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BSI Congress 2021

Posted on by KatieH

The British Society for Immunology (BSI) Congress 2021 took place from 28 November to 1 December 2021 online and in-person in Edinburgh, UK. A primary aim of the Myrovlytis Trust is advancing research into immunotherapies and new routes to treatment for rare cancers, focusing on osteosarcoma. As the UK’s largest immunology event, the Myrovlytis Trust were thrilled to be able to attend and listen to the latest updates in cancer immunology. 

Of particular interest was the session entitled ‘The Unique immunological landscape of the tumour microenvironment’ with talks focusing on different immune cells, their pro- and anti-cancer roles, and importantly how they can be harnessed to target cancer and improve responses to immunotherapies. Several talks focused on the role tertiary lymphoid structures (TLS) play in the response to immunotherapies. Catherine Sautés-Fridman (University de Paris, Centre de Recherche des Cordeliers, France) opened the session presenting her work on the interplay between TLS and B cells. Her research demonstrated that the presence of TLS in tumours correlated with B cell infiltration, which in turn indicated a better response to immunotherapy and overall prognosis in several cancers, including soft-tissue sarcomas (1). This was corroborated further by Karen Willard-Gallo (Institut Jules Bordet, Belgium) whose work in triple negative breast cancer also revealed the importance of an active TLS and B cell infiltration resulting in reduced disease progression and increased survival rates (2). However, work needs to be done to understand how to induce activity of TLS to improve the prognosis in individuals with tumours that lack high density, active TLS.

Another session with key relevance to the Myrovlytis Trust was ‘Defining the state and functional relevance of T cell exhaustion’ with talks from Andrea Schietinger (Memorial Sloan Kettering Cancer Center, USA), Benjamin Youngblood (St. Jude Children’s Research Hospital, USA) and Dietmar Zehn (Technical University of Munich, Germany). T cell exhaustion, a common state of T cell dysfunction found in many cancers, is defined by poor effector function. Understanding the mechanism by which T cells display an exhaustion phenotype and lose their effector function is critical to be able to restore T cell-mediated anti-cancer immunity. Andrea Schietinger’s lab took an innovative approach to this and studied T cells in the context of autoimmunity in which T cells remain highly functional in the presence of chronic antigen stimulation. In a mouse model of type 1 diabetes (resulting in CD8 T cell-mediated killing of pancreatic cells) she discovered a population of T cells with ‘stem cell-like’ properties which had the ability to self-renew and lead to terminally differentiated populations (3). Adoptive transfer of as few as 10 of these stem cell-like T cells led to the induction of type 1 diabetes, indicating the power of this pool of cells. The challenge now, however, is to be able to apply this principle in cancer, perhaps through reprogramming of autoimmune T cells using cancer-specific T cell transcription factors. CAR T cell therapy has the potential to revolutionise cancer treatment. However, these T cells also suffer from exhaustion, and the ability of CAR T cells to persist is critical for their success as an anti-cancer therapy. Epigenetic modification can alter the gene expression profile of a cell, and therefore can modulate T cell exhaustion. Benjamin Youngblood identified a DNA methyltransferase, DNMT3A, which when deleted from CAR T cells allowed enhanced survival, proliferation and activity in the context of chronic antigen presentation. In a mouse model of osteosarcoma, mice that received DNMT3A knockout CAR T cells exhibited a significant survival advantage over mice that received control CAR T cells (4).

Finally, the session entitled ‘Advances in cancer immunology: bringing two communities together’ highlighted the work of Sophie Papa (King’s College London, UK) who’s research focuses on CAR T cell therapy in solid tumours and how translation of this technology to the clinic can be enhanced. Trials for CAR T cell therapy in solid tumours have shown limited efficacy in patients and there is desperate need for enhancement of this for CAR T cell therapy to progress to the clinic. Understanding the metabolic factors that influence the efficacy of CAR T cells is one area of interest, as Dr Papa highlighted the artificially high levels of glucose cells are cultured in in vitro. Lowering the levels of glucose in culture media led to a reduction in effectiveness of PSMA-targeting CAR T cells through a lack of proliferation. Understanding these mechanisms will undoubtedly reveal novel strategies to enhance CAR T cell therapy and facilitate its progression to the clinic in a wider range of cancers.

Take Home Messages

Understanding of the tumour microenvironment and the role of immune cells in cancer is a rapidly changing field. Advances in technologies such as single cell RNA sequencing allow detailed mapping of changes occurring within individual cells. However, studies characterising the immune-cancer microenvironment are only the first step and research now needs to progress to identify how to harness the power of immune cells in tumours to reprogramme or enhance their anti-cancer properties. Areas of research presented at the BSI congress that are of great interest to the Myrovlytis Trust included inducing the activity of TLS, metabolic reprogramming of immune cells, and reprogramming T cells to prevent an exhaustion phenotype.

The Myrovlytis Trust is committed to advancing research into immunotherapies for rare conditions to rapidly bring novel and effective treatments to the clinic. We are open to discussions with clinicians and researchers about their work to identify ways in which we can support your research. Please visit our website for more information on our funding streams or contact us by email.

References

1.        Petitprez F, de Reyniès A, Keung EZ, Chen TWW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nat 2020 5777791 [Internet]. 2020 Jan 15 [cited 2021 Dec 9];577(7791):556–60. Available from: https://www.nature.com/articles/s41586-019-1906-8

2.        Boisson A, Noël G, Saiselet M, Rodrigues-Vitória J, Thomas N, Fontsa ML, et al. Fluorescent Multiplex Immunohistochemistry Coupled With Other State-Of-The-Art Techniques to Systematically Characterize the Tumor Immune Microenvironment. Front Mol Biosci [Internet]. 2021 Sep 21 [cited 2021 Dec 9];8. Available from: https://pubmed.ncbi.nlm.nih.gov/34621785/

3.        Gearty S V., Dündar F, Zumbo P, Espinosa-Carrasco G, Shakiba M, Sanchez-Rivera FJ, et al. An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature [Internet]. 2021 Nov 30 [cited 2021 Dec 9]; Available from: https://pubmed.ncbi.nlm.nih.gov/34847567/

4.        Prinzing B, Zebley CC, Petersen CT, Fan Y, Anido AA, Yi Z, et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci Transl Med [Internet]. 2021 Nov 17 [cited 2021 Dec 9];13(620). Available from: https://www.science.org/doi/abs/10.1126/scitranslmed.abh0272

BHD Toolkit: What is a mutation?

Posted on by Jazzmin Huber

When researchers talk about BHD mutations they use phrases such as ‘Missense, Deletion and Frameshift’. But what do these words mean, how do mutations occur and what type of BHD mutation do you have? In today’s BHD toolkit we explore these terms and explain the different types of genetic mutations.

DNA carries all your genetic information, in the form of a code. Imagine a computer code tirelessly running to make sure everything is working smoothly. It is made up of components called nucleotides and it is the order of these nucleotides that determines the bodies programming in other words which proteins are made. Every 3 nucleotides encode for one amino acid, the building blocks of protein, so a change in the nucleotide sequence, can alter the amino acids which ultimately changes the final protein product. This change is called a mutation. Mutations can be caused by the environment or inherited from family members. In BHD, the change in nucleotide sequence and resulting amino acids changes the function of folliculin (FLCN). Several types of FLCN mutations have been identified across the world.

Types of genetic mutation found in BHD

* Splice-site mutation diagram

It can be surprising how one nucleotide change can have the same impact as a large deletion of genetic material, however, going back to our computer analogy it just takes one mistake in the code to stop the programme from working. Therefore, any changes to FLCN which stops it from functioning will result in BHD.

Currently, the management for BHD patients is the same regardless of mutation type but scientists are interested in discovering whether certain mutations are associated with particular BHD characteristics. This could lead to a patient-tailored treatment plan including kidney cancer screening.

In our next BHD Toolkit, we will be diving further into specific FLCN mutations, how to understand your sequencing results and what to expect when you see a clinical geneticist.

A New Role for Folliculin in Cancer Prevention

Posted on by Jazzmin Huber

We are excited to be sharing with you a recently published paper by Woodford et al., exploring the reason why the loss of folliculin (FLCN), the gene mutated in Birt-Hogg-Dubé syndrome (BHD), drives tumour development.

Cancer cells have characteristics that allow them to grow and replicate uncontrollably. One of these is the deregulation of cellular metabolism, in other words, cancer cells can change how they get their energy. To produce energy cells normally break up glucose to produce pyruvate which then interacts with oxygen and releases carbon dioxide (CO2). If there is limited or no oxygen pyruvate is converted to lactate instead. However, cancer cells will rapidly take up glucose and convert pyruvate into lactate, even in the presence of oxygen, which is beneficial for the cancer cell. This shift in cellular metabolism is known as the Warburg effect and is driven by Lactate Dehydrogenase A (LDHA), the enzyme which converts pyruvate into lactate. Interestingly, loss of FLCN has previously been shown to increase LDHA activity. Woodford et al., examined this relationship further and investigated whether LDHA could be targeted to treat Kidney cancer.

Several different experiments were undertaken to characterise the relationship between FLCN and LDHA. Detailed examination of the FLCN protein in a kidney cell line showed that FLCN interacted with 114 different proteins including LDHA and that high FLCN expression reduced LDHA activity. To determine how FLCN reduced LDHA activity the relationship between LDHA and its cofactor (a small molecule needed for LDHA activity) was examined. High levels of FLCN reduced the binding between LDHA and its cofactor likely through alteration of LDHA’s structure thereby reducing the activity of LDHA. Taken together these results demonstrate a new role for folliculin as a binding partner and inhibitor of LDHA.  

Next Woodford et al., examined the significance of this finding in cancer cells. 13 cell lines, including a kidney cell line, showed a metabolic shift and hyperactivity of LDHA. 11 of these cell lines also showed a dissociation between FLCN and LDHA suggesting that the inhibitory effects of FLCN are lost in many cancer cell lines.

The creation of targeted therapies against LDHA has always been an appealing area of investigation for cancer treatments, however creating a target that is specific to LDHA has been challenging because there are other similar proteins. The discovery of FLCN as an inhibitor of LDHA creates a new opportunity for such therapies. Firstly, Woodford et al, showed that FLCN binds specifically to LDHA and none of its similar proteins. They then identified the specific region of the FLCN protein which binds to LDHA.  They produced a series of peptides (a chain of amino acids which is the building blocks of proteins) derived from FLCN to target LDHA based on their findings of how FLCN binds to LDHA. These peptides were tested in normal kidney cells in vitro and those that were taken up by the cells and reduced LDHA activity were selected for further tests. They then examined the response to the peptides in a kidney cancer cell line. One of the peptides named FLCN-10 was able to bind to LHDA and this resulted in cancer cell death. Next tissue samples from a kidney cancer of a BHD patient were treated with FLCN-10. FLCN effectively reduced LDHA activity in the kidney cancer cells.  

Altogether Woodford et al., have demonstrated a new role of FLCN as an inhibitor of LDHA. It binds to LDHA and regulates its activity. Therefore, in BHD, loss of FLCN results in LDHA hyperactivity resulting in the Warburg effect which is beneficial for cancer cells.  An understanding of this interaction between FLCN and LDHA meant Woodford et al., were able to create a folliculin derived peptide which bound to LDHA and inhibited its activity. This discovery could pave the way for a new LDHA targeted cancer treatment not only for BHD patients but other cancer patients as well.

We are sorry that the paper is currently not freely available. Please message us if you have any further questions at contact@bhdsyndrome.org.

References

1. Woodford MR, Baker-Williams AJ, Sager RA , Backe SJ , Blanden AR, Hashmi F, et al. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. Nat Struct Mol Biol [Internet]. 2021 Aug 1 [cited 2021 Sep 3];28(8):662–70. Available from: https://pubmed.ncbi.nlm.nih.gov/34381247/

World Kidney Cancer Day

Posted on by Jazzmin Huber

Today is World Kidney Cancer day and the theme is ‘We need to talk about how we are feeling’. A patient survey revealed that 96% of kidney cancer patients experience psychosocial problem but less than half talk about it. It is not always easy to discuss how you are feeling but research shows that it does improve wellbeing.  World kidney day is striving to make this easier.  They have produced a personalised psychosocial wellbeing report for you to complete with recommendations on how to improve your mental wellbeing. The report is available here.

The BHD Foundation is talking about kidney cancer and wellbeing because up to 30% of patients with BHD develop kidney cancer and we want you to know you are not alone. In addition to initiatives such a world cancer day there is a welcoming patient lead BHD Facebook group who are always happy to answer questions and share their stories. Earlier this year we also interviewed a member of the BHD community about her experience being diagnosed with kidney cancer and it is available to read here. The BHD Foundation can help connect you with others who have been diagnosed with BHD.

Drug Repurposing for Rare Diseases

Posted on by Jazzmin Huber

This June we will be attending the annual drug repurposing conference organised by Findacure, a charity dedicated to bringing the rare disease community together. There are over 7000 rare diseases but currently, only 400 have licenced treatments. It is paramount that we increase the available medication for rare disease and drug repurposing is one way we can do this. Repurposing involves taking a known licensed drug and finding new therapeutic uses for it; It is usually quicker and cheaper than drug discovery. The conference will be discussing drug repurposing for rare disease.

The event is open to everyone in the rare disease community and will be held virtually from 15th -16th June 2021. You can register for free here.

We will be attending the event and updating you with the latest developments in drug repurposing for rare diseases.

European International Kidney Cancer Symposium Report

Posted on by Jazzmin Huber

In April we attended the European International Kidney Cancer Symposium (EIKCS). Many of the discussions focused on future therapeutic approaches and the use of immunotherapies to treat kidney cancer. Immunotherapies are drugs that harness the body’s immune system and help it to destroy cancer cells. Here we share with you some of the highlights of the symposium. 

Keynote

The Keynote address was given Dr David McDermott, Chief, Division of Medical Oncology at the Beth Israel Deaconess Medical Center. Dr McDermott discussed the importance of identifying novel biomarkers and using combination therapy to treat kidney cancer. He also emphasized the importance of not only aiming to treat cancer but to strive for patients to live treatment-free lives.

Clinical Trials

Dr Hans Hammers, Associate Professor of Internal Medicine at UT Southwestern Medical Center, discussed some of the novel therapeutics being trialed in kidney cancer patients. A phase 3 clinical trial with 1069 patients found that the combination of Lenvatinib and pembrolizumab, immunotherapy drugs, was associated with longer progression-free survival than sunitinib, which is a protein kinase inhibitor currently used in kidney cancer (1). He also referenced a phase 2 clinical trial testing belzutifan (an inhibitor of HIF-2α) on patients with Von Hippel-Lindau disease (VHL). Similar to Birt-Hogg-Dubé syndrome, VHL patients develop multiple tumors in their kidneys. Preliminary results show that belzutifan is both well tolerated by patients and reduces tumor size (2). To find out more about clinical trials including current research into BHD visit our Clinical Trials webpage. 

Biomarkers

A biomarker is a molecule that is naturally present in or on specific cells and can therefore be targeted for treatment of a disease. Medical oncologist Dr Yann-Alexandre Vano from Georges Pompidou European Hospital discussed his research looking for specific biomarkers (gene signatures) in tumors and targeting them with specific therapies. The BIONIKK trial was the first to investigate tailoring treatment options in metastatic kidney cancer to patient’s tumor characteristics and showed an improved patient response (3). Dr Yann-Alexandre Vano discussed the importance of collaboration between different centers and countries to help facilitate the discovery of novel biomarkers and improve patient outcomes.

The Microbiome

The microbiome is the collection of microorganisms that live on and in the human body and are essential for the body to function normally. Everyone’s microbiome is unique and dynamic, changing in response to environmental and genetic factors. It is suspected that the microbiome may affect responses to cancer therapy. Dr Lisa DeRosa researcher at the Gustave Roussy Hospital investigated how a patient’s microbiome may affect their response to checkpoint inhibitors, a type of immunotherapy. She compared the response to therapy in patients who had required antibiotics, which are known to disrupt the microbiome, with those who had not. Patients who had been treated with antibiotics had a reduced response to checkpoint inhibitors (4). Therefore, she hypothesized that altering those patient’s microbiome may improve their response to immunotherapy. This idea is supported by a recent study where melanoma patients, who were given fecal transplants to change their microbiome, had an improved response to checkpoint inhibitors (5). Further research is required to identify the specific microorganisms responsible for these changes in response. 

EIKCS demonstrated the extent of innovative research being conducted into kidney cancer. The Myrovlytis trust/ BHD Foundation will be keeping up to date with the latest research and funding studies looking at kidney cancer treatments with an initial focus on Birt-Hogg-Dubé syndrome.

Interested to find out more? You can now watch all the talks from the conference here.

References

1.          Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med [Internet]. 2021 Apr 8 [cited 2021 May 28];384(14):1289–300. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2035716

2.          Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan V, Maughan BL, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020 May 20;38(15_suppl):5003–5003.

3.          Epaillard N, Simonaggio A, Elaidi R, Azzouz F, Braychenko E, Thibault C, et al. BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer. Bull Cancer [Internet]. 2020 Jun 1 [cited 2021 May 28];107(5):eS22–7. Available from: https://pubmed.ncbi.nlm.nih.gov/32620212/

4.          Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol [Internet]. 2018 Jun 1 [cited 2021 May 28];29(6):1437–44. Available from: https://pubmed.ncbi.nlm.nih.gov/29617710/

5.          Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science (80- ) [Internet]. 2021 Feb 5 [cited 2021 May 28];371(6529):595–602. Available from: https://pubmed.ncbi.nlm.nih.gov/33542131/

Rare Disease Study Day

Posted on by Myrovlytis Trust

Rare Disease Study Day

Sheffield Institute for Translational Neuroscience.

7th September 2017.

The Sheffield Institute for Translational Neuroscience will be hosting a day of informative talks about Rare diseases and will include a presentation by Dr Derek Lim, consultant in clinical genetics and BHD expert at Birmingham Women’s Hospital.

Clinicians and rare disease families welcome!

Travel and accommodation can be paid for thanks to the support from the Galton Institute and the Genetics Society.

To attend email: a.mcneill@sheffield.ac.uk