On April 8, 2022 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of four preclinical data abstracts focused on its natural killer cell platform and pipeline at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Nkarta, APR 8, 2022, View Source [SID1234611701]).
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"The data we presented at this year’s AACR (Free AACR Whitepaper) meeting highlight the breadth and diversity of our scientific efforts, as we continue to expand our ability to deliver off-the-shelf cell therapies with the potential to disrupt the cancer treatment landscape," said James Trager, PhD, Chief Scientific Officer of Nkarta. "Our research activities are designed to extend the capabilities of NK cells, to lay the groundwork for further pipeline programs – including our pioneering NK+T cell program – and to implement cutting edge translational methods to support our ongoing clinical programs. Our findings reported at AACR (Free AACR Whitepaper) further support exploration of multiply edited CD70 CAR NK cells for clinical application, one focus of our ongoing collaboration with our partners at CRISPR Therapeutics."
Details of the preclinical poster presentations at AACR (Free AACR Whitepaper) follow. Posters are available for download on the Nkarta website (View Source) and on the AACR (Free AACR Whitepaper) e-poster website (View Source).
Presented jointly with CRISPR Therapeutics:
Title: CBLB, CISH and CD70 multiplexed gene knockout with CRISPR/Cas9 enhances cytotoxicity of CD70-CAR NK cells and provides greater resistance to TGF-β for cancer immunotherapy
Session Category:Immunology
Session Title:Preclinical Immunotherapy
Abstract Number:5512
This study illustrates gene editing approaches that enhance the ability of NK cells to target CD70, an antigen highly expressed in a variety of malignant settings, including renal cell carcinoma (RCC) and adenocarcinoma. Editing targets included cytokine inducible SH2-containing protein (CISH) and the E3 ubiquitin ligase CBLB, both negative regulators of NK cell function. Preclinical results showed that a combined editing and engineering strategy to armor primary NK cells via co-expression of the CD70 CAR and a membrane bound form of IL-15 (mbIL-15), together with a triple knockout of CISH, CBLB and CD70 genes using the CRISPR/Cas9 system enhanced anti-tumor activity against renal cell carcinoma (RCC) solid tumor cell lines and provide greater resistance to TGF-β mediated inhibition. These data support the further exploration of CD70/CISH/CBLB triple gene knockout CD70 CAR NK cells for clinical application.
Nkarta presentations:
Title: Surveying surface antigen expression in multiple myeloma preclinical models
Session Category: Tumor Biology
Session Title: Nonclinical Models of Cancer
Abstract Number: 6004
Multiple myeloma (MM) is a progressive hematological cancer with a 5-year survival rate of 53%. Novel therapeutic strategies are being developed to target specific MM surface antigens. Yet, changes in antigen expression through MM progression are poorly understood in the clinic and have not been well characterized in preclinical models. Data presented in this study highlighted antigen expression differences in MM cells when analyzed in mouse tissue compared to in vitro culture. Like the widely variable expression observed between patients, BCMA and CD138 were differentially expressed in the mouse bone marrow between MM models. Commonly targeted antigens in MM also vary kinetically in vivo and can be measured and tracked using flow cytometry. The present findings also support the use of specific cell lines when assessing BCMA, CD38 and CD138-specific immunotherapies or combinatorial approaches to MM treatment.
Title: Development of multiomics approaches to evaluate NKG2D ligand dynamics and anti-tumor immune responses during CAR-NK treatment
Session Category: Clinical Research Excluding Trials
Session Title:Immuno-oncology
Abstract Number:5187
NKX101 is an investigational NK cell therapy engineered to overexpress a chimeric receptor consisting of NKG2D ectodomain, costimulatory signaling motifs, and a membrane-bound form of IL-15. NKX101 is currently under clinical evaluation for treatment of relapsed/refractory acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). To better understand patterns of response to NKX101, we describe the development of several key translational methods, including (i) a single-cell (sc) RNAseq approach to assess gene expression pattern changes in NKX101 and patient cells, (ii) a multiplex IHC panel to monitor NKG2D-ligand expression by cancer cells, and (iii) an ELISA method to detect shed NKG2D-ligand in serum. Employing multiplex IHC and digital image analysis, we found that membrane bound NKG2D-ligands are upregulated in AML and HCC compared to age-matched normal tissue controls. Lastly, using in-house developed ELISAs, we determined that shed NKG2D-ligands can be successfully detected in serum isolated from patients with MDS. Taken together, these assays provide methods for evaluation of NKG2D-ligand dynamics as well as the detection and phenotypic analysis of CAR-NK and immune cell populations in clinical samples.
Title:Immune masking strategies to extend the pharmacokinetics of allogeneic cell therapies
Session Category: Immunology
Session Title:Preclinical Immunotherapy
Abstract Number:5511
Development of immune evasion strategies are underway to improve the pharmacokinetics of allogeneic cell therapies by engineering them to avoid host vs. graft disease, where allogeneic NK and T cells are rapidly targeted by the patient’s own immune system. Hypoimmune strategies are particularly important for the development of allogeneic products containing mixed NK and T cell populations to minimize product cell fratricide. A conventional method for preventing host T rejection of allogenic T cells, is to combine knockout (KO) β-2 microglobulin (β2M) to diminish expression of MHC class I proteins with overexpression of nonclassical MHC class I protein, HLA-E, to evade host NK cell rejection. This study evaluated the effectiveness of HLA-E and other molecules in β2M deficient T cells for inhibiting NK cell cytotoxicity. Concurrently, a high throughput platform was developed to screen NK inhibitory peptides and synthetic ligands to identify novel immune masking strategies for extending allogeneic cell therapy persistence for broad patient populations.
The study showed that the benefit of HLA-E expression in suppressing NK cell cytotoxicity is highly correlated with the expression of NKG2A on the host NK cells. Viral peptides were potent suppressors of NK cell activity, and less dependent on donor NKG2A expression. These data support further exploration of different immune masking strategies in order to extend the pharmacokinetics of allogeneic cell therapies.