A Phase 2/3, Randomized, Double Blind, Placebo-controlled, Multicenter Study of NKTR-255 vs Placebo Following CD19-directed CAR-T Cell Therapy in Patients With Relapsed/Refractory Large B-cell Lymphoma
This study will evaluate the safety and efficacy of NKTR-255 following CD19-directed chimeric antigen (CAR)-T cell therapy in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. T cells are infection fighting blood cells that can kill tumor cells. Chimeric antigen (CAR)-T cell product consists of genetically engineered T-cells, modified to recognize CD19, a protein on the surface of cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19-positive cancer cells. Giving NKTR-255 following the treatment with CD19 CAR-T cell therapy may work better in treating large B-cell lymphoma than either drug alone.
A Phase Ib Open-Label Study Evaluating the Safety and Efficacy of NKTR-255 in Combination With CD19-Directed CAR-T Cell Therapy in Patients With Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)
This phase Ib trial studies the effects of NKTR-255 in combination with chimeric antigen (CAR)-T cell therapy and to see how well they work in treating patients with large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. T cells are infection fighting blood cells that can kill tumor cells. Lisocabtagene maraleucel is a CAR-T cell product that consists of genetically engineered T cells, modified to recognize CD19, a protein on the surface of cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19-positive cancer cells. Giving NKTR-255 together with lisocabtagene maraleucel may work better in treating large B-cell lymphoma than either drug alone.
A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR-T cell immunotherapy.
作者: Alexandre V Hirayama ; Cassie K Chou ; Takahiro Miyazaki ; Rachel N Steinmetz ; Henna A Di ; Simon P Fraessle ; Jordan Gauthier ; Salvatore Fiorenza ; Reed M Hawkins ; Willem W Overwijk ; Stanley R Riddell ; A Mario Q Marcondes ; Cameron J Turtle
Chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapies targeting CD19 represent a new treatment for patients with relapsed/refractory (R/R) B-cell malignancies. However, CAR-T therapy fails to elicit durable responses in a significant fraction of patients. Limited in vivo proliferation and survival of infused CAR-T are key causes of failure. In a phase I/II clinical trial of CD19 CAR-T for B-cell malignancies (NCT01865617), low serum interleukin-15 (IL-15) concentration after CAR-T infusion was associated with inferior CAR-T kinetics. IL-15 supports T cell proliferation and survival, and therefore supplementation of IL-15 may enhance CAR-T therapy. However, clinical use of native IL-15 is challenging due to its unfavorable pharmacokinetics and toxicity. NKTR-255 is a polymer-conjugated IL-15 that engages the entire IL-15 receptor complex (IL-15R/IL-2Rβɣ) and exhibits reduced clearance, providing sustained pharmacodynamic responses. We investigated pharmacokinetics and immune cell pharmacodynamics in non-human primates treated with NKTR-255 and found that NKTR-255 enhanced in vivo proliferation of T and NK cells. In vitro, NKTR-255 induced dose-dependent proliferation and accumulation of human CD19 CAR-T, especially at low target cell abundance. In vivo studies in lymphoma-bearing immunodeficient mice demonstrated enhanced antitumor efficacy of human CD19 CAR-T. In contrast to mice treated with CAR-T alone, those that received CAR-T and NKTR-255 had markedly higher CAR-T counts in blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation/exhaustion assessed by Ki-67 and inhibitory receptor co-expression. These data support an ongoing phase I clinical trial of combined CD19 CAR-T and NKTR-255 for R/R B-cell malignancies. This trial is registered at www.clinicaltrials.gov as NCT01865617.
Improving NK Cell Function in Multiple Myeloma with NKTR-255, a Novel Polymer-Conjugated Human IL-15.
作者: Rafael Alonso Fernández ; Jessica Encinas ; Laetitia Pierre-Louis ; Yao Yao ; Yan Xu ; Shidai Mu ; Joaquin Martínez-López ; Daniel Primo ; Takahiro Miyazaki ; Rao H Prabhala ; Kenneth C Anderson ; Willem W Overwijk ; Nikhil C Munshi ; Mariateresa Fulciniti
Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal for new immunotherapeutic approaches, increasing tumor cell recognition, avoiding tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance towards an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of MM patients, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared to placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.
2021-10-01·Journal of Clinical Investigation1区 · 医学
Insights into the anticancer mechanisms of interleukin-15 from engineered cytokine therapies
1区 · 医学
作者: Bernstein, Zachary J. ; Spangler, Jamie B.
Innovative approaches in the field of cytokine engineering are revolutionizing the cancer therapeutic landscape. The IL-15 cytokine is particularly enticing as a cancer immunotherapy due to its natural propensity for stimulating the proliferation and activation of NK and CD8+ T cells. In a recent IL-15 engineering approach, the cytokine was conjugated to polyethylene glycol, and the resulting molecule (NKTR-255) exhibited potent antitumor activities. In this issue of the JCI, Robinson et al. mechanistically explored NKTR-255 and compared its immune profile to that of the unconjugated IL-15 cytokine. The authors found that NKTR-255 employs distinct activities on NK compared with CD8+ T cells. NKTR-255 signaling also showed less dependence on the expression of the IL-15 receptor-α (IL-15Rα) chain compared with unconjugated IL-15. Collectively, these findings will advance IL-15-based clinical therapies and, more generally, benefit the field of cancer immunotherapy.
Multiple companies are working on IL-15 candidates.
Sotio Biotech has dealt another blow to attempts to establish cytokines as a cornerstone of cancer care, scrapping ongoing studies of its IL-15 superagonist after seeing insufficient efficacy in the clinic.
The Czech biotech raised 280 million euros ($295 million) to advance the IL-15 candidate, nanrilkefusp alfa, late in 2021. Months later, Bristol Myers Squibb and Nektar Therapeutics’ closely watched IL-2 program imploded, prompting soul searching in the cytokine space, but Sotio forged ahead with its work on the structurally similar IL-15.
Now, Sotio faces its own dark day. A look at interim data on nanrilkefusp alfa, also known as SOT101, has revealed “insufficient efficacy to warrant further development in larger randomized trials” in the settings targeted to date, prompting Sotio to immediately stop enrollment in three studies.
The clinical trials were evaluating nanrilkefusp alfa in combination with Eli Lilly’s Erbitux and Merck & Co.’s Keytruda in solid tumor patients. While Sotio has abandoned hopes of bringing those combinations to market, it continues to see potential to pair its IL-15 drug candidate with other modalities such as cell therapies. The biotech has seen “promising” preclinical data on a cell therapy combination.
Multiple other companies are working on IL-15 candidates. ImmunityBio got as far as filing for approval of its antibody cytokine fusion protein, only for the FDA to reject the request on manufacturing grounds. Nektar Therapeutics is running a phase 2/3 clinical trial of an IL-15 receptor agonist, NKTR-255. Novartis is closing in on the end of a phase 1 trial of its IL-15 prospect, NIZ985, but stopped enrollment well short of its goal.
Sotio retains an interest in cytokines, noting that its next-generation PD-1-inhibiting candidate is set to enter the clinic in the second quarter of next year. But its R&D pipeline now skews toward antibody-drug conjugates, a modality with a star that has risen as enthusiasm for cytokines has fallen away.
SAN FRANCISCO, Sept. 27, 2023 /PRNewswire/ -- Nektar Therapeutics (Nasdaq: NKTR) announced today that it has entered into a new clinical study collaboration with Cellular Biomedicine Group Inc. ("CBMG"). The study will evaluate Nektar's NKTR-255, a novel interleukin-15 (IL-15) receptor agonist, in combination with CBMG's C-TIL051, a tumor-infiltrating lymphocyte (TIL) therapy, in advanced non-small cell lung cancer (NSCLC) patients that are relapsed or refractory to anti-PD-1 therapy.
NKTR-255 is a novel polymer-conjugated human IL-15 receptor agonist currently being studied in two separate Phase 2 studies in combination with cell therapies and immunotherapies. Preclinical and early clinical data suggest that IL-15 can improve proliferation and persistence of cellular therapies including TIL, TCR, and CAR-T therapies to increase specific anti-tumor activity.
"Early results have shown that NKTR-255 has the potential to emerge as a valuable adjuvant therapy for a range of cell therapy platforms," said Mary Tagliaferri, M.D., Chief Medical Officer at Nektar Therapeutics. "We are excited to partner with CBMG, a leader in the development of the next generation of cell therapies, to evaluate this novel combination in the clinical setting of lung cancer. Combining NKTR-255 and C-TIL051 could have the potential to deliver deep and durable objective responses with a well-tolerated regimen to patients battling relapsed or refractory NSCLC."
C-TIL051 is an autologous adoptive cell therapy being developed by CBMG that is comprised of a patient's ex vivo expanded lymphocytes using CBMG's proprietary manufacturing process. The development of C-TIL051 was based on initial NSCLC TIL studies demonstrating encouraging safety and efficacy results (NCT03215810, NCT03645928). In October of last year, CBMG received clearance of an Investigational New Drug (IND) application for C-TIL051 for late-stage NSCLC patients that are relapsed or refractory to anti-PD-1 therapy.
Under the new collaboration, CBMG will add NKTR-255 to its ongoing CBMG-sponsored Phase 1 clinical trial evaluating C-TIL051 in NSCLC patients who have relapsed on or were refractory to anti-PD-1 therapy, which is being conducted at Duke Cancer Institute (NCT05676749). The study is expected to enroll a total of 20 patients. Nektar will contribute NKTR-255 supply for the study. Nektar and CBMG will each maintain existing global rights to their respective investigational medicines.
NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body's innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.
Preclinical and early clinical findings suggest IL-15 can improve proliferation and persistence of cellular therapies including TIL, TCR, and CAR-T therapies to increase specific anti-tumor activity.
NKTR-255 is currently being studied in two separate Phase 2 studies in combination with cell therapies and immunotherapy. A Phase 2/3 study is underway that combines NKTR-255 with approved CAR-T cell therapies in patients with diffuse large B-cell lymphoma, which is currently recruiting (NCT05664217). NKTR-255 is also being studied in a Phase 2 study in combination with avelumab as a maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma in the Merck KGaA-sponsored JAVELIN Bladder Medley trial (NCT05327530), as well as in combination with durvalumab in patients with locally advanced NSCLC in an IST conducted at M.D. Anderson Cancer Center.
In addition, there are two ongoing investigator sponsored trials (ISTs) evaluating NKTR-255 as adjunct therapy following a CAR-T cell therapy. Fred Hutchinson Cancer Center is conducting a Phase 1 study evaluating NKTR-255 following lisocabtagene maraleucel treatment in patients with relapsed/refractory large B-cell lymphoma (NCT05359211), and Stanford University is conducting a Phase 1 study evaluating NKTR-255 following an investigational CD19/22 CAR-T cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (NCT03233854).
About Nektar Therapeutics
Nektar Therapeutics is a biopharmaceutical company with a robust, wholly owned R&D pipeline of investigational medicines in immunology and oncology as well as a portfolio of approved partnered medicines. Nektar is headquartered in San Francisco, California, with additional manufacturing operations in Huntsville, Alabama. Further information about the company and its drug development programs and capabilities may be found online at .
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements which can be identified by words such as: "will," "may," "evaluate," "develop," "provide," "potential" and similar references to future periods. Examples of forward-looking statements include, among others, statements regarding the therapeutic potential of, and future development plans for NKTR-255, and our other drug candidates in research programs, the prospects and plans for our collaborations with other companies, the timing of the initiation of clinical studies and the data readouts for our drug candidates. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results to differ materially from those indicated in the forward-looking statements include, among others: (i) our statements regarding the therapeutic potential of NKTR-255, and our other drug candidates are based on preclinical and clinical findings and observations and are subject to change as research and development continue; (ii) NKTR-255 and our other drug candidates are investigational agents and continued research and development for these drug candidates is subject to substantial risks, including negative safety and efficacy findings in ongoing clinical studies (notwithstanding positive findings in earlier preclinical and clinical studies); (iii) NKTR-255 and our other drug candidates are in various stages of clinical development and the risk of failure is high and can unexpectedly occur at any stage prior to regulatory approval; (iv) the timing of the commencement or end of clinical trials and the availability of clinical data may be delayed or unsuccessful due to challenges caused by the COVID-19 pandemic, regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, changing standards of care, evolving regulatory requirements, clinical trial design, clinical outcomes, competitive factors, or delay or failure in ultimately obtaining regulatory approval in one or more important markets; (v) we may not achieve the expected cost savings we expect from our 2022 corporate restructuring and reorganization plan or our 2023 cost restructuring plan and we may undertake additional restructuring and cost-saving activities in the future, (vi) patents may not issue from our patent applications for our drug candidates, patents that have issued may not be enforceable, or additional intellectual property licenses from third parties may be required; and (vii) certain other important risks and uncertainties set forth in our Annual Report on Form 10-Q filed with the Securities and Exchange Commission on August 9, 2023. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.
Vivian Wu of Nektar Therapeutics
David Rosen of Argot Partners
SOURCE Nektar Therapeutics
The new IDMO smart factory at Bridgewater in New Jersey is spread over 118,000ft². Credit: Cellares.
Integrated development and manufacturing organisation (IDMO) Cellares has raised $255m in a Series C financing round for a
cell therapy development facility
at Bridgewater in New Jersey, US.
New investor Koch Disruptive Technologies led the funding round and its managing director David Mauney will join Cellares’s board of directors.
Head and Neck Squamous Cell Carcinoma - Global Drug Forecast and Market Analysis to 2030
LOA and PTSR Model - NKTR-255 in Squamous Cell Carcinoma
Bristol-Myers Squibb Co
Decheng Capital LLC
Koch Disruptive Technologies
Willett Advisors LLC
The financing round saw participation from Bristol Myers Squibb, Willett Advisors and DFJ Growth, along with current investors Eclipse, Decheng Capital and 8VC.
To be spread over 118,000ft², the new commercial-scale IDMO smart factory will feature robotics, tailored technology and interconnected software.
The facility will manufacture 40,000 cell therapy batches annually.
IDMO smart factories use combined technologies to manufacture ten times more cell therapy batches annually versus standard CDMO plants, utilising the same labour and footprint.
Cellares’s technology adoption partnership programme aids the collaboration of cell therapy developers in automating and transferring technology manual processes onto the manufacturing platform within six months.
This platform merges all the technologies needed to carry out the operations in the unit.
Cellares CEO Fabian Gerlinghaus stated: “The creation of the first IDMO marks the beginning of a new era, in which cell therapies will finally be able to reach those in need.
“We’ve developed integrated technologies for the entire drug development and manufacturing lifecycle.
“Now we’re leveraging these technologies to offer global manufacturing services for the living drugs of the 21st century.”
Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.
Editorial content is independently produced and follows the
of journalistic integrity. Topic sponsors are not involved in the creation of editorial content.
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