We’ve covered quite a lot on the science, biology and even various therapeutics relating to the adaptive immune system, which involves lymphocytes such as T cells and B cells, but what about the innate immune system?
In 1891 a surgeon named William Cooley wrote the first case report of what happens when you inject people who have inoperable cancer with bacterial toxins (history buffs who want to read more should click the following open access link to download one of his historical papers).
Cooley’s work led to him being considered the ‘father of immunotherapy’ although there were quite a few sceptics until the mechanism of action was finally understood nearly a century later, when it was determined by Beutler and colleagues in 1985 that his rudimentary vaccine acts through what is now know as Toll-like receptor 4 (TLR4) on immune cells.
Innate immunity is sensed and controlled by completely different aspects of the immune system, which include TLRs, STING, natural killer (NK) and dendritic cells, not to mention macrophages and even neutrophils.
In this episode, we’re going to home in on two elements namely STING and TLRs.
Choreography of the Immune System
The title for this show was inspired by Eric Vivier of Innate Pharma, who talks eloquently about the choreography between the innate and adaptive immune systems.
In short, it’s really not about an either/or approach, but rather how these elements can play in concert with each other.
Could this be what’s missing if we want to help more people with cancer respond to immunotherapy approaches?
Before we begin, for some basic background and context, do check out Episode 2.
This included a discussion with Tom Gajewski (Chicago) about his work with the STING pathway in mice and how he hoped that targeting it could potentially increase the number of people who respond to immunotherapy, particularly those with non-T cell-inflamed tumours.
To set the scene on this episode we’ve included a short excerpt from the interview Dr Gajewski kindly gave us at the Immunology 2015 meeting in New Orleans.
Dr Gajewski also featured on Episode 9 where he talked about his research into the microbiome. Do have a listen if you are new to the podcast!
This is another innate pathway that could have the potential to impact the effectiveness of cancer immunotherapy, and one we expect to hear more on about in the future.
Subsequently at AACR 2016, Tom Dubensky the then Chief Scientific Officer (CSO) of Aduro Biotech (he is now CEO of Tempest Therapeutics) talked to us about the rationale behind stimulating the STING/cGAS pathway.
He discussed the fundamental science behind how it works and why it is a seen as promising target for cancer immunotherapy. Aduro Biotech are developing a STING agonist called MIW815 (formerly ADU-S100), which is being evaluated in combination with an anti-PD–1 antibody in a phase 1 trial in advanced solid tumours or lymphomas.
A number of other companies are also evaluating this target with the goal of jumpstarting the immune system.
Glen Barber is Chairman and Professor of the Department of Cell Biology at the University of Miami where he conducts research into understanding the role of innate immunity and the control of cancer.
Along with Dr Hiroki Ishikawa, he first identified STING (stimulator of interferon genes) in 2008, which is essential for effective innate immune signalling processes (doi: 10.1038/nature07317).
They observed that reduction in STING signalling dampened the ability of intracellular DNA to induce IFN-β, but did not significantly affect the TLR pathway.
Dr Barber describes the potential for Yin and Yang effects depending on how it is used, and explains why he’s a big fan of this target therapeutically.
Ira Mellman is a regular on the podcast and popular with scientists and researchers.
He is VP cancer immunology at Genentech, with a long time interest in dendritic cells (link to review paper) and the innate immune system.
You can hear more about them on Episode 11 where he and Dan Chen talk about the Cancer Immunity Cycle.
In this episode, we welcome him back for some thoughtful and insightful perspectives where he candidly opens up about biomarkers, how thinking has evolved on them over the last couple of year while also offering a real world perspective on their utility.
Toll Like Receptor Agonists
George Coukos is Director of Oncology at the University Hospital of Lausanne who has been on the show before.
This time around he explains the role of that toll-like receptors (TLRs) play in the innate immune system. We also review some of the trial readouts he previously discussed in Episode 15 and explore the potential importance of different combinations.
Incidentally, both Dr Mellman and Prof Coukos last appeared together on Episode 20, which highlighted cancer vaccines especially those focused on neoantigens and neoepitopes.
Vaccines are one of many approaches that can be employed to activate the innate immune system.
By the way, as an aside that particular show is second in the allcomers list just behind the show on Overcoming Immunotherapy Resistance and slightly ahead of the Titans show from season 1 with Drs Carl June and Steven Rosenberg) to give the three most popular shows since we launched Novel Targets in 2015!
Adi Diab is an Assistant Professor at MD Anderson Cancer Center who specialises in melanoma and immunotherapeutics.
He has been involved in several trials focusing on novel combinations that seek to target both the innate and adaptive immune systems.
In this episode, he is back to tell us about his personal experience in treating people with advanced melanoma in whom anti-PD–1 checkpoint blockade failed to work with a novel combination approach that included a TLR9 agonist injected directly into lesions.
It’s always humbling to hear personal clinical stories and what we can learn from them.
Jonathan Zalevsky is the Chief Scientific Officer at Nektar Therapeutics. (Update: he’s now the Chief R&D Officer).
We heard on the last episode of the podcast how he is involved with developing novel approaches to targeting cytokines in order to generate fresh waves of T cells every three weeks.
(see: Episode 23 for more details).
Nektar also have another compound in early development that may surprise a few people, a TLR7/8 agonist.
He explains how a combination approach involving the innate and adaptive immune systems may potentially avoid the need for chronic therapy with checkpoint blockade in some people.
(See: REVEAL trial).
All the interviews excerpted on the podcast were first published on Biotech Strategy Blog (subscription required). It’s where you can find transcripts for the full interviews, along with additional commentary and analysis.
The music in this episode is by violinist and composer David Schulman, find out more about his music 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.
Fred Cuevas was the sound engineer when we recored 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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