On May 31, 2019 NantKwest (Nasdaq:NK), a leading clinical-stage, natural killer cell based therapeutics company, NantCell Inc., a privately held immunotherapy company, and NantOmics, a privately held molecular diagnostic company, reported that preclinical and clinical updates will be provided in four abstracts as part of the upcoming Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, IL, which runs from May 31st – June 4th, 2019 (Press release, NantKwest, MAY 31, 2019, https://ir.nantkwest.com/news-releases/news-release-details/nantkwest-nantcell-and-nantomics-provide-updated-preclinical-and?field_nir_news_date_value[min]=2019 [SID1234536734]).
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Dr. Patrick Soon-Shiong, Chairman and CEO of NantKwest, NantCell and NantOmics, commented, "Through a unique collaboration, combining the expertise of NantOmics’ multi-omics diagnostic capabilities with NantKwest’s and NantCell’s therapeutic capabilities, we are pleased to report for the first time the ability to comprehensively analyze a patient’s circulating cell-free RNA (cfRNA) and T Cell Receptor (TCR) repertoire and therapeutically intervene across a range of tumor types. We believe this type of fully integrated diagnostic and therapeutic intervention represent the next-generation in cancer care and shows real promise in improving response rates in comparison to traditionally single agent approaches. We look forward to transitioning these advances in medicine to the clinical care setting as quickly as possible."
Abstract Title: Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater Triple-Negative Breast Cancer (TNBC).
Sub-category: Triple-Negative
Category: Breast Cancer—Metastatic
Meeting: 2019 ASCO (Free ASCO Whitepaper) Annual Meeting
Abstract Number: e12566
Citation: J Clin Oncol 37, 2019 (suppl; abstr e12566)
Author(s):Chaitali Singh Nangia, Mira Kistler, Leonard S. Sender, John H. Lee, Frank R. Jones, Omid Jafari, Patrick Soon-Shiong; Chan Soon Shiong Institute for Medicine, Laguna Hills, CA; Chan Soon Shiong Institute of Medicine, El Segundo, CA; Children’s Hospital of Orange County, Laguna Hills, CA; Sanford Health, Sioux Falls, SD; Etubics Corporation, Seattle, WA; Medical Imaging Center of Southern California, Santa Monica, CA; NantKwest, Culver City, CA
Summary: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: (1) reverses the immune-suppressive tumor microenvironment, (2) induces immunogenic tumor cell death and (3) Re-engages NK and T-cell tumor response against a cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Preliminary results reported on 8 subjects treated with 3rd-line or greater TNBC that have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.
Abstract Title: Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.
Sub-category: Pancreatic Cancer
Category: Gastrointestinal (Noncolorectal) Cancer
Meeting: 2019 ASCO (Free ASCO Whitepaper) Annual Meeting
Abstract Number: e15787
Citation: J Clin Oncol 37, 2019 (suppl; abstr e15787)
Author(s): Tara Elisabeth Seery, Mira Kistler, Leonard S. Sender, John H. Lee, Arvind Manohar Shinde, Anand Annamalai, Patrick Soon-Shiong; Chan Soon Shiong Institute for Medicine, Laguna Hills, CA; Chan Soon Shiong Institute of Medicine, El Segundo, CA; Chan Soon Shiong Institute for Medicine, El Segundo, CA; NantKwest, Culver City, CA; St. Vincent Medical Center, Los Angeles, CA; St. Vincent’s Medical Center, Los Angeles, CA
Summary:
Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. Our hypothesis is that sustained response against pancreatic cancer requires a coordinated approach that: (1) reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and (3) re-engages NK and T-cell tumor response against a cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting.
Preliminary results of 12 subjects treated with 3rd-line or greater metastatic pancreatic cancer. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment
Preliminary Overall Survival of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.
Abstract Title: Correlation between circulating cell-free RNA biomarkers and response during combination immunotherapy in previously refractory metastatic TNBC patients.
Sub-category: Circulating Biomarkers
Category: Developmental Immunotherapy and Tumor Immunobiology
Meeting: 2019 ASCO (Free ASCO Whitepaper) Annual Meeting
Abstract No: e14027
Citation: J Clin Oncol 37, 2019 (suppl; abstr e14027)
Author(s):Chad Garner, Tara Elisabeth Seery, Chaitali Singh Nangia, John H. Lee, Liyang Huang, Leonard S. Sender, Shahrooz Rabizadeh, Patrick Soon-Shiong; NantHealth, Culver City, CA; Chan Soon Shiong Institute for Medicine, Laguna Hills, CA; NantKwest, Culver City, CA; Chan Soon-Shiong Institute for Medicine, El Segundo, CA; NantOmics, LLC, Culver City, CA; CSS Institute of Molecular Medicine, Culver City, CA.
Summary: A commercial liquid biopsy test was included as an exploratory component of an integrated immunotherapy clinical trial in previously refractory metastatic TNBC patients, combining innate, high-affinity natural killer cell (haNK) therapy with adenoviral and yeast-based vaccines and an IL-15 superagonist (NCT 03387085). The purpose of the study was to assess the utility of cell-free circulating RNA (cfRNA) as a predictor of treatment response. The amount and variability of cfRNA was found to be positively correlated with the tumor size. As cfRNA quantity and variability increased or decreased, a corresponding increase or decrease in tumor size was observed, respectively. Not all 18 genes showed consistent patterns of change across the six patients, however the average expression and variability of the 18 genes showed evidence of a correlation with tumor size change from baseline (p-values = 0.08 and 0.03, respectively). Only trace levels of PD-L1 expression were observed in all 6 patients at baseline, prior to the initiation of the combination immunotherapy. Among the 5 patients that showed a reduction in tumor size of at least 10%, 4 also showed an associated increase in cfRNA PD-L1 expression from nearly 0 to normalized values between 2.1 and 6.8. In an exploratory analysis in an ongoing combination immunotherapy clinical trial for TNBC showed that increasing and decreasing cfRNA levels are correlated with increasing and decreasing tumor size, respectively. Increased PD-L1 cfRNA levels are correlated with beneficial treatment response. Liquid biopsy of cfRNA could provide an effective biomarker of treatment response. Clinical trial information: NCT03387085.
Abstract Title: TCR repertoire analysis from peripheral blood for prognostic assessment of patients during treatment
Sub-category: Circulating Biomarkers
Category: Developmental Immunotherapy and Tumor Immunobiology
Meeting: 2019 ASCO (Free ASCO Whitepaper) Annual Meeting
Abstract Number: e14040
Citation:J Clin Oncol 37, 2019 (suppl; abstr e14040)
Author(s): Sadanand Vodala, Andrew Nguyen, Noe Rodriguez, Peter Sieling, Charles Joseph Vaske, Jon Van Lew, Kayvan Niazi, John H. Lee, Patrick Soon-Shiong, Shahrooz Rabizadeh; NantOmics, LLC, Culver City, CA; NantOmics, LLC, Santa Cruz, CA; NantBio, Inc, Culver City, CA; Sanford Health, Sioux Falls, SD; NantKwest, Culver City, CA
Summary:
Immune checkpoint inhibitor therapy offers substantial clinical advantage to a subset of patients but predictive/novel prognostic indicators are still scarce. T cell receptors (TCRs) play a crucial role in adaptive immunity and anti-tumor immune responses. Net diversity of TCR repertoires are altered in patients receiving immune checkpoint inhibitors. To study the prognostic significance of T cell repertoires as a biomarker of immune responses in cancer patients, TCR repertoires were characterized from peripheral blood using high throughput sequencing. Patients that show positive response had TCR clones that were stable, which may indicate an existing immune related response towards their tumor. TCR-targeted therapy potentially allows these existing T-cells to overcome blockade by tumor cells. Patients showing poor response show a TCR repertoire that is constantly changing potentially indicating that the tumor cells are not eliciting a strong T cell specific response. Further functional studies of T cell populations are planned to expand our understanding of T cell based immune therapies.
For additional information, please visit www.nantkwest, www.nantcell.com, and www.nantomics.