In this episode we’re continuing our look at the innate immune system by considering the potential of Natural Killer or NK cells for cancer immunotherapy:
Why do NK cells matter, what do they see, and how can then be targeted?
Just like with T cells, it turns out there are a number of different therapeutic approaches that can be used for NK cells, ranging from allogeneic cell therapies and CAR NK cells to BiKEs, TriKEs, as well as monoclonal antibodies and small molecules that target NK checkpoints.
In this episode we’ll hear experts from the United States, France and Australia give us some examples of how they are translating NK cell biology into innovative and novel cancer immunotherapies. It’s an exciting and emerging field to watch.
This episode is not intended to be an exhaustive review – we could do a whole series just on NK cells – but much like sending postcards from your holidays, it is intended to offer a few flavours and snapshots of possibilities that hopefully capture your interest to explore further.
Mike Caligiuri, MD is Physician-in-Chief and President of the City of Hope National Medical Center in California. He’s also the past President of AACR.
He’s spent the last 30 years working on the biology of NK cells and has developed NK checkpoint antibodies. He also talks about some of his research experience with CAR modified NK cells (CAR NK cells).
In this episode, he explains the importance of basic science, and how if you can’t understand how the NK cells ‘see’ in the immune system, you can’t understand what they do, and therefore how to target them.
Dr Caligiuri inspired the title for this episode by telling us about his story, “my whole life’s been in the shadow of T cells.”
- Chu et al., (2014) CAR-Engineered NK Cells in multiple myeloma. doi: 10.1038/leu.2013.279
- Han et al., (2015) CAR-Engineered NK Cells in GBM. doi: 10.1038/srep11483
- Chat et al., (2018) A CS1-NKG2D bispecific antibody for multiple myeloma. doi: 10.1158/2326-6066.CIR-17-0649
Todd Fehniger, MD PhD is an Associate Professor at Washington University in St Louis.
He’s the narrator for this episode, explaining NK cell biology, including the concept of the “missing self” hypothesis propounded by Klas Kärre and Rolf Kiessling (doi: 10.1038/319675a0) and how that influences our understanding of how NK cells function.
Dr Fehniger also shares with us some of his recent translational and clinical research into allogeneic NK cell therapy for the treatment of acute myeloid leukaemia (AML).
His lab has demonstrated the importance of cytokines such as IL-15 and how a cocktail of them can help culture NK cells with memory-like properties in hematologic malignancies.
- Romée et al., (2018) Phase 1 clinical data with the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. doi: 10.1182/blood-2017-12-823757
- Berrien-Elliott et al., (2017) NKG2A Represents an Important Immune Checkpoint for Human Cytokine-Induced Memory-like NK Cells in Patients with AML. ASH Abstract # 167
- Cooper et al., (2017) Is there Natural Killer Cell Memory? doi: 10.1101/cshperspect.a029512
Nick Huntington, PhD (@Dr_Nick_Bikes) is an Associate Professor at the Walter and Eliza Hall Institute of Medical Research in Melbourne.
Dr Huntington leads a laboratory focusing on NK cell development and their role in innate immunotherapy.
On this show, he talks about the important role of NK cells in immune surveillance, targeting NK cell checkpoints, and the critical role of cytokines.
- Rautela et al., (2018) Molecular insight into targeting the NK cell immune response to cancer. doi: 10.1111/imcb.12045
- Souza‐Fonseca‐Guimaraes et al., (2018) A new checkpoint for Natural Killer cell activation. doi: 10.1111/imcb.1027
Jeff Miller, MD is Professor of Medicine at the University of Minnesota and Deputy Director of the Masonic Cancer Center.
His research has focused on the biology of NK cells and other immune effector cells, as well as their practical use in clinical immunotherapy.
He has developed bi- and tri-specific NK cell engagers (BiKEs and TriKEs) for testing as cancer therapeutics for the treatment of leukemia.
- Gleason et al., (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells. doi: 10.1182/blood-2013-10-533398
- Miller et al., (2015) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells. doi: 10.1182/blood-2004-07-2974
- Don Yun et al., (2018) Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity. doi: 10.1182/bloodadvances.2018018176
Eric Vivier, DVM PhD (@EricVivier1) is Chief Scientific Officer of Innate Pharma and was formerly Director of the Centre d’immunologie de Marseille-Luminy.
Prof Vivier discussed the importance of understanding the choreography between the innate and adaptive immune systems in the last podcast episode.
He’s back in this show where takes that concept on further and elaborates on practical therapeutic aspects such as using monoclonal antibodies to target NK checkpoints.
- Chiossone et al., (2018) Natural killer cells and other innate lymphoid cells in cancer. doi: 10.1038/s41577-018-0061-z.
James Gulley, MD PhD (@gulleyj1) is Chief of the GU Branch and Director of the Medical Oncology service at the National Cancer Institute (NCI).
He has been a popular guest on the show discussing a wide variety of topics. In this latest episode, he talks about the importance of cytokines and how targeting them in conjunction with a vaccine in a T cell poor solid tumour such as prostate cancer may activate NK cells and lead to more sustained immune responses.
- Jochems et al., (2017) Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). doi: 10.18632/oncotarget.20680.
- Redman et al., (2018) ASCO QuEST1 study exploring combination immunotherapy with BN-brachyury vaccine, M7824, ALT-803 and epacadostat in metastatic castration-resistant prostate cancer. Abstract # TPS3130.
- Redman et al., Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer. doi: 10.1186/s40425-018-0409-8
All the interviews excerpted on the podcast were first published on Biotech Strategy Blog. It’s where you can find transcripts for the full interviews, along with additional commentary and analysis (subscription required).
The music in this episode is by violinist and composer David Schulman, find out more at QuietLifeMotel.com.
This episode was sponsored by Genentech. We’re grateful to their ongoing support of the podcast.
What we do is editorially independent and sponsors have no control over the topics we cover, who we interview, or the questions we ask.
Instead of a sponsor message, we typically do a mini-interview or vignette of a company scientist or researcher.
In this episode, we had the pleasure of speaking to Dr Deepak Sampath, who is a Principal Scientist and Translational Research Leader at Genentech.
He discussed his translational research with the Bcl2 inhibitor, venetoclax, and the potential of combination therapy to impact NK cell activity.
- Romani et al., (2018) Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells. doi: 0.1158/0008-5472.CAN-17-3024.
Fred Cuevas was the sound engineer when we recorded the script at Audacity Recording Studios in South Florida. Elspeth Morrison kindly provided coaching and script advice. Their production support is greatly appreciated.
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