Pharmacodynamic Analysis of CAR-T Cell Persistence in Patients with Hematologic Malignancies Treated with NKTR-255, an IL-15 Receptor Agonist That Enhances CD8 + T-Cells: Preliminary Results from a Phase 1 Study
Authors: Turtle Cameron J. , Budde Elizabeth , Patel Krina K. , Perales Miguel-Angel , Cowan Andrew J. , Saeed Hayder , Chavez Julio C. , Hirayama Alexandre V. , Kirchmeier Delaney R. , Janakiram Murali , Wu Kai , Fong Lawrence , Lee Zachary , Dixit Neha , Wang Xiaoli , Kai Kazuharu , Marcondes Mario Q. , Zalevsky Jonathan , Shah Nina 
Published: November 2021

Background: Autologous T cells engineered to express a CD19 or BCMA-specific chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory B-cell non-Hodgkin lymphoma (NHL) and BCMA + multiple myeloma (MM), respectively. However, most patients will eventually relapse, and thus strategies are needed to further improve the efficacy and durability of CAR-T cell products. NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist designed to engage the IL-15 pathway to stimulate and expand natural killer (NK) cells and promote the survival and expansion of memory CD8 + T cells. Preclinical data in B-cell lymphoma xenograft models have shown that NKTR-255 enhanced expansion, survival, and anti-tumor activity of human CD19 CAR-T cells. Furthermore, clinical studies have validated that IL-15 augments anti-tumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Here we report pharmacodynamic (PD) analysis of CAR-T cells from relapsed/refractory (R/R) NHL or MM patients who had prior CAR-T therapy and were subsequently enrolled in an ongoing Phase 1 study of NKTR-255.

Methods: Patients with R/R NHL or MM who progressed following prior CAR-T therapy were enrolled in a Phase 1 open-label trial evaluating safety, tolerability, and PD after treatment with NKTR-255 (NCT04136756). Patients received single-agent NKTR-255 IV administered every 3 weeks. Peripheral blood (PB) mononuclear cell samples were obtained before and at intervals following NKTR-255 infusion. CAR-T cells were identified by flow cytometry (FCM) using proprietary reagents to detect the CD19-CAR and BCMA-CAR in combination with antibodies to identify CD3 +, CD4 +, and CD8 + T cells. PD data were analyzed for patients with measurable CAR-T cells at baseline; fold change was calculated as treatment with NKTR-255 over baseline (baseline=1).

Results: Patient characteristics are shown in Table 1. A total of 6 patients with prior CAR-T/CAR-NK treatment were evaluated for T/ CAR-T cell counts and Ki67 expression to assess proliferation before and after NKTR-255 administration. A total of 3 patients who received NKTR-255, at 1.5 µg/kg (n=1), 4.5 µg/kg (n=1), and 6.0 µg/kg (n=1), had detectable CAR-T cells at baseline. Following NKTR-255 administration, CD3+ CAR-T cell numbers in PB demonstrated a peak average increase of ~1.7-fold (~70% increase) compared to baseline (range 1.4 to 1.8-fold); Table 1. Three patients had low CAR-T/CAR-NK cell counts at baseline and/or post-NKTR-255 treatment. NKTR-255 treatment led to a reversal of the CD4 +:CD8 + CAR-T ratio in 1 patient, with a ~2-fold increase in CD8 + compared with CD4 + CAR-T cells. FCM in PBMC demonstrated an average of ~1.6-fold increase in total CD8 + T-cell with an average 9-fold increase in the percentage of Ki67 +CD8 + T cells in all CAR-T patients following 1 dose of NKTR-255. Among the 6 patients with prior CAR-T/CAR-NK therapy, NKTR-255 was generally well tolerated, with no treatment-related AEs leading to discontinuation, change of dose, or death.

Conclusions: Following treatment with NKTR-255, there was an increase in CAR-T-cells as well as a reversal of the CD4 +:CD8 + ratio in 1 patient. Additionally, NKTR-255 induced expansion of total CD8 + cell fraction with an increase of proliferation index of Ki67 in all reported patients, supporting its role in enhancing the expansion and proliferative ability of cytotoxic T cells. Low baseline CAR-T/CAR-NK cell counts observed in patients may be due to longer time intervals between CAR-T infusion and the first dose of NKTR-255. Although preliminary, these data provide promising evidence of CAR-T cell rescue with NKTR-255 administration and represent a potentially novel means of CAR-T augmentation through enhancement of CD8 + T-cells and supports the further evaluation of NKTR-255 and CAR-T therapy as a potential strategy to enhancing the persistence of CAR-T therapy. Additional CAR-T cell patients are being evaluated following NKTR-255 treatment.

Ethics approval

The study was approved by the institutional review board of each participating site.

Trial registration

ClinicalTrials.gov NCT04136756

Figure 1 Figure 1.

Disclosures

Turtle: Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Amgen: Consultancy; AstraZeneca: Consultancy, Research Funding; TCR2 Therapeutics: Research Funding; Allogene: Consultancy; PACT Pharma: Consultancy; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; T-CURX: Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding. Budde: Merck, Inc: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy. Perales: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Merck: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Cowan: GSK: Consultancy; Bristol Myers Squibb: Research Funding; Nektar: Research Funding; Cellectar: Consultancy; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Harpoon: Research Funding; Sanofi Aventis: Consultancy, Research Funding; Secura Bio: Consultancy. Saeed: Bristol-Myers Squibb Company: Consultancy; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; Nektar Therapeutics: Consultancy, Other: research investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chavez: Kite/Gilead: Consultancy; Abbvie: Consultancy; Epizyme: Speakers Bureau; Beigene: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Adaptive Biotech: Research Funding; Novartis: Consultancy; Astra Zeneca: Research Funding; Morphosys: Speakers Bureau; karyopharm: Consultancy; Merck: Research Funding. Hirayama: Bristol myers Squibb: Honoraria; Novartis: Honoraria. Janakiram: BMS: Honoraria; Fate: Research Funding; Nektar Therapeutics: Research Funding. Fong: Dendreon: Research Funding; Janssen: Research Funding; Merck: Research Funding; Roche genentech: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Bavarian Nordic: Research Funding. Lee: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Dixit: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Wang: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kai: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Marcondes: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zalevsky: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shah: Amgen: Consultancy; Janssen: Research Funding; Indapta Therapeutics: Consultancy; Precision Biosciences: Research Funding; Poseida: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Sanofi: Consultancy; GSK: Consultancy; CSL Behring: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Kite: Consultancy; Oncopeptides: Consultancy; Bluebird Bio: Research Funding; Sutro Biopharma: Research Funding; Teneobio: Research Funding.