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Methods

Study Design (QUILT-3.080; NCT03586869)! Non-randomized, open-label, single-arm phase Ib/II trial.! Combination chemotherapy, radiotherapy, CD16 haNK, and immunotherapy administered over a 3-week

induction cycle for up to 1 year.! If long-term disease control or objective response is observed, patient has opportunity to cross into 2-week

maintenance cycle, which has reduced therapeutic interventions, for up to 1 year.Enrollment Criteria! Histologically-confirmed metastatic pancreatic adenocarcinoma that has progressed after SoC therapy.! ! 18 years old with ECOG performance status of 0–2.!"#$%&"'(! Primary endpoint: Incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs).! Secondary endpoints: overall response rate (ORR), progression-free survival (PFS), overall survival (OS),

duration of response (DOR), disease control rate (DCR), and quality of life (QoL) by patient-reportedoutcomes (PROs).

! Exploratory endpoints: CA-19-9 level and correlations with subject outcomes, tumor molecular profiles andcorrelations with subject outcomes, therapy-induced changes in immune responses and correlations withsubject outcomes.

Pancreatic Cancer! Pancreatic cancer is an aggressive and lethal disease. Annually, > 50,000 patients in the

US are diagnosed and > 40,000 die from the disease.1! There is a strong unmet need for novel pancreatic cancer treatments. Patients treated with

second-line standard-of-care (SoC) chemotherapy have poor prognoses with a median OS of less than 2-5 months.2

Immunosuppressive Tumor Microenvironment (TME)! Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibroinflammatory

stroma that is primarily immunosuppressive in nature.! Increased numbers ofimmunosuppressive cells in the PDAC TME, such as alternatively-activated (M2)macrophages and regulatory T (Treg) cells, prevent effective antitumor immunity and areassociated with decreased survival." Furthermore, these cells may have a causative role incarcinogenesis, having been shown to infiltrate premalignant pancreatic lesions andincrease with disease progression.5 Additionally, the PDAC TME is characterized by poorvascularization and a dense fibrous stroma, which leads to a hypoxic environment thatsupports tumor cell survival and which also impedes drug delivery and effector immune cellinfiltration.6,7

! We hypothesize that effective and sustained response against pancreatic cancer requires acoordinated approach that: 1. reverses the immune-suppressive tumor microenvironment,2. induces immunogenic cell death (ICD) and 3. re-engages NK and T-cell tumor responseagainst a 4. cascade of tumor antigens. To test this hypothesis, we developed the NANTCancer Vaccine (NCV), which combines metronomic low-dose chemotherapy, radiotherapyand multifaceted immunotherapy.

! In proof-of-concept trials, the NCV was tested in 10 patients with 3rd-line or greaterpancreatic cancer. These trials showed that the NCV could be safely administered in anoutpatient setting, with AEs that were manageable by dose-reduction, and preliminarysurvival results that exceed the standard of care in this heavily-treated population. Webelieve these results warrant further research, and this poster describes our newly-designed trial.

NANT Cancer Vaccine (NCV): An Orchestration of Immunogenic Cell Death by Overcoming Immune Suppression and Activating Natural Killer (NK) and T Cell Therapy in Patients with Greater than 3rd Line Metastatic Pancreatic Cancer

Tara Seery,1 Arvind Shinde,1 Mira Kistler,1 Lennie Sender,1 Anand Annamalai,1 Omid Jafari4 Frank Jones,2 John H. Lee,3 Patrick Soon-Shiong,31Chan Soon-Shiong Institute for Medicine, El Segundo, CA; 2NantCell, Inc, Culver City, CA; 3NantKwest, Inc, Culver City, CA; 4Medical Imaging Center of Southern California, Santa Monica, CA

At a Glance

Disease Type Metastatic Pancreatic Cancer

IndicationHistologically-confirmed metastatic pancreatic adenocarcinoma that has progressed after SoC therapy

Key Enrollment Criteria ECOG 0-2At least 18 years of age

EndpointsPrimary: Incidence of AEs and SAEsSecondary: ORR, PFS, OS, DOR, DCR, and QoL

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NANT Cancer Vaccine (NCV) to Induce Immunogenic Cell Death! The NCV includes metronomic low-dose nab-paclitaxel and stereotactic body radiation therapy (SBRT) with cryopreserved

off-the-shelf, high-affinity CD16 natural killer cells (haNK) and cytokine NK & T-cell superagonist IL-15R"Su/Fc (N-803)combined with adenovirus (Ad5) & yeast tumor-associated antigen (TAA) vaccines, and checkpoint inhibitors (Table 1).

! Chemotherapies such as nab-paclitaxel, as well as SBRT, have been shown to mitigate immunosuppression in the TME.8,9

! Immune-activating cytokines, such as IL-15, have been shown to increase NK and T-cell activation and proliferation.10

! haNK cells have been shown to mediate antibody-dependent cellular cytotoxicity (ADCC) of PD-L1-expressing cells whenadministered with IgG1 antibody avelumab.11 PD-L1 can be expressed on tumor cells, as well as immunosuppressivecells.

! Cancer vaccines provide a means to increase immune recognition of TAAs, by conditioning dendritic and CD8+ T cells tomediate specific antitumor responses.12

! The NCV is a strategy that uses immunomodulatory doses of chemotherapies, in combination with multifaceted immune-activating investigational agents, in an effort to reprogram the TME towards antitumor immunity (Figure 1).

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AcknowledgmentsThis study is sponsored by NantKwest, Inc. Medical writing support was provided by Eric Carlson, MS.

References1) National Cancer Institute. www.cancer.gov. 2) Pelzer U, et al. Eur J Cancer 2011; 47:1676-81. 3)Vonderheide RH and Bayne LJ. Curr Opin Immunol 2013; 25:200-5. 4) Ino Y et al. Br J Cancer 2013;108:914-23. 5) Hiraoka N et al. Clin Canc Res 2006; 12:5423-34. 6) Koong AC et al. Int J Radiat OncolBiol Phys 2000; 48:919-22. 7) Apte MV, et al. Gut 1999; 44:534-41. 8) Cullis J, et al. Cancer Immunol Res2017; 5:182-90. 9) Arnold KM, et al. Cancer Growth Metastasis 1-17. 10) Kim PS. Oncotarget 2016;7:16130-45. 11) Jochems C, et al. Int J Cancer 2017; 141:583-93. 12) Melief CJ, et al. J Clin Invest 2015;194:1013-20. 13) Seery T, et al. Poster at SITC 2018, Washington, DC.

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Fig. 1: QUILT 3.080 NANT Cancer Vaccine – A Orchestration of the Entire Immune System Against Cancer

© 2019 NantKwest, Inc. All Rights Reserved. ASCO GI Symposium 2019. January 17-19, San Francisco, CA, USA

Composition Intended Mechanism of Action in NCV Route of Admin.

Approved or Investigational

5-FU/LV, oxaliplatin, cyclophosphamide, nab-paclitaxel, aldoxorubicin, bevacizumab

Modulate immunosuppressive TME, expose DAMPs on tumor cells, modulate vasculature

Depends on the agent

FDA approved, except for aldoxorubicin

[E1-,E2b-] Ad5 viral vectors containing TAAs: CEA, HER2 (if expressed), brachyury, MUC1

Present tumor-associated antigens (TAAs) to antigen presenting cells (APCs) such as dendritic cells SubQ Investigational

Yeast-based vectors containing TAAs: RAS, CEA, brachyury

Present tumor-associated antigens (TAAs) to antigen presenting cells (APCs) such as dendritic cells SubQ Investigational

Mutated IL-15 / IL-15R" Fc protein complex

Activation and proliferation of NK and CD8+ T cells, without proliferation of Tregs SubQ Investigational

Cryopreserved NK cells with high-affinity CD16 receptor (v/v)

Direct cytotoxicity against tumor cells via recognition of NKG2D ligands, etc, as well as via ADCC (antibody-dependent)

IV Investigational

Anti-PD-L1 monoclonal antibody (avelumab)

Prevents tumor cell expression of PD-L1 from inhibiting T cells. Also allows for ADCC of PD-L1-expressing MDSCs and tumor cells

IV FDA approved

Stereotactic Body Radiotherapy (SBRT)

Hypofractionated doses of radiation that have immunostimulatory effect on TME; cause expression of DAMPs

N/A FDA approved

*Low-dose immunomodulators include FDA-approved drugs 5-FU/LV, oxaliplatin, cyclophosphamide, nab-paclitaxel, and bevacizumab, as well as the investigational drug aldoxorubicin

Table 1: Treatment Components of QUILT 3.080 NANT Pancreatic Cancer Vaccine

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! The NCV is anticipated to reduce immunosuppression in thetumor microenvironment, while increasing immunogenic celldeath, cytotoxic NK and T-cell activity, and innate immuneresponses.8-12

! Previous phase Ib studies of the NCV in 10 metastaticpancreatic cancer patients (QUILT-3.039, QUILT-3.060, QUILT-3.070) used similar treatment regimens to the present study.These studies showed that NCV treatment could beadministered in the outpatient setting without G-CSF support andwith AEs that are manageable by dose-reduction.13

! The ongoing phase Ib study (QUILT-3.080; NCT03586869) seeks to evaluate the overall safety profile of the NCV and toestablish preliminary estimates of efficacy.

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