of CAR-NK cells, challenges and coping strategies, as well as managing the challenges and obstacles related to its protection, which promises to eliminate the shortcomings of conventional CARs.
[Allogeneic CAR-NK cells: A promising alternative to autologous CAR-T cells - State of the art, sources of NK cells, limits and perspectives]. [2021]Immunotherapy with chimeric antigen receptor engineered-T cells (CAR-T) has revolutionized the landscape of treatment of relapsed or refractory B-cell. However, the use of autologous T cells has limitations: variable quality of collected effector T cells, duration of the process sometimes incompatible with uncontrolled hemopathy, limited number of available CAR cells, sometimes fatal toxicities, extremely high cost. Natural Killer (NK) cells are an interesting alternative to T cells. NK cells are very powerful cytotoxic effectors that have demonstrated an anti-tumor effect after haploidentical hematopoietic stem cells transplantation or in adoptive cell therapy against a number of solid or hematological tumors. Mainly, they can be used in allogeneic situations without causing major toxic side effects. The sources of NK cells are multiple: cell line, cord blood, peripheral blood, induced pluripotent stem cells. Recent advances in manufacturing engineered CAR-NK cells make it possible to promote antibody-dependent cell-mediated cytotoxicity (ADCC), as well as the activation and persistence of these cells, notably via the cytokine Il-15. The majority of the reports on CAR-NK cells concern pre-clinical or early clinical trials. However, the many advantages of "off-the-shelf" allogeneic CAR-NK cells provide great potential in cancer treatments.
NK Cell-Based Immunotherapy for Hematological Malignancies. [2023]Natural killer (NK) lymphocytes are an integral component of the innate immune system and represent important effector cells in cancer immunotherapy, particularly in the control of hematological malignancies. Refined knowledge of NK cellular and molecular biology has fueled the interest in NK cell-based antitumor therapies, and recent efforts have been made to exploit the high potential of these cells in clinical practice. Infusion of high numbers of mature NK cells through the novel graft manipulation based on the selective depletion of T cells and CD19+ B cells has resulted into an improved outcome in children with acute leukemia given human leucocyte antigen (HLA)-haploidentical hematopoietic transplantation. Likewise, adoptive transfer of purified third-party NK cells showed promising results in patients with myeloid malignancies. Strategies based on the use of cytokines or monoclonal antibodies able to induce and optimize NK cell activation, persistence, and expansion also represent a novel field of investigation with remarkable perspectives of favorably impacting on outcome of patients with hematological neoplasia. In addition, preliminary results suggest that engineering of mature NK cells through chimeric antigen receptor (CAR) constructs deserve further investigation, with the goal of obtaining an "off-the-shelf" NK cell bank that may serve many different recipients for granting an efficient antileukemia activity.
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.