In this latest episode, we tackle the family of protein molecules called cytokines that can have a yin and yang effect on the tumour microenvironment in many solid tumours.
What are they and can we manipulate them and modulate their signal so as to tip things in a more positive direction in people with cancer?
Examples of cytokines include the interleukin (IL) family, interferon gamma (IFN𝛄), and transforming growth factor beta (TGFβ).
We have known for a while now that while a small subset of patients with an inflamed phenotype have responded well to single agent immunotherapy, there are many factors that hinder the majority of patients from responding.
- How can we approach the majority of people whose cancer either has T cells trapped in the stroma outside the tumours (excluded phenotype) or have a non-inflamed phenotype (immune deserts) that may be due to a low mutation burden or perhaps some other factor is involved?
- What sort of rational combinations can we consider to help modulate the tumour microenvironment more favourably in these cases?
To find out more about immune phenotypes, do check out this important paper (open access) entitled, “The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition,” by Dr Priti Hegde and colleagues, where they describe the immune excluded phenotype in detail for greater context.
To explore the idea behind the cytokine concept, we interviewed various academic and industry experts to find out more about the latest progress in this field.
Dr Mario Sznol is a medical oncologist and Professor of Medicine at Yale Cancer Center in New Haven, CT.
He has a long standing interest in cancer immunotherapy in melanoma and renal cell carcinoma, including original research conducted on high dose interleukin-2 (IL-2):
“Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer.” doi: 10.1097/CJI.0b013e318177a4ba
He has previously been on the show in the past in Season 1 on The Pioneers – Part 1 with Dr Stephan Grupp and in Season 3 on the popular episode with Drs Jerome Galon and Carlos Paya in Revolutionary Thinking Required.
This time around, Dr Sznol enthusiastically talks about what cytokines are and why they matter in an understated and intelligible way. He also highlights some of the pitfalls of the past therapeutic approaches and how these are being overcome with new developments currently being evaluated in the clinic. Dr Sznol will be President of the Society for Immunotherapy of Cancer (SITC) in 2019.
Dr Adi Diab is an Assistant Professor in the department of medical oncology at MD Anderson Cancer Center in Houston, Texas. He is particularly active in clinical research involving immunotherapeutic strategies to improve outcomes for people with melanoma. These include both innate therapies, as well as immuno-modulators.
Dr Diab is the PI for the phase 1/2 PIVOT study that explores NKTR-214 in combination with checkpoint blockade in several tumour types.
Dr Jonathan Zalevsky is Senior Vice President of research and Chief Scientific Officer at Nektar Therapeutics.
He led the discovery and preclinical development of NKTR-262, a TLR agonist being developed in combination with the CD122 agonist, NKTR-214, as well as being involved in the latter’s development.
The ‘dynamic duo’ had updated data at ASCO last month for the ongoing PIVOT trial in melanoma, renal, urothelial, and triple negative breast cancer (TNBC).
They explain the science behind their strategy, why it’s different, and also why they’re excited about the early new product development they are currently working on.
There has been growing interest in the role of TGFβ and how it affects response to immunotherapy.
Earlier this year an important paper published in the journal Immunity (open access) highlighted a large immunogenomic analysis of over 10,000 tumours across 33 diverse cancer types, utilizing data compiled by TCGA. From this work, the scientists described six immune subtypes across multiple cancer types and molecular subtypes. Importantly, one of these immune phenotypes was a TGFβ signature.
What can we learn from researchers active in the TGFβ niche and how might it apply to clinical research?
Dr Sanjeev Mariathasan is an immunologist and Senior Scientist in the oncology biomarker program at Genentech, where he studies biomarkers associated with resistance to anti-PD-L1 checkpoint blockade.
Dr Mariathasan and Prof Tom Powles (Barts) were the lead and senior authors on a recent Nature paper exploring the potential role of TGFβ in urothelial carcinoma:
“TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.” doi: 10.1038/nature25501.
The work was based on analysis from clinical trial data and supported by subsequent mice experiments to validate the findings.
Prof Tom Powles is Professor of Genitourinary oncology with a particular focus on renal and bladder carcinomas at Barts Cancer Institute in London.
In addition, this intriguing molecular analysis in urothelial cancer was also presented at the recent AACR annual meeting by Dr Mariathasan:
“A balance of genomic instability, tumor-immune contexture and TGF-β signaling contributing to exclusion of T cells governs response to PD-L1 checkpoint blockade.”
They explain the thinking behind what they did with their reverse translation approach, why it matters, and how they hope it will improve further in future clinical trials so that more people can be helped by cancer therapy.
Dr James Gulley is Chief of the Genitourinary malignancies branch and Director of the Medical Oncology service at the NCI. He has a keen interest in cancer vaccines and immunostimulatory agents such as cytokines in clinical trials, see example:
“Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors.” doi: 1158/1078-0432.CCR-17-2653.
Dr Gulley discusses the strategic intent in using cytokines to boost wakefulness of the immune system, thereby setting it up so that immunotherapy can be more effective.
He also discusses some new clinical data that his group presented in HPV+ cancers at ASCO last month.
Not all of the interesting molecules are small molecules, fusion proteins, or even antibodies. There’s also growing interest in the idea behind incorporating cytokines into cell therapy products and we offer some interesting examples in this episode.
Dr Kunle Odunsi is the Deputy Director of the department of gynecologic oncology and Executive Director of the center for immunotherapy and co-Leader of the tumour immunology and immunotherapy research program at Roswell Park.
His research has focused on the molecular characterisation of tumour antigens in ovarian cancer and on the application of immunotherapy to the disease.
Dr Odunsi discusses the role of TGFβ, the effects they induce, and how he and his colleagues have developed a novel cell therapy approach they are now evaluating in their patients that incorporates antigen targeting with a cytokine to address several potential immune defects.
Meanwhile, Dr Renier Brentjens is one of the pioneers of research involving chimeric antigen receptor (CAR) T cell therapy in leukemia at Memorial Sloan Kettering.
Over the last couple of years he has also been particularly active in developing the next generation constructs of what is now known as armoured CARs. These are thought to be a better way to tackle solid tumours, where heterogeneity and inhibitory factors in the TME can lead to significant immune suppression.
Now that several CAR T cell therapies have been approved in hematologic malignancies, can the same concept be adapted and successfully used to treat solid tumours?
Can we realistically build cytokines into a CAR, and what sort of effects might we expect to see? He talks about how these ideas led to the first example they are testing in the clinic for ovarian cancer.
All the interview excerpts you’ve heard in this episode were previously published on Biotech Strategy Blog (subscription required). It’s where you’ll find the full interview transcripts along with additional commentary and analysis.
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.
The music in this episode is by violinist and composer David Schulman, find out more about his music at QuietLifeMotel.com.
Fred Cuevas was the sound engineer for the recording of 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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