NK Cell Therapy + Chemotherapy for Advanced Kidney, Lung, or Bone Cancer
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: Anticancer agents, Immunosuppressives
Disqualifiers: Infections, Autoimmune disease, Neurological disorders, others
No Placebo Group
Trial Summary
What is the purpose of this trial?To find a recommended dose of donated NK cells that can be given with lymphodepleting chemotherapy to patients with advanced renal cell carcinoma, mesothelioma, or osteosarcoma. The effects of this therapy will also be studied.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, such as cytotoxic chemotherapy, tyrosine kinase inhibitors, or other targeted therapies, at least 2 weeks before starting the trial's lymphodepleting chemotherapy. If you are on systemic steroid therapy, you may need to stop or adjust your dose, unless it's a low dose or specific type like topical or inhaled steroids.
What data supports the effectiveness of the treatment NK Cell Therapy + Chemotherapy for Advanced Kidney, Lung, or Bone Cancer?
Research shows that NK cells engineered with chimeric antigen receptors (CARs) and interleukin-15 (IL-15) have demonstrated strong anti-tumor activity in preclinical studies, particularly against leukemia and lymphoma. These engineered NK cells can be produced from cord blood and have shown potential as a safe and effective 'off-the-shelf' cancer treatment, offering advantages over traditional CAR-T cell therapies.
12345Is NK cell therapy safe for humans?
Research shows that NK cell therapy, especially using engineered NK cells from cord blood, is generally safe for humans. 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.
12346How is the NK Cell Therapy + Chemotherapy treatment different from other treatments for advanced kidney, lung, or bone cancer?
This treatment uses engineered natural killer (NK) cells from cord blood, which are modified to express IL-15 and a chimeric antigen receptor (CAR) to target cancer cells. Unlike traditional therapies, these NK cells can be used 'off-the-shelf' without causing severe side effects like graft-versus-host disease, making them a novel and potentially safer option for cancer treatment.
12789Eligibility Criteria
Adults aged 18-80 with advanced renal cell carcinoma, mesothelioma, or osteosarcoma showing CD70 expression can join. They must have proper organ function and agree to birth control use. Exclusions include serious medical conditions, recent heart issues or major surgery, other cancer treatments or investigational drugs within specific time frames.Inclusion Criteria
I've had targeted radiation before chemo, but still have untreated cancer areas.
I can do all my daily activities without help.
My cancer shows high CD70 levels in tests.
+10 more
Exclusion Criteria
I do not have any serious health conditions that could make the treatment unsafe for me.
I have active hepatitis B or C, or HIV with a detectable viral load.
I have symptoms or uncontrolled issues in my brain or spinal cord.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Lymphodepleting Chemotherapy
Participants receive lymphodepleting chemotherapy prior to NK cell infusion
1-2 weeks
NK Cell Infusion
Participants receive CAR.70/IL15-transduced cord blood-derived NK cells at assigned dose levels
1 week
Follow-up
Participants are monitored for safety, tolerability, and antitumor activity after treatment
4-8 weeks
Participant Groups
The trial is testing the safety and dosage of CAR.70/IL15-transduced CB-derived NK cells combined with lymphodepleting chemotherapy (Fludarabine phosphate and Cyclophosphamide) in patients with certain advanced cancers to see how well they work together.
1Treatment groups
Experimental Treatment
Group I: Chemotherapy and NK Cell InfusionExperimental Treatment3 Interventions
Participants will be assigned to a dose level of NK cells. A computer will decide by chance which of the dose level you will receive, and this will not be based on the doctor's or patient's decision. Up to 5 dose levels of NK cells will be tested. Each new patient will receive a different dose. If any dose shows to be not tolerable, this dose and the higher doses will not be given anymore.
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
[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.
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-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.
GMP-Compliant Universal Antigen Presenting Cells (uAPC) Promote the Metabolic Fitness and Antitumor Activity of Armored Cord Blood CAR-NK Cells. [2022]Natural killer (NK) cells are innate lymphocytes recognized for their important role against tumor cells. NK cells expressing chimeric antigen receptors (CARs) have enhanced effector function against various type of cancer and are attractive contenders for the next generation of cancer immunotherapies. However, a number of factors have hindered the application of NK cells for cellular therapy, including their poor in vitro growth kinetics and relatively low starting percentages within the mononuclear cell fraction of peripheral blood or cord blood (CB). To overcome these limitations, we genetically-engineered human leukocyte antigen (HLA)-A- and HLA-B- K562 cells to enforce the expression of CD48, 4-1BBL, and membrane-bound IL-21 (mbIL21), creating a universal antigen presenting cell (uAPC) capable of stimulating their cognate receptors on NK cells. We have shown that uAPC can drive the expansion of both non-transduced (NT) and CAR-transduced CB derived NK cells by >900-fold in 2 weeks of co-culture with excellent purity (>99.9%) and without indications of senescence/exhaustion. We confirmed that uAPC-expanded research- and clinical-grade NT and CAR-transduced NK cells have higher metabolic fitness and display enhanced effector function against tumor targets compared to the corresponding cell fractions cultured without uAPCs. This novel approach allowed the expansion of highly pure GMP-grade CAR NK cells at optimal cell numbers to be used for adoptive CAR NK cell-based cancer immunotherapy.
How do we manufacture clinical-grade interleukin-15-stimulated natural killer cell products for cancer treatment? [2018]Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use.
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.
Exploiting Human NK Cells in Tumor Therapy. [2020]NK cells play an important role in the innate defenses against tumor growth and metastases. Human NK cell activation and function are regulated by an array of HLA class I-specific inhibitory receptors and activating receptors recognizing ligands expressed de novo on tumor or virus-infected cells. NK cells have been exploited in immunotherapy of cancer, including: (1) the in vivo infusion of IL-2 or IL-15, cytokines inducing activation and proliferation of NK cells that are frequently impaired in cancer patients. Nonetheless, the significant toxicity experienced, primarily with IL-2, limited their use except for combination therapies, e.g., IL-15 with checkpoint inhibitors; (2) the adoptive immunotherapy with cytokine-induced NK cells had effect on some melanoma metastases (lung), while other localizations were not affected; (3) a remarkable evolution of adoptive cell therapy is represented by NK cells engineered with CAR-targeting tumor antigens (CAR-NK). CAR-NK cells complement CAR-T cells as they do not cause GvHD and may be obtained from unrelated donors. Accordingly, CAR-NK cells may represent an "off-the-shelf" tool, readily available for effective tumor therapy; (4) the efficacy of adoptive cell therapy in cancer is also witnessed by the αβT cell- and B cell-depleted haploidentical HSC transplantation in which the infusion of donor NK cells and γδT cells, together with HSC, sharply reduces leukemia relapses and infections; (5) a true revolution in tumor therapy is the use of mAbs targeting checkpoint inhibitors including PD-1, CTLA-4, the HLA class I-specific KIR, and NKG2A. Since PD-1 is expressed not only by tumor-associated T cells but also by NK cells, its blocking might unleash NK cells playing a crucial effector role against HLA class I-deficient tumors that are undetectable by T cells.
The prospect of genetically engineering natural killer cells for cancer immunotherapy. [2022]The use of natural killer (NK) cells in cancer immunotherapy demonstrates promising potential, yet its efficacy is often limited due to the loss of tumor-killing capacity and lack of specificity in vivo. Here, we review current approaches to confer enhanced tumor-killing capacity and specificity by genetic engineering. Increasing sensitivity to cytokines and protecting NK cells from the immune checkpoint endowed sustainability of NK cells in the tumor microenvironment. Transducing chimeric antigen receptor (CAR) in NK cells successfully targeted both hematologic and solid tumors in preclinical models. The use of human pluripotent stem cells as an expandable and genetically amenable platform offers a stable source of engineered NK cells for cancer immunotherapy. We highlight that CAR-NK cells from human pluripotent stem cells are a promising approach for cancer immunotherapy.
Chimeric antigen receptor-engineered NK cells: new weapons of cancer immunotherapy with great potential. [2022]Chimeric antigen receptor (CAR)-engineered T (CAR-T) cells have obtained prominent achievement in the clinical immunotherapy of hematological malignant tumors, leading to a rapid development of cellular immunotherapy in cancer treatment. Scientists are also aware of the prospective advantages of CAR engineering in cellular immunotherapy. Due to various limitations such as the serious side effects of CAR-T therapy, researchers began to investigate other immune cells for CAR modification. Natural killer (NK) cells are critical innate immune cells with the characteristic of non-specifically recognizing target cells and with the potential to become "off-the-shelf" products. In recent years, many preclinical studies on CAR-engineered NK (CAR-NK) cells have shown their remarkable efficacy in cancer therapy and their superiority over autologous CAR-T cells. In this review, we summarize the generation, mechanisms of anti-tumor activity and unique advantages of CAR-NK cells, and then analyze some challenges and recent clinical trials about CAR-NK cells therapy. We believe that CAR-NK therapy is a promising prospect for cancer immunotherapy in the future.