Welcome back to Season 3!
In this episode we’re tackling one of the hottest topics in cancer research, why do cancer immunotherapies work in some people, but not in others? Why do they stop working? If we want to obtain long durable responses, then we have to understand and overcome resistance. Some of the meaty topics covered on this episode include:
- Initial resistance
- Acquired resistance
- Immune escape
- How we may be able to turn non-responders into responders
- Overcoming immuno-suppression within the tumor microenvironment.
Most of the interviews you’ll hear were recorded at the 2017 annual meeting of the American Association for Cancer Research (AACR) in Washington DC.
Cancer Immunotherapy Manifesto
Dr Gordon Mills (MD Anderson, now at OHSU) is a global cancer expert and among his numerous academic appointments is Professor of Medicine and Immunology. He often advises companies on their drug development strategy.
In this episode he shares some of the concerns he when companies move forward with cancer immunotherapy combination trials, just because they have two compounds in their pipeline, rather than because it makes logical sense.
In the rush to the clinic, the worry is that many of the 800 or more cancer immunotherapy trials will fail to make a significant difference in turning non-responders into responders or significantly boosting the response rate to PD-1/PD-L1 checkpoint therapy.
Dr Mills spoke to Executive Producer, Sally Church at the 2016 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics meetings held in Munich. What we’re calling his “manifesto for immuno-oncology research” can be read on Biotech Strategy Blog (link)
Update: Dr Mills moved to OHSU in October 2017. (News Release)
Strategies to Overcome Resistance
Dr Jason Luke is a melanoma specialist and at the time of the interview ran cancer immunotherapy trials at the University of Chicago.
Update: Dr Luke moved to the University of Pittsburgh in May 2019. (News Release)
Throughout the episode he provides a clinical perspective on the challenges and opportunities in overcoming resistance to cancer immunotherapy. As Dr Luke (@jasonlukemd) notes on the podcast:
There’s a very different phenomenon between taking a 20% tumor shrinkage upto 80% tumor shrinkage in an individual patient and taking the 20% response rate population and increasing that to an 80% response rate population. Probably the mechanisms that we’re going to need to go about those two approaches are completely different.
In addition, he gives an update on the who he thinks should receive a STING agonist, something we first heard about from Dr Tom Gajewski in Episode 2 of Novel Targets.
The full interview with Dr Luke can be read on Biotech Strategy Blog (subscription required).
How do we get Checkpoints to work in Prostate Cancer?
Early research from Dr James Gulley (National Cancer Institute) and colleagues shows that combining a PARP inhibitor (olaparib) with an anti-PD-L1 checkpoint monoclonal antibody (durvalumab) yielded some exciting results.
Preliminary data was presented at the ASCO GU meeting earlier this year, and more data is expected at the forthcoming ASCO annual meeting in Chicago.
It turns out the STING pathway may have an important role to play in prostate cancer immunotherapy.
Dr Gulley and colleagues at the NCI are rapidly enrolling an additional 15 patients into this trial and we look forward to hearing if the early promise is confirmed in a larger group. Could this be a way to light the campfire in men with advanced prostate cancer?
As Dr Gulley (@gulleyj1) says, “stay tuned.” A novel combination strategy to watch as more clinical data becomes available.
Immuno-suppression in Tumor Microenvironment
One of the many approaches to targeting immuno-supression in the tumor microenvironment is to target adenosine signalling. Dr Leisha Emens (Johns Hopkins, now at University of Pittsburgh) says on the podcast:
“I think of adenosine signalling as sort of being like a wet blanket over the immune system, so really you want to kick that off, so that the immune system can really wake up and become active and kill that tumor.”
At the AACR annual meeting, Dr Emens presented early clinical data for CPI-444 (Corvus) an A2A receptor antagonist in combination with the anti-PDL1 monoclonal antibody atezolizumab (Genentech).
There’s more on the scientific rational behind this target on Biotech Strategy Blog (sub req’d) “Corvus moves fast to target tumor microenvironment and improve checkpoint responses.”
Adenosine signalling is attracting a lot of interest from companies. We await more clinical data to fully understand the optimal combination strategy. The interview with Dr Emens was recorded at the 2016 San Antonio Breast Cancer Symposium (SABCS).
Acquired Resistance to PD1 Checkpoints in Lung Cancer
Dr Julie Brahmer (Johns Hopkins) discussed acquired resistance to anti PD-1 checkpoint therapy.
Data was published earlier this year in Cancer Discovery (open access) and presented at AACR17 by Dr Valsamo Anagostou. “Evolution of Neoantigen Landscape During Immune Checkpoint Blockade in Non-Small Cell Lung Cancer” (link).
As we heard from Dr Anagostou in her AACR presentation, there are multiple mechanisms of resistance to immune checkpoint blockade, suggesting that overcoming resistance will be have to be personalised.
Antigen Loss with CD19 CAR T Cell Therapy
“We’ve looked into the mechanism of antigen loss, it’s particularly sophisticated and evil the way these leukemia cells do this.”
Dual targeting of CD19 and CD22 may be one way to overcome this.
The interview with Dr Grupp was recorded at the 2016 ASH annual meeting in San Diego.
CAR T Cell Therapy for Brain Tumours
On the last day of the 2017 AACR annual meeting, Christine E. Brown, PhD, (City of Hope) shared her research on Chimeric Antigen Receptor (CAR) T cell therapy targeting IL13Rα2 for the treatment of glioblastoma.
Dr Brown’s research was proof of concept for the first administration of CAR T cells into the cerebrospinal fluid (CSF) of a patient with glioblastoma.
The case report, “Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy” by Dr Brown and colleagues was published in The New England Journal of Medicine in December, 2016 (link
A phase 1 clinical trial is ongoing and we look forward to the presentation of data for a larger group of patients in due course (NCT02208362).
As we heard on the podcast the results were astonishing and lasted for several months, until antigen loss occurred and the patient relapsed.
The full interview, along with additional commentary is available on Biotech Strategy Blog (subscription required).
Update: Dr Brown and colleagues subsequently published a paper in Molecular Therapy on “Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma” DOI:https://doi.org/10.1016/j.ymthe.2017.10.002 (link to open access paper).
Podcast Sponsorship – Vignette with Drs Chen & Mellman, Genentech
Genentech kindly sponsored this episode of the podcast. We’re grateful for their support! Instead of reading a corporate message, for Genentech sponsored episodes, we’re doing mini-interviews or vignettes with company scientists.
For this episode, we spoke with Dr Ira Mellman (VP, Cancer Immunology) and Dr Daniel Chen (at the time VP/Global Head, Cancer Immunotherapy, now Chief Medical Officer at IGM Biosciences) (@DanChenMDPhD) about their recent publication in Nature, (open access): “Elements of cancer immunity and the cancer-immune set point.” (link).
This piece follows on from the Cancer Immunity Cycle that they talked about in Episode 11 of Novel Targets.
The music in this episode is by David Schulman, from his album Quiet Life Motel.
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