2016 Archived Content
To date, most immune-modulatory strategies have focused on agents and cell-based therapies developed to enhance T cell immunity. Recently, there has been a surge of interest in harnessing the relatively underexplored natural killer (NK) cell system for therapeutic intervention. A growing number of studies into elucidating NK cell biology, the development of pharmacological and genetic methods to enhance NK cell anti-tumor immunity, and the ability to expand NK cells ex vivo have set the stage for a new generation of cancer immunotherapies.
Cambridge Healthtech Institute’s inaugural NK Cell-Based Cancer Immunotherapy Symposium will convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss current challenges and opportunities from discovery NK immuno-oncology to clinical studies, share latest technologies and development approaches, as well as to provide updates on preclinical, clinical, and combination studies.
Final Agenda
Monday, September 19
7:00 am Registration Open and Morning Coffee
8:30 Chairperson’s Opening Remarks
Jeffrey Miller, M.D., Professor, Medicine; Deputy Director, Masonic Cancer Center; Roger L. and Lynn C. Headrick Chair in Cancer Therapeutics, University of Minnesota
8:40 Novel Ways to Target and Activate NK Cells to Treat Cancer
Jeffrey Miller, M.D., Professor, Medicine; Deputy Director, Masonic Cancer Center; Roger L. and Lynn C. Headrick Chair in Cancer Therapeutics, University of Minnesota
We have performed a number of clinical trials using NK cell infusions. The major limitation of NK cells is their lack of specificity and their inability to proliferate when targeted through antibody dependent cellular cytotoxicity, which may limit their clinical efficacy. IL-15, a natural cytokine that is critical for NK cell development and homeostasis, will be discussed. We have recently developed a class of molecules that combine antigen specificity and IL-15’s proliferative activity together into a novel class of multifunction molecules we call trispecific killer engagers (TriKEs). Lastly, we have discovered a new subset of NK cells termed adaptive with properties of immunologic memory induced by cytomegalovirus that mediate potent CD16 signaling.
9:10 Off the Shelf, Engineered Allogeneic Natural Killer Cell Therapeutics: aNK, haNK, taNK
Hans Klingemann, M.D., Ph.D., Vice President, Research & Development, NantKwest, Inc.
NantKwest has developed the NK cell line NK-92 into an “off the shelf” activated NK (aNK) cell therapeutic. The cells can be expanded to 1010 within two weeks without feeder layer using FDA compliant medium. The safety of aNK as well as their activity against a broad range of cancers have been confirmed in several phase I clinical trials in the U.S., Canada and Europe. The aNK cells can be administered in the outpatient setting and serve as a universal cell-based therapy without need for individualized patient matching. Moreover, the aNK cell platform has been bioengineered to incorporate a high-affinity antibody binding Fc-receptor (haNK). Both aNK and haNK cells can be equipped with chimeric antigen receptors (CARs) (called taNK) to further optimize targeting and potency in the therapeutic setting.
9:40 The Bispecific CD30/CD16A Antibody AFM13 Induces Strong NK Cell Cytotoxicity towards CD30+ Hodgkin Lymphoma and Is Enhanced by Checkpoint Modulation
Thorsten Gantke, Ph.D., Project Leader, Affimed
AFM13 is an NK cell-engaging CD30/CD16A bispecific tetravalent antibody currently in clinical development. Similar to T-cells, NK cells are also regulated by a number of checkpoints, prompting us to investigate the combination of AFM13 with several immuno-modulatory antibodies to enhance antitumor efficacy. While monotherapy with AFM13 was potent itself, significant synergy was observed in the AFM13 and anti-PD-1 combination in vitro, and in in vivo PDX models with human CD30+ HL tumors. Analysis of the tumors revealed a strong correlation between tumor growth inhibition and levels of tumor-infiltrating NK cells, T-cells, myeloid cells and intratumoral cytokines such as IFN-gamma. In conclusion, our data support strong synergistic antitumor efficacy when AFM13 is combined with anti-PD-1 checkpoint blockade and provide strong evidence for crosstalk between innate and adaptive immunity induced by AFM13-recruited human NK cells.
10:10 Coffee Break
10:40 Harnessing Adaptive NK Cells in Cancer Therapy
Karl-Johan Malmberg, M.D., Ph.D., Professor, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital
We have recently completed a Phase I/II clinical trial with transfer of haploidentical NK cells to patients with high-risk myelodysplastic syndrome. Six of the 16 treated patients achieved morphological complete remission and five of these underwent allogeneic stem cell transplantation resulting in long-term survival in four patients. The quality and number of infused NK cells as well as their transient engraftment in the recipient correlated with decrease in mutational burden and clinical outcomes. These results suggest that adoptive transfer of allogeneic NK cells may hold utility as a bridge to transplant in patients who are refractory to induction therapy. Current efforts to selectively expand metabolically optimized adaptive NK cells for the next generation NK cell cancer immunotherapy will be discussed.
11:10 Update on Systemic and Locoregional Cancer Immunotherapy with IL-21-Expanded NK Cells
Dean Anthony Lee, M.D., Ph.D., Professor, Pediatrics; Director, Cellular Therapy and Cancer Immunotherapy Program, Nationwide Children’s Hospital; James Comprehensive Cancer Center/Solove Research Institute, The Ohio State University
The ability to generate clinical-grade NK cell products of sufficient purity, number, and function has enabled broader application of adoptive NK cell therapy in clinical trials. We translated our IL-21-based NK cell expansion platform to clinical grade and scale and initiated 7 clinical trials that administer NK cell immunotherapy with high cell doses or repeated dosing in transplant, adjuvant, or stand-alone settings. These trials have collectively delivered approximately 150 infusions to over 60 patients at doses of up to 10e8/kg. We will discuss the importance of STAT3 signaling in this setting, describe early outcome and correlative data from these studies, and present preclinical data supporting future clinical trials that build on this platform.
11:40 Sponsored Presentation (Opportunity Available)
12:10 pm Enjoy Lunch on Your Own
1:40 Chairperson’s Opening Remarks
Karl-Johan Malmberg, M.D., Ph.D., Professor, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital
1:50 oNKord® - The First Allogeneic, “Off-the-Shelf” NK Cell Product in Oncology
Jan Spanholtz, Ph.D., CSO, Glycostem Therapeutics
Glycostem Therapeutics is developing allogeneic cellular immunotherapy to treat various types of cancer. Glycostem’s patented industrial applicable production platform technology enables the generation of a multitude of products like expanded stem cells, NK cells, dendritic cells or others. The universal allogeneic treatment principle, allowed by the unrestricted use of immune cells in various types of cancer, is enabled by unlimited source of cord blood stem cells. Glycostem’s production platform technology and the allogeneic therapeutic use serves as basis for off-the-shelf products enabling blockbuster potential. Glycostem’s lead product are Natural Killer (NK) cells derived from hematopoietic stem and progenitor cells. The technology enables ex vivo generation of high numbers of very pure and highly activated NK cells for clinical applications. The current NK cell product (oNKord®) has successfully passed phase I clinical trial (elderly AML patients) showing safety and biological activities including response on MRD leading to prolonged PFS and OS. These results show that oNKord® can be safely infused in elderly AML patients. After infusion, NK cells repopulate, mature and migrate to BM. The reduction in MRD lead to a sustained CR in elderly AML patients resulting in an improved overall survival (90% after 1 year) for AML patients at this age.
2:20 Potent ex vivo Expanded, Human CD34+ Cord Blood-Derived Natural Killer Cells for Cancer Immunotherapy
Xiaokui Zhang, Ph.D., Director, Research & Development, Celgene Cellular Therapeutics
Clinical studies suggest that adoptive transfer of allogeneic natural killer (NK) cells represent a promising treatment for patients with hematological malignancies and solid tumors. Celgene Cellular Therapeutics has established a cultivation process to generate human NK cells from umbilical cord blood (UCB) CD34+ cells with substantial cytolytic activity against several human tumor cell lines, primary AML and primary MM cells. A Phase 1, multicenter, open-label, dose-escalating safety study of PNK-007 infusion with subcutaneous recombinant human IL-2 in adults with relapsed and/or refractory AML will be discussed.
2:50 Naïve Human-Induced Pluripotent Stem Cells: An Ideal Platform for Developing Off-the-Shelf and Genetically Enhanced Natural Killer Cell Adoptive Therapeutics
Bahram (Bob) Valamehr, Ph.D., MBA, Executive Director, Reprogramming Biology, Fate Therapeutics Inc.
Harnessing the power of human-induced pluripotent stem cell (hiPSC) technology represents a powerful approach to make cell-based immunotherapies available to a wide range of patients through the generation of a consistent “off-the-shelf” source of cellular therapeutics genomically engineered with enhanced potency, persistence, targeting and safety mechanisms. By coupling the unique capacity of our naïve hiPSC platform to efficiently facilitate multiple genomic modifications at the single hiPSC level with our ability to accurately recapitulate the stages of early embryonic hematopoiesis towards the definitive program, we demonstrate a viable method for the derivation of engineered hematopoietic cells, including NK cells, from hiPSCs in a highly scalable manner. The hematopoietic cells generated can be successfully cryopreserved and banked, serving as a highly stable feedstock for subsequent derivation of various cell types for therapeutic use. Furthermore, we demonstrate that when properly designed, hiPSC-level engineered modalities targeted to safe harbor loci, such as AAVS1, are highly active during the hematopoietic differentiation process and NK cell maturation. Characterization of hiPSC-derived NK cells demonstrates that these cells can be differentiated without the generation of substantial CD3+ T cell contamination, are phenotypically and functionally mature (including expression of CD16, KIR3DL1, NCRs and CD94) and exhibit the canonical NK cell functions of tumor cytotoxicity and production of effector cytokines in response to tumor challenge.
3:20 Refreshment Break
4:00 Autologous ex vivo Expanded NK Cells for Solid Tumor Immunotherapy
Ali Ashkar, D.V.M., Ph.D., Professor, Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University
In healthy individuals, the innate immune system, particularly natural killer (NK) cells, are crucial for immune surveillance. In patients with advanced tumors number and activity of NK cells decline significantly. Recent advances in NK cell expansion and activation have generated renewed interest in adoptive NK cell therapy for cancers. We have expanded NK cells from blood of breast, lung and ovarian cancer patients and have investigated their activities against autologous primary tumor cells. In addition, we have established xenograft models with the primary tumors to study the antitumor activities of autologous NK cells against primary tumor cells in vivo. Ex vivo expanded NK cells survive and proliferate in vivo in the presence of autologous PBMCs.
4:30 Novel CARs Introduced into NK Cells Facilitate Potent Tumor Cell Killing that Results in Tumor Regression
Rohit Duggal, Ph.D., Director, Experimental Cellular Therapy, Sorrento Therapeutics
This presentation features an introduction of chimeric antigen receptors (CARs), which provide homing and specificity to cytotoxic cells of the immune system. Novel CARs isolated from Sorrento’s G-MAB library targeting various tumor antigens will be described. The characterization of the NK cells modified to express these CARs will also be described.
5:00 Understanding of NK Cell Effector Functions: A Single-Cell Lab-on-a-Chip Perspective
Tania Konry, Ph.D., Assistant Professor, Department of Pharmaceutical Sciences, Northeastern University
Natural Killer (NK) cells are an essential component of innate immunity that actively inhibit tumor development. Here we present a novel single-cell method of analyzing the mechanisms underlying the cellular interactions of NK cells with multiple myeloma cells. The integrated droplet microfluidics device developed by our group permits compartmentalization of cell pairs and secreted products within sub-nanoliter volumes and thereby controls cell-to-cell communication by limiting it to interactions between the co-encapsulated cells. It allows monitoring of both contact-dependent (immune synapse formation, delivery of lytic hits) and contact-independent cellular interactions (release of cytokines, chemokines) simultaneously. This dynamic single-cell experimental model is expected to provide preclinical information particularly relevant to the scenario of NK cell-cancer cell interactions.
5:30 Close of Symposium
* Separate registration required for Short Courses, Symposia, Training Seminar